Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas ( AA ) , 27 % of anaplastic oligoastrocytomas ( AOA ) and 10 % of Canceranaplastic oligodendrogliomas ( AO ) .
CancerMost lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma .
BAP1 loss-of-function is increasingly reported in cancers including Cancerthoracic malignancies , with frequent mutation in malignant pleural mesothelioma .
OBJECTIVES : There is no molecular biomarker available in the clinical practice to assess the prognosis of Canceradvanced pancreatic carcinoma .
Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with CancerMGMT deficient tumors ( all pancreatic neuroendocrine tumors ) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the myeloproliferative disorders ( MPDs ) Diseasepolycythemia vera , essential thrombocythemia , and myeloid metaplasia with myelofibrosis .
In addition , RIT1 mRNA expression was elevated in 36 freshly Cancerfrozen endometrial cancer tissues compared to 21 non cancerous endometrial tissue samples .
CancerSequential tumor sampling investigated multiple markers of pathway activation and tumor effects , including ERK phosphorylation and Ki-67 expression .
Additionally , among WHO grade I tumors differential expression between NR and Canceraggressive R+M tumors was affirmed for PTTG1 , AURKB , ECT2 , UBE2C and PRC1 , while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors .
None of the other benign or Cancermalignant epithelioid vascular tumors examined demonstrated these abnormalities .
PURPOSE : To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities : thrombocytopenia , Diseaseleukopenia , mucosal inflammation , hand-foot syndrome , and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2 .
INTERPRETATION : Cediranib plus olaparib seems to improve PFS in women with recurrent platinum sensitive high-grade serous or Cancerendometrioid ovarian cancer , and warrants study in a phase 3 trial .
Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with CancerHer2+ breast cancers .
CONCLUSION : Alterations affecting the mitogen activated protein kinase pathway are present in the majority of patients with CancerLGS ovarian cancer .
PURPOSE Cetuximab or panitumumab are effective in 10 % to 20 Cancer% unselected metastatic colorectal cancer ( CRC ) patients .
Mutations in the VHL gene were found in 54 % of clear cell renal cell carcinomas ( CCRCC ) and in 18 % of Cancerchromophilic cancers but in no chromophobe cancers or oncocytomas ( P = 0.016 ) .
In multivariate analysis , patients with variant genotypes were at a AdverseOutcomereduced risk of disease progression ( hazard ratio [ HR ] = 0.75 , 95 % confidence interval [ CI ] = 0.59-0 .96 , p = 0.022 ) .
The aim of this investigation was to evaluate Cancerelevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients .
Response rates ( 45.5 % versus 45.5 % ) and median progression-free survival ( 97 versus 92 days ) following cetuximab based therapy were similar in patients with p16 ( INK4A )-positive and p16 ( CancerINK4A )-negative tumors .
We show that ( i ) ATM- and ATR mutated cells are hypersensitive to temozolomide , ( ii ) O ( 6 )-MeG triggers ATM and ATR activation , ( iii ) knockdown of ATM and ATR enhances cell kill in Cancergliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells , ( iv ) ATR , but not ATM , knockdown abolished phosphorylation of H2AX , CHK1 , and CHK2 in glioma cells , and ( v ) temozolomide induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2 .
Here we show that 6 out of 16 Cancermelanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors .
Thus , activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in Cancerestablished neuroblastoma cell lines , and confer sensitivity to ALK inhibition with small molecules , providing a molecular rationale for targeted therapy of this disease .
The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8 % of cases , Diseasestable disease in 23 % , progression in 46 % , and nonassessable disease in 23 % .
Here , it is shown that heterozygous germ line mutations in hCHK2 occur in DiseaseLi-Fraumeni syndrome , a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene .
The Hedgehog ( Hh ) signaling pathway is inappropriately activated in certain human cancers , including Cancermedulloblastoma , an aggressive brain tumor .
Identical EGFR amplification status was found in 29 Cancerprimary tumours and 29 matched lymph node metastases .
Treatment with small molecule inhibitors ( erlotinib or HKI-272 ) as well as prolonged treatment with a humanized anti-hEGFR antibody ( cetuximab ) led to Cancerdramatic tumor regression .
PURPOSE : DiseasePeutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies .
Proportional-hazards models were used to compare the risk of death among patients with HPV positive cancer and those with CancerHPV negative cancer .
BACKGROUND : We analyzed the expression of heme oxygenase-1 ( HO-1 ) in patients undergoing radical nephrectomy for Canceradvanced clear cell renal cell carcinoma ( CC-RCC ) and evaluated the effects of the targeted therapies treated with sorafenib and sunitinib .
CONCLUSION : This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and Cancerother hypermutant cancers arising from primary ( genetic predisposition ) or secondary MMRD .
A t ( 2 ; 5 ) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as Cancernucleophosmin-anaplastic lymphoma kinase ( NPM-ALK ) has been implicated in the pathogenesis of anaplastic large-cell lymphoma ( ALCL ) .
The tumor suppressor gene PTEN is frequently mutated in diverse human cancers and in Cancerautosomal dominant cancer predisposition disorders .
DiseaseHuman stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or lymphoma .
BACKGROUND : Despite good initial response to chemotherapy , 30 % of Ewing 's sarcoma ( EWS ) patients with Cancerlocalised tumours develop recurrent disease , associated with poor prognosis .
In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated CancerRET- thyroid cancer cell lines , likely through direct RET inhibition in cancer cells as well as by modulation of the microenvironment ( e.g. via JAK and phospho-STAT 3 inhibition in endothelial cells ) .
After 11.3 years of follow-up , 337 incident cases with histologically confirmed Cancerepithelial cancers were identified .
CancerALK positive diffuse large B-cell lymphomas ( DLBCL ) are a distinct lymphoma subtype associated with a poor outcome .
BACKGROUND AND METHODS : TP53 gene mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and Cancerneck carcinomas .
Our results suggest that although ERBB4 is dispensable for naive ERBB2+ breast cancer cells , it may play a key role in the survival of CancerERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors , lapatinib and trastuzumab .
AIMS : The epidermal growth factor receptor ( EGFR ) is a tyrosine kinase ( TK ) involved in the tumour progression of Cancermany cancer types and may serve as an important therapeutic target ( erlotinib , cetuximab ) .
We further demonstrate dose dependent effects of oncogenic signaling , with physiologic Braf ( V600E ) expression being sufficient for hyperplasia induction , but later stage intensified Mapk signaling driving both tumor progression and activation of Cancerintrinsic tumor suppression .
BACKGROUND : DiseaseIdiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction .
We noted 18 occurrences of cancer at various anatomical sites , including a case of thyroid cancer and Cancerpenile cancer .
Novel FISH probes identified 2 additional cases of t ( 15 ; 17 Cancer)-negative acute promyelocytic leukemia that had cytogenetically invisible insertions .
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder ( MPD ) that evolves to acute myeloid leukemia and/or Cancerlymphoma .
Treatment of mice bearing either a cell line or two patient derived xenograft models of synovial sarcoma leads to Cancerdose dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2 specific substrate , lysine 27 on histone H3 .
We undertook a histology independent phase 2 " basket " study of vemurafenib in CancerBRAF V600 mutation positive nonmelanoma cancers .
EXPERIMENTAL DESIGN : Mutational analysis of PIK3CA was done in 188 Cancerprimary breast cancers of Japanese women .
METHODS : Overall response rate ( ORR ) was extracted from phase I-III trials investigating nivolumab , pembrolizumab and MPDL3280A for advanced melanoma , non small cell lung cancer ( NSCLC ) and Cancergenitourinary cancer , and cumulated by adopting a fixed and random-effect model with 95 % confidence interval ( CI ) .
The PFS of patients with TP53 mutations was significantly greater than CancerTP53 wild-type tumors with the median PFS of 208 versus 136 days , respectively [ P = 0.036 , hazards ratio 0.38 ( 95 % confidence interval 0.09-0 .83 ) ] .
Among 21 patients with Cancerevaluable tumor tissue who had also received treatment with temozolomide , 4 of 5 patients with MGMT deficient tumors ( all pancreatic neuroendocrine tumors ) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment ( P = 0.001 ) .
However , Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy , a sensitive marker of DPC4 genetic status , was highly correlated with the presence of Cancerwidespread metastasis but not with locally destructive tumors ( P = .007 ) .
Apitolisib was reasonably tolerated at 30 mg , the selected dose for Cancerpleural mesothelioma patients given limited respiratory reserve .
A cytostatic effect of flavopiridol on the growth of six Cancermelanoma cell lines with a mutated or non expressed p16 ( p16-) was seen at low concentrations of flavopiridol ( mean 50 % inhibitory concentration [ IC ( 50 ) ] = 12.5 nM ) , while the three melanoma cell lines with intact p16 ( p16+ ) required higher concentrations ( mean IC ( 50 ) = 25 nM ) to produce this effect .
We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of CancerNRAS mutant cancers .
It was mostly restricted to CancerIDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion .
Regular aspirin use conferred a significant reduction in the AdverseOutcomerisk of colorectal cancers that overexpressed COX-2 ( multivariate relative risk , 0.64 ; 95 % confidence interval [ CI ] , 0.52 to 0.78 ) , whereas regular aspirin use had no influence on tumors with weak or absent expression of COX-2 ( multivariate relative risk , 0.96 ; 95 % CI , 0.73 to 1.26 ) .
Therefore , we have compared RT-PCR with FISH using ' home brew ' fusion probes for Ewing sarcoma ( EWS )-FLI1 and a commercial EWS break apart probe set in 67 Cancerarchival round cell tumors , including 27 EWS and PNETs .
Grade 1/2 asthenia ( 96.3 % ) recorded as the leading toxicity and Diseasehyperglycaemia ( 20.4 % ) was the most common non hematological grade 3/4 toxicity .
After the recent discovery of mutations in KDM6A ( UTX ) , which encodes the histone H3K27me3 demethylase UTX , in Cancerseveral cancer types , EZH2 is the second histone methyltransferase gene found to be mutated in cancer .
RESULTS : We showed that IMO was able to significantly restore the sensitivity of CancerK-Ras mutant cancer cells to cetuximab , producing a marked inhibition of cell survival and a complete suppression of mitogen activated protein kinase phosphorylation , when used in combination with cetuximab .
The similar rate of homologous recombination mutations in Cancernonserous carcinomas supports their inclusion in PARP inhibitor clinical trials .
RESULTS : High betaIotaIotaIota-tubulin expression was significantly associated with poorly differentiated Cancerhigh-grade breast cancers ( P = .003 ) but not with tumor size , estrogen receptor ( ER ) status , or human epidermal growth factor receptor 2 ( HER2 )/neu overexpression .
RESULTS : The present analysis is based on 114 patients with Cancersquamous cell carcinoma of the larynx , pharynx and oral cavity diagnosed between March 1992 and October 1996 .
Peutz-Jeghers syndrome is a Diseasehereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an increased risk of cancer in the GI tract and at extraintestinal sites .
Proportional-hazards models were used to compare the risk of death among patients with CancerHPV positive cancer and those with HPV negative cancer .
The recognition of recurrent genetic alterations in Cancerspecific tumour types has provided the basis for the reclassification of certain soft tissue neoplasms , and molecular analysis of patient material has the potential to provide both diagnostic and prognostic information .
RESULTS : From Cancerconsecutive lung adenocarcinoma cases ( n = 253 ) , we identified 11 specimens ( 4.35 % ) positive for fusion transcripts , 9 of which were positive for the previously identified variants 1 , 2 , and 3 .
RESULTS : Among patients with Cancermutated-PIK3CA colorectal cancers , regular use of aspirin after diagnosis was associated with superior colorectal cancer specific survival ( multivariate hazard ratio for cancer related death , 0.18 ; 95 % confidence interval [ CI ] , 0.06 to 0.61 ; P < 0.001 by the log-rank test ) and overall survival ( multivariate hazard ratio for death from any cause , 0.54 ; 95 % CI , 0.31 to 0.94 ; P = 0.01 by the log-rank test ) .
CancerSpindle cell sarcomas often present the surgical pathologist with a considerable diagnostic challenge .
Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in Cancerhigh-grade serous ovarian carcinoma , which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity .
Drug related adverse events were usually of grade 1 or 2 , and the events most frequently leading to dose reductions were rash and arthralgia or Diseasearthritis .
Flavopiridol has been shown to mimic , in part , the effect of the cell cycle control gene p16 , which is frequently lost or mutated in Cancermalignant melanoma , making it an ideal candidate for targeted therapy in this disease .
The negative prognostic effect of GNAS mutations in Cancergastrointestinal cancers warrants further confirmatory studies and may prompt the development of effective targeted strategies .
In contrast , the NRAS mutation was frequently evident in patients with Cancernodular melanoma ( OR = 1.894 ; P < 0.001 ) and in melanomas arising in chronic sun damaged skin ( OR = 1.887 ; P = 0.018 ) .
Oncogenic TRK fusions induce cancer cell proliferation and engage Cancercritical cancer related downstream signaling pathways .
Screening of a large collection of Cancerpatient tumor samples showed the presence of EML4-ALK fusion in 2.4 % of breast ( 5 of 209 ) , 2.4 % of colorectal ( 2 of 83 ) , and in 11.3 % of NSCLC ( 12 of 106 ) .
A similar screening in 18 patients with Cancersporadic hemangioblastoma revealed 2 missense DNA variants .
We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety , pharmacokinetics , pharmacodynamics , and response rate in individuals with Canceradvanced solid tumours .
We conclude that 3 ' end EPCAM deletions are a recurrent cause of Lynch syndrome , which should be implemented in Diseaseroutine Lynch syndrome diagnostics .
The majority of Canceruterine sarcomas are leiomyosarcoma and endometrial stromal sarcoma ( ESS ) .
In 1 responder with Cancerrectal melanoma who later progressed , the recurring tumor had a previously undetected mutation in NRAS , which was found in addition to the persisting mutation in KIT .
PURPOSE : The causes of the aggressive nature of CancerBCR-ABL1-positive adult acute lymphoblastic leukemia ( ALL ) are unknown .
Therapeutic options for Cancermalignant pleural mesothelioma ( MPM ) are limited despite the increasing incidence globally .
This dual therapy synergistically reduced cell viability in vitro and Cancerxenograft tumor growth in vivo .
CONCLUSIONS : The frequency of PIK3CA mutations in Japanese breast cancers is similar to that of CancerCaucasian breast cancers .
Besides the estrogen receptor , there are no predictive biomarkers to help Cancerselect breast cancer patients for tamoxifen treatment .
For comparison , we analyzed 13 epithelioid hemangiomas , five epithelioid angiosarcomas , and four Cancerepithelioid sarcoma like EHE .
Here we report a novel isoform of the anaplastic lymphoma kinase ( ALK ) that is expressed in ~ 11 % of melanomas and sporadically in Cancerother human cancer types , but not in normal tissues .
METHODS : We sequenced kinase domains in the EGFR and human EGFR type 2 ( Her2 and neu ) genes and analyzed the expression of EGFR , EGFR deletion mutant variant III ( EGFRvIII ) , and the tumor-suppressor protein PTEN in Cancerrecurrent malignant gliomas from patients who had received EGFR kinase inhibitors .
Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 Cancerunselected tumors from Japan and 1 of 61 from the United States .
No somatic mutations were detected in 8 Cancernon clear cell carcinomas .
RESULTS : PD-1 expression by tumor infiltrating lymphocytes ( TILs ) was found in 22 % , whereas tumor cell associated PD-L1 expression was observed in 24 % of the CancerNSCLC tumors .
This study provides first data for immune-context AdverseOutcomerelated risk stratification of NSCLC patients .
BACKGROUND : CancerMedullary thyroid carcinoma ( MTC ) is a well differentiated thyroid tumor that maintains the typical features of C cells .
However , Dpc4 immunolabeling status of Cancercarcinoma tissues harvested at autopsy , a sensitive marker of DPC4 genetic status , was highly correlated with the presence of widespread metastasis but not with locally destructive tumors ( P = .007 ) .
The prognosis for patients with Cancermantle cell lymphoma ( MCL ) is poor , and at present there is no truly effective therapy .
A t ( 1 ; 3 ) ( p36 .3 ; q25 ) translocation was reported in two cases of Cancerepithelioid hemangioendothelioma ( EHE ) , however , no follow-up studies have been performed to identify the gene fusion or to assess its prevalence in a larger cohort of patients .
CONCLUSIONS : These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes , and may become useful as a AdverseOutcomepoor risk marker in these patients .
METHODS : Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy ( given with curative intent ) or with adjuvant radiation therapy ( following complete surgical extirpation of Diseasegross disease ) were included in the analysis .
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 Cancerinvasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 mucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
The canonical Wnt pathway ( beta-catenin and TCF-LEF ) , implicated in the pathogenesis of Cancernumerous cancers , is constitutively active in half of MCLs .
METHODS : Cell viability assays , drug dose responses , immunoblots , rescue with gene transfer , Cancermice tumour models , and statistical comparisons of tumour growth and Kaplan-Meier survival curves .
CONCLUSION : Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression ; conversely , patients with CancerER rich tumors may derive additional benefit from exemestane .
EXPERIMENTAL DESIGN : ROS1 kinase domain mutations were examined in Cancerfresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing .
These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma , breast cancer , and Cancerbrain tumors , and they also provide a link between the central role of p53 inactivation in human cancer and the well defined G2 checkpoint in yeast .
betaIotaIotaIota-tubulin expression was evaluated by immunohistochemical methods and was correlated with pathologic characteristics and response to neoadjuvant chemotherapy using Cancerresidual cancer burden ( RCB ) score .
Activating mutations in either BRAF or NRAS are seen in a significant number of Cancermalignant melanomas , but their incidence appears to be dependent to ultraviolet light exposure .
BRCA1/2 mutation status might be added as strata in future trials in Cancerprimary ovarian cancer .
In summary , mutated SETBP1 represents a newly discovered oncogene present in aCML and closely Diseaserelated diseases .
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , NCI-N87 gastric cancer cells , CancerSK-Ov3 ovarian cancer cells and EGFR overexpressing A431 epidermoid carcinoma cancer cells .
CancerPrimary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000 .
Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex ( TSC ) , a Cancerhamartoma syndrome with lung involvement .
We identified frequent and focal fibroblast growth factor receptor 1 ( FGFR1 ) amplification in squamous cell lung cancer ( n = 155 ) , but not in Cancerother lung cancer subtypes , and , by fluorescence in situ hybridization , confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples ( 22 % of cases ) .
PURPOSE : Peutz-Jeghers syndrome ( PJS ) is a unique disorder characterized by the development of Cancerhamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies .
AIM : To investigate the role of coding region mutation and promoter hypermethylation of TP53 in Canceradrenocortical cancer formation .
The risk of developing any cancer in carriers by age 65 years was 47 % ( 95 % CI : 27-73 % ) with AdverseOutcomeelevated risks of both gastrointestinal and breast cancer .
A pathologic complete response to neoadjuvant chemotherapy ( NAC ) containing platinum is a strong prognostic determinant for patients with Cancermuscle-invasive bladder cancer ( MIBC ) .
Therefore , we developed a uveal melanoma metastatic mouse model with CancerEGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis .
These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming , suggesting crizotinib as a potential adjuvant therapy for patients with Cancerprimary uveal melanoma who are at high risk for the development of metastatic disease .
NTRK1 fusions were mutually exclusive oncogenic drivers of colon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12 , a Cancerhuman colon cancer cell line harboring TPM3-NTRK1 fusion .
The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in Cancerestablished tumor cell lines and in an orthotopic mouse xenograft model .
We examined 848 comparative genomic hybridization profiles of Cancermelanocytic tumors and found copy number transitions within BRAF in 10 tumors , of which six could be further characterized by sequencing .
Collectively , our results suggest that multitargeted intervention is the most Cancereffective tumor therapy , and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib resistant NSCLC .
Patients with CancerPTEN deficient breast cancers had significantly poorer responses to trastuzumab based therapy than those with normal PTEN .
PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of Cancersubcutaneous bladder tumour xenografts .
There was a significant relation ( P = 0.003 ) between histologic subtype ( monophasic vs. biphasic ) and SSX1 or SSX2 involvement in the fusion transcript : all 12 Cancerbiphasic synovial sarcomas had a SYT-SSX1 fusion transcript , and all 16 tumors that were positive for SYT-SSX2 were monophasic .
These data support the use of both PI3K and mTOR inhibitors to treat Cancerurothelial carcinoma , in particular in the absence of functional PTEN .
De novo lipogenesis is activated in Cancermost cancers .
Malignant peripheral nerve sheath tumor , leiomyosarcoma , fibrosarcoma , and Cancermonophasic synovial sarcoma may all appear similar histologically .
IDH2 mutations were identified in approximately 20 % of angioimmunoblastic T-cell lymphomas ( AITLs ) , but not in Cancerother peripheral T-cell lymphoma entities .
Mutations occurred exclusively in CancerMSI positive tumors ( P = .02 ) , with an overall mutation rate of 8.5 % .
The role of a polymorphism at position 72 of the tumor suppressor gene TP53 in the development of Cancercervical cancer is not well established .
RESULTS : pRB was overexpressed in Cancerpancreatic ductal adenocarcinomas but was hardly detectable in other pancreatic malignancies , chronic pancreatitis , or nontransformed human pancreatic tissue .
CONCLUSIONS : The presence of minimal residual disease , as determined by quantitation of NPM1 mutated transcripts , provided powerful prognostic information independent of AdverseOutcomeother risk factors .
CancerAdvanced basal cell carcinomas ( BCCs ) frequently acquire resistance to Smoothened ( SMO ) inhibitors through unknown mechanisms .
From this perspective , AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in Cancerpostmenopausal ER positive breast cancer patients .
The effect was specific to pRB depletion because two Cancerother human pancreatic cancer cell lines that retained high pRB expression after p16 transfection were resistant to chemotherapy induced apoptosis .
We studied the influence of different components on the MAP and extracellular signal regulated ( ERK ) kinase ( MEK ) and PI3K and mammalian target of rapamycin ( mTOR )-signaling cascade in CancerNRAS mutant melanoma cells .
Mutations in the von Hippel-Lindau ( VHL ) gene are responsible for VHL disease , Diseasecongenital polycythemia , and are found in many sporadic tumor types as well .
Three of 8 clear ( 38 % ) Cancercell carcinomas and 7 of 25 serous carcinomas ( 28 % ) screened exhibited HER2 amplification compared with 7 % ( 2/29 ) of endometrioid adenocarcinomas .
Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of Cancermyeloid malignancies ( familial platelet disorder with propensity to acute myeloid leukaemia , FPD and AML ) .
Main toxicities reported were grade 1 photosensitivity and Cancerskin cancers .
OBJECTIVE : The aim of this study was to understand the role of PIK3CA and PTEN on the resistance of Cancerhuman ovarian cancer cells to cisplatin induced apoptosis .
RAF inhibitors such as vemurafenib and dabrafenib block BRAF mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAF ( CancerV600E )-mutant melanoma .
We report the case of a patient with an initial diagnosis of Cancersalivary acinic cell carcinoma later reclassified as MASC after next generation sequencing revealed an ETV6-NTRK3 fusion .
Among patients with stage II cancer , the difference in 5-year disease-free survival was significant both in the discovery data set ( 49 % among 15 patients with CancerCDX2 negative tumors vs. 87 % among 191 patients with CDX2 positive tumors , P = 0.003 ) and in the validation data set ( 51 % among 15 patients with CDX2 negative tumors vs. 80 % among 106 patients with CDX2 positive tumors , P = 0.004 ) .
ALK tyrosine kinase domain mutations occurred in 8 % of samples -- at three hot spots and 13 minor sites -- and correlated significantly with poorer survival in high- and Cancerintermediate-risk neuroblastoma .
To understand the role of human epidermal growth factor receptor ( hEGFR ) kinase domain mutations in lung tumorigenesis and response to EGFR targeted therapies , we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in Cancerhuman lung cancer .
Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations ( mean , 17,740 +/- standard deviation , 7,703 ) , all Cancerother high-grade tumors were hypermutant ( mean , 1,589 +/- standard deviation , 1,043 ) , similar to other cancers that responded favorably to immune checkpoint inhibitors .
STAG2 loss , however , is present in more than 15 % of CancerEwing sarcoma tumors ; occurs by point mutation , rearrangement , and likely nongenetic mechanisms ; and is associated with disease dissemination .
BACKGROUND : No targeted therapies are available for CancerKRAS-mutant non-small-cell lung cancer ( NSCLC ) .
PATIENTS AND METHODS : We performed exome sequencing and neoantigen prediction on 37 CancerbMMRD cancers and compared them with childhood and adult brain neoplasms .
CONCLUSIONS : One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with CancerHER2 positive breast cancer .
Vemurafenib , an oncogenic BRAF kinase inhibitor approved for BRAF positive melanoma , showed clinical benefit in three patients with BRAF ( CancerV600E )-positive papillary thyroid cancer in a phase 1 trial .
Whereas many studies have analyzed RAF and PI3K signaling in Cancermutant NRAS melanoma , the role of RalGEF and Ral is understudied and TBK1 has not been examined .
We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of CancerKRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase ( PI3K ) inhibition caused synergistic cell death .
Efficacy at the recommended phase 2 dose was studied in patients with CancerBRAF-mutant tumours , including those with non Val600Glu mutations , in three cohorts : metastatic melanoma , melanoma with untreated brain metastases , and non melanoma solid tumours .
Ewing 's sarcoma is a poorly characterized Cancermalignant tumor with a relatively uniform histologic appearance , made up of densely packed small cells with round to oval nuclei , without distinct cell borders and without any structural differentiation .
The primary endpoint , assessed in the intention-to-treat population , was patient benefit at 12 weeks , defined by an absence of CNS or Diseaseextra-CNS disease progression , no tumour related worsening of neurological signs or symptoms , and no increase in corticosteroid dose .
NF1 mutations were observed in BRAF-mutant tumor cells that are intrinsically resistant to RAF inhibition and in Cancermelanoma tumors obtained from patients exhibiting resistance to vemurafenib , thus showing the clinical potential for NF1 driven resistance to RAF and MEK targeted therapies .
Malignant mesenchymal tumors consist of approximately 10 % of Canceruterine tumors .
Some of these refractory PCs regress after discontinuation of Diseaseantiandrogen administration [ antiandrogen withdrawal syndrome ( AWS ) ] .
We identified alterations in MAPK pathway genes in resistant tumors not present in matched Cancerpretreatment tumors , including KRAS amplification , BRAF amplification , and a MEK1 mutation .
To examine the risk of Cancerlung cancer associated with the codon 72 , intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken .
Low mitotic activity , < or = 5 mitoses/50HPF was detected in 81 % of analyzed GISTs including larger , > 5 Cancercm tumors .
Patients with tumours with strong Akt2 and pAkt Thr308 ( n+ c ) had superior TTP ( 17.0 vs. 7.6 months , P = 0.024 ; HR 0.52 ) and OSt ( 51.8 vs. 16.8 months , P = 0.0009 ; HR 0.34 ) compared to Cancerother tumours .
Persistent RET activation is a frequent event in Cancerpapillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( MTC ) .
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the myeloproliferative disorders ( MPDs ) polycythemia vera , Diseaseessential thrombocythemia , and myeloid metaplasia with myelofibrosis .
CONCLUSIONS AND RELEVANCE : In this hypothesis generating study of patients with Canceradvanced uveal melanoma , selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate ; however , no improvement in overall survival was observed .
The results showed that , OCT4B1 promoted the growth of colon cancer and Cancerdrug resistant cancer cells by maintaining the activity of ES cells and by facilitating the transition of the cell cycle and reducing apoptosis .
RESULTS : Unsupervised gene expression clustering showed 3 robust molecular classes of tumors : the proliferation class ( 51 % of samples ) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation ; the inflammation class ( 26 % of samples ) had altered expression of genes that regulate inflammation and cytokine enriched production ; and the unannotated class ( 23 % of samples ) had a gene expression signature that was not associated previously with Cancerliver tumors .
Additional western blotting was performed for four Cancerbreast cancer and four gastric cancer cell lines and 35 fresh frozen gastric cancer samples , to confirm the cyclin D1 , D2 , and cdk4 data .
Evidence of single-agent activity included 10 RECIST partial responses ( PR ; confirmed for peritoneal mesothelioma , CancerPIK3CA mutant head-and-neck cancer , and three pleural mesotheliomas ) .
Ponatinib has demonstrated early clinical efficacy in Cancerchemotherapy resistant acute myeloid leukemia ( AML ) patients with internal tandem duplication ( ITD ) mutations in FLT3 .
BACKGROUND : Palbociclib ( PD-0332991 ) is an oral , small-molecule inhibitor of cyclin dependent kinases ( CDKs ) 4 and 6 with preclinical evidence of growth-inhibitory activity in Canceroestrogen receptor positive breast cancer cells and synergy with anti-oestrogens .
The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher AdverseOutcomerisk of hypothyroidism ( OR : 10.0 p = 0.041 and OR : 10.5 ; p = 0.015 , respectively ) .
Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and Cancersubcutaneous tumours in nude mice .
Therefore , AIB1 might be helpful to identify those CancerERalpha positive breast cancers patients who are candidates for adjuvant chemotherapy .
Imatinib , a Bcr-Abl tyrosine kinase inhibitor , is a highly effective therapy for patients with Cancerchronic myelogenous leukemia ( CML ) .
CONCLUSION : Positive p53 immunostaining and p53 mutation status in Cancerpretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT .
Together , these data provide genetic evidence that the DLBCL subtypes are Diseasedistinct diseases that use different oncogenic pathways .
Overall , this pharmacogenomic and pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of Cancerovarian cancers ( and perhaps other tumor types ) , with ASNS as a biomarker for patient selection .
Recurrent translocation of BRD4 is observed in a genetically defined , incurable subtype of Cancerhuman squamous carcinoma .
To identify predictive biomarkers , sensitivity to GSK1120212 was profiled for 218 Cancersolid tumor cell lines and 81 hematologic malignancy cell lines .
In other histological types , we observed 8 mutations in 7 out of 48 patients ( 15 % ) , 1 mutation in 1 of 6 oncocytoma , 3 mutations in 2 of 7 chromophobe RCC , 2 mutations in 2 of 30 papillary RCC , no mutations in 1 collecting Cancerduct carcinoma and 2 mutations in 2 of 4 unclassified RCC .
We investigated whether prognosis after surgical resection for Cancerinvasive pancreatic adenocarcinoma is influenced by SMAD4 status .
This is the case of an 84-year-old woman diagnosed with CancerStage IVb colon adenocarcinoma ( CRC ) metastatic to the liver , retroperitoneum , anastomotic site , and distal rectal sigmoid colon .
We have established an automated platform for examining the sensitivity to various molecularly targeted inhibitors across a large panel of Cancerhuman tumor derived cell lines to identify additional genotype correlated responses that may be clinically relevant .
RESULTS : Low expression of THBS2 was significantly associated with advanced pretreatment tumor ( P < 0.001 ) and nodal status ( P = 0.004 ) , post-treatment tumor ( P < 0.001 ) and nodal status ( P < 0.001 ) , increased vascular invasion ( P = 0.003 ) , increased perineural invasion ( P = 0.023 ) and Cancerinferior tumor regression grade ( P = 0.015 ) .
We identified a novel germline mutation in the PTPRD gene in three of eight patients ( 37.5 % ) with Cancermetastatic Ewing sarcoma .
While 95 % of patients were former or current smokers , smoking related G : C > T : A transversions were significantly less frequent in NRAS mutated lung tumors than CancerKRAS-mutant non small cell lung cancer [ NSCLC ; NRAS : 13 % ( 4/30 ) , KRAS : 66 % ( 1772/2733 ) , P < 0.00000001 ] .
CONCLUSION : Panitumumab monotherapy efficacy in mCRC is confined to patients with CancerWT KRAS tumors .
BACKGROUND : CancerVarious human cancers have ALK gene translocations , amplifications , or oncogenic mutations , such as anaplastic large-cell lymphoma , inflammatory myofibroblastic tumours , non-small-cell lung cancer ( NSCLC ) , and neuroblastoma .
CancerFanconi anemia defective cancer cells were hypersensitive to the cross linking agents mitomycin C ( MMC ) , cisplatin , chlorambucil , and melphalan but not to 5-fluorouracil , gemcitabine , doxorubicin , etoposide , vinblastine , or paclitaxel .
CancerGastrointestinal stromal tumor ( GIST ) is the most common mesenchymal tumor of the gastrointestinal tract .
Although 85 % of the Cancersynovial sarcomas studied demonstrated t ( X ; 18 ) , 75 % of the malignant peripheral nerve sheath tumors in our cohort also demonstrated this translocation .
CONCLUSIONS : Our results suggest that it may be appropriate to offer PALB2 c. 1592delT mutation testing to Finnish women with breast cancer , especially those with an early age at onset or a family history of breast or related cancers , and to offer carriers the option of participation in Diseaseextended disease surveillance programs .
Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8 % of Cancersquamous cell lung cancers and cell lines .
FISH was tested in 19 fibrolamellar carcinomas and in 6 Cancerscirrhous hepatocellular carcinomas , which can closely mimic fibrolamellar carcinoma .
Targeted sequencing revealed TSC1 mutations in about 8 % of 109 Canceradditional bladder cancers examined , and TSC1 mutation correlated with everolimus sensitivity .
Moreover , ERBB4 was upregulated at the protein level in CancerERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment .
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , CancerB-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
Korean patients with CancerTrkA positive colon cancer had a marginal but significant shorter overall survival time than TrkA negative colon cancer [ hazard ratio ( HR ) = 0.5346 , 95 % confidential interval ( CI ) = 0.2548-0 .9722 , p = 0.0411 ] .
PURPOSE : The Tamoxifen and Exemestane Adjuvant Multinational ( TEAM ) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor ( PgR ) expression for outcome of estrogen receptor positive ( ER positive ) Cancerearly breast cancer treated with exemestane versus tamoxifen .
PATIENTS AND METHODS : Eligible patients with Canceravailable tumour tissue for HER2 analysis were included .
The primary aim was to estimate the percentage of pathologic complete response ( pCR ; no Cancerinvasive tumor in breast and axillary nodes ) .
At the recommended phase 2 dose in 36 patients with CancerVal600 BRAF-mutant melanoma , responses were reported in 25 ( 69 % , 95 % CI 51.9-83 .7 ) and confirmed responses in 18 ( 50 % , 32.9-67 .1 ) .
MATERIALS AND METHODS : The expression of EGFR , p53 , Cyclin D1 , p16 , p21 , p27 , p-AKT , HIF-1alpha , Caspase 3 and BCL2 was analyzed by immunohistochemistry in 41 primary laryngeal and Cancerhypopharyngeal squamous cell carcinomas of patients that received induction chemotherapy ( cisplatin and 5-fluorouracil ) as part of their treatment .
PURPOSE : CDK4 is amplified in > 90 % of well differentiated ( WDLS ) and Cancerdedifferentiated liposarcomas ( DDLS ) .
The predominance of NRAS codon 61 mutations as a feature of carcinomas indicates that the diagnosis of Canceradenoma alongside the presence of this mutation should be made cautiously .
Detailed mutational profiling confirmed RAS and RAF screening and identified additional aberrations ( NRAS and Cancernon-BRAF melanomas ; PIK3CA and KRAS colorectal cancer ) without therapeutic implications .
We examined IDH1 R132 and IDH2 R140 and R172 mutations by high resolution melting analysis and direct sequencing in Chinese patients with Cancerdifferent myeloid malignancies including 198 acute myeloid leukemia ( AML ) , 82 myelodysplastic syndrome ( MDS ) , 85 chronic myeloid leukemia , and 57 myeloproliferative neoplasms .
The receptor tyrosine kinase RET is implicated in the progression of Cancerluminal breast cancers ( BC ) but its role in estrogen receptor ( ER ) negative tumors is unknown .
EXPERIMENTAL DESIGN : CancerPrimary imatinib resistant tumor cells and cell lines expressing clinically identified imatinib resistant KIT-V654A , KIT-T670I , or PDGFRA D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays .
Additionally , HM781-36B shows an excellent efficacy in a variety of EGFR- and CancerHER-2-dependent tumor xenograft models , including erlotinib sensitive HCC827 NSCLC cells , erlotinib resistant NCI-H1975 NSCLC cells , HER-2 overexpressing Calu-3 NSCLC cells , NCI-N87 gastric cancer cells , SK-Ov3 ovarian cancer cells and EGFR overexpressing A431 epidermoid carcinoma cancer cells .
Surgery remains an essential component in the treatment of ovarian cancer ; however , the importance of surgical specialization and defining " optimal cytoreduction " as no Diseasevisible residual disease has been further validated .
Furthermore , in vivo assay of xenograft transplantation confirmed the higher tumorigenicity of DU145-TxR cells , suggesting that these paclitaxel resistant PCa cells possessed Cancerpotent cancer stem cell ( CSC )-like properties and eventually developed paclitaxel-resistance .
Our suite of patient derived xenografts from Cancermetastatic colorectal carcinomas reliably mimicked disease response in humans , prospectively recapitulated biomarker based case stratification , and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting .
With intensified pediatric like therapy and genetic disease dissection , the field of Canceradult acute lymphoblastic leukemia ( ALL ) has evolved recently .
METex14 mutations are detected most frequently in lung adenocarcinoma ( 3 % ) , but also frequently in other lung neoplasms ( 2.3 % ) , Cancerbrain glioma ( 0.4 % ) , and tumors of unknown primary origin ( 0.4 % ) .
By studying the Cancerresidual tumor cells that remain after chemotherapy in several in vivo non small cell lung cancer models , we found that these cells have increased levels of human epidermal growth factor receptor ( HER ) signaling due , in part , to the enrichment of a preexisting NRG1 ( HI ) subpopulation .
Patients with STAT3 mutations presented more often with neutropenia and Diseaserheumatoid arthritis than did patients without these mutations .
These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in Cancerlymphoid malignancies .
In vivo , motesanib significantly inhibited the growth of CancerTT tumor cell xenografts ( expressing Ret C634W ) and significantly reduced tumor blood vessel area and tumor cell proliferation , compared with control .
Carrying the C allele ( TC+CC ) was associated with an AdverseOutcomeincreased risk of positive CA125 ( OR = 3.20 , 95 % CI [ 1.15-8 .71 ) .
These results indicate that cytogenetic findings may provide a new criterion , not only for establishing the diagnosis of liposarcoma , but also for differentiating confusing histologic types of liposarcoma and these lesions from other types of Cancersarcomas .
However , MTAP expression was significantly higher in CancerLuminal-A breast tumors than in TNBC , suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC .
We report that Cancerrecurrent ovarian carcinomas after paclitaxel and carboplatin treatment have higher levels of spleen tyrosine kinase ( SYK ) and phospho-SYK .
The tumor suppressor gene PTEN is frequently mutated in Cancerdiverse human cancers and in autosomal dominant cancer predisposition disorders .
Immunohistochemical prevalence screening in clinical samples of Cancerrelevant adult-type tumours revealed that 12.5 % of sarcomas ( among them malignant peripheral nerve sheath tumours , pleomorphic liposarcomas , leiomyosarcomas , dedifferentiated liposarcomas , synovial sarcomas and angiosarcomas ) and 23.2 % of GIST show high HR23b expression .
Most anaplastic lymphoma kinase ( CancerALK )-positive non small cell lung cancers ( NSCLCs ) are highly responsive to treatment with ALK tyrosine kinase inhibitors ( TKIs ) .
Using FLO-1 , OE19 , and CancerOE33 esophageal adenocarinoma cell lines , with constitutive AURKA overexpression and mutant p53 , we observed inhibition of colony formation with a single treatment of 0.5 mumol/L MLN8237 ( P < 0.05 ) .
003 ) , the presence of lymph node metastasis ( p = 0.0014 ) , vascular invasion by cancer cells ( p < 0.0001 ) , and AdverseOutcomepoor prognosis ( p < 0.0001 ) , while cyclin D1 did not correlate with any of these except age ( p = 0.00193 ) .
We analyzed p53 mutations in 121 Cancerfresh primary oral squamous cell carcinomas ( SCCs ) by polymerase chain reaction-single-strand conformation polymorphism or a yeast functional assay .
BACKGROUND : A recent genomewide mutational analysis of glioblastomas ( World Health Organization [ WHO ] grade IV Cancerglioma ) revealed somatic mutations of the isocitrate dehydrogenase 1 gene ( IDH1 ) in a fraction of such tumors , most frequently in tumors that were known to have evolved from lower-grade gliomas ( secondary glioblastomas ) .
DNA was isolated from Cancerprechemotherapy tumor tissue and used for next generation sequencing of 178 cancer associated genes ( discovery cohort ) or targeted sequencing ( validation cohort ) .
We have identified the Cancerfirst human melanoma cell line with an endogenous L576P mutation , the most common KIT mutation in melanoma ( approximately 30-40 % ) .
Eligible patients ( > = 18 years , left ventricular ejection fraction > = 50 % , Eastern Cooperative Oncology Group performance status 0-2 ) with Cancerprogressive HER2 positive advanced breast cancer who had received two or more HER2 directed regimens in the advanced setting , including trastuzumab and lapatinib , and previous taxane therapy in any setting , were randomly assigned ( in a 2:1 ratio ) to trastuzumab emtansine ( 3.6 mg/kg intravenously every 21 days ) or physician 's choice using a permuted block randomisation scheme by an interactive voice and web response system .
Through a prospective clinical sequencing program for advanced cancers , four index cases were identified which harbor gene rearrangements of FGFR2 , including patients with Cancercholangiocarcinoma , breast cancer , and prostate cancer .
A patient with sporadic , Cancerhigh grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy , and 340 VUS alterations .
Grade 3 to 4 neutropenia was seen more commonly with the combination ( 32 % ) than with docetaxel alone ( 22 % ) , and there was a slightly higher incidence of Diseasefebrile neutropenia in the combination arm ( 23 % v 17 % ) .
Nucleophosmin ( NPM1 ) exon-12 gene mutations are the hallmark of a Cancerlarge acute myelogenous leukemia ( AML ) subgroup with normal karyotype , but their prognostic value in this AML subset has not yet been determined .
KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis , occurring in 10 % to 30 % and 26 % to 80 % of Cancerendometrial cancers , respectively .
His symptoms alleviated for a short time but soon worsened and the patient died of Diseasemassive progressive disease .
CONCLUSIONS : NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in Cancerpreclinical human cancer models .
In the present study , clear antitumor activity was observed with PI-103 treatment in two Cancergefitinib resistant non small cell lung cancer ( NSCLC ) cell lines , A549 and H460 , by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition .
Results were confirmed in vivo with strongest efficacy on growth in CancerKKLS tumors and only minor impairment of TMK-1 lesions .
Mutations in Cancerknown mesothelioma related genes NF2 , CDKN2A , LATS2 , amongst others , were identified .
The data are consistent with CancerHER2 positive tumours being resistant to tamoxifen .
The number of Cancersecondary cutaneous cancers decreased with the combination therapy .
The capability of IMO to restore cetuximab sensitivity was further confirmed by using CancerK-Ras mutant colorectal cancer cell models obtained through homologous recombination technology .
CancerMeningiomas are frequent central nervous system tumors .
Furthermore , combining ALK and HSP90 inhibitors might enhance tumor shrinkage in CancerEML4-ALK-driven tumors .
Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes , Diseasechronic lymphocytic leukaemia , uveal melanoma , and pancreatic cancer , and at lower frequencies in breast cancer .
As previously observed , MDS and AML were the most Cancercommon malignancies , often of the erythroblastic subtype , and 1 family displayed early-onset follicular lymphoma .
OBJECTIVES : To evaluate the frequency of the activating mutation BRAF ( V600E ) in Cancerlow-risk papillary thyroid microcarcinoma ( pT1aNo-x at the moment of diagnosis ) and the association of the mutation with the clinical outcome in a retrospective analysis .
CancerEsophageal adenocarcinomas are poorly responsive to chemotherapeutics .
A subset of 20 samples was also sequenced for EGFR exons 18-21 and CancerKirsten rat sarcoma viral oncogene homologue ( KRAS ) exons 2-3 mutations .
HER2 is reported to be overexpressed in 20 % of cases of Cancernon-small-cell lung cancer ( NSCLC ) , principally adenocarcinoma .
METHODS : In this phase 2 , multicentre , open-label , non randomised study , women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or Cancertriple negative breast cancer were enrolled and received olaparib 400 mg twice a day .
BACKGROUND : CancerHigh-grade endometrial stromal sarcoma ( HGES ) is an aggressive disease with dismal prognosis .
FINDINGS : We established a AdverseOutcomeclinicogenetic risk model ( termed m7-FLIPI ) that included the mutation status of seven genes ( EZH2 , ARID1A , MEF2B , EP300 , FOXO1 , CREBBP , and CARD11 ) , the Follicular Lymphoma International Prognostic Index ( FLIPI ) , and Eastern Cooperative Oncology Group ( ECOG ) performance status .
Previous studies have suggested that patients with CancerSYT-SSX2 tumors do better than those with SYT-SSX1 tumors , but the study groups were too limited to be conclusive .
Neither diarrhea nor Diseaseneutropenia were dose limiting in any of the 57 patients treated .
Familial platelet disorder with predisposition to acute myelogenous leukemia ( FPD and AML ) is an autosomal dominant familial platelet disorder characterized by Diseasethrombocytopenia and a propensity to develop AML .
Conversely , Cancerunmethylated tumors with low MGMT mRNA expression ( N = 6 ) did better than their counterparts .
Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop Diseasefatal metastatic disease to the liver and the lung .
Inactivation of the switch and sucrose nonfermentable complex component SMARCB1 is extremely prevalent in Cancerpediatric malignant rhabdoid tumors ( MRTs ) or atypical teratoid rhabdoid tumors .
EXPERIMENTAL DESIGN : Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway , PL11 ( FANCC mutated ) and Hs766T ( FANCG mutated ) , as well as Cancerseveral parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia and BRCA2 pathway , were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents .
Oncogenic RAS expression occurs in up to 40 % of Cancermultiple myeloma ( MM ) cases and correlates with aggressive disease .
We used preclinical models to identify targeted therapies likely to be of benefit against CancerNRAS-mutant lung cancer cells .
Inflammatory myofibroblastic tumor ( IMT ) is a relatively Cancerrare soft tissue tumor .
Disabling mutations in the gene encoding ATM occur frequently in various human tumors , including lung cancer and Cancerhematological malignancies .
DiseaseInfection with human papillomaviruses ( HPVs ) characterizes a distinct subset of head and neck squamous cell cancers ( HNSCCs ) .
However , the expression of HIF-1alpha in Cancersoft-tissue sarcomas has not yet been characterized .
Two ETS transcription factors , ERG and ETV1 , were identified as outliers in Cancerprostate cancer .
Expression analysis confirms that combined MEK and PI3K and mTOR1 ,2 inhibition predominantly influences genes in the Cancerrat sarcoma ( RAS ) pathway and growth factor receptor pathways , which signal through MEK and ERK and PI3K and mTOR , respectively .
Phosphorylated serine 473 AKT declined in all tumor biopsies assessed ( P = .015 ) , and phosphorylated threonine 246 proline rich AKT substrate 40 was suppressed in hair follicles at 6 hours ( P = .008 ) , on days 7 ( P = .028 ) and 15 ( P = .025 ) with MK-2206 ; Diseasereversible hyperglycemia and increases in insulin c-peptide were also observed , confirming target modulation .
This study was conducted at an academic oncology hospital which is a prime referral centre for Diseasethyroid diseases .
BACKGROUND : CancerOropharyngeal squamous-cell carcinomas caused by human papillomavirus ( HPV ) are associated with favorable survival , but the independent prognostic significance of tumor HPV status remains unknown .
Recently , it has been made possible to identify characteristic chromosomal rearrangements associated with Cancercertain solid tumors .
We performed biological and biochemical studies to determine whether CancerPTEN deficient cancer cells are sensitive to pharmacologic inhibition of FRAP and mTOR by using the rapamycin derivative CCI-779 .
RESULTS : In comparison with patients with other KRAS mutated tumors , patients with Cancerp.G13D-mutated tumors ( n = 32 ) treated with cetuximab had longer overall survival ( median , 7.6 [ 95 % confidence interval { CI } , 5.7-20 .5 ] months vs 5.7 [ 95 % CI , 4.9-6 .8 ] months ; adjusted hazard ratio [ HR ] , 0.50 ; 95 % CI , 0.31-0 .81 ; P = .005 ) and longer progression-free survival ( median , 4.0 [ 95 % CI , 1.9-6 .2 ] months vs 1.9 [ 95 % CI , 1.8-2 .8 ] months ; adjusted HR , 0.51 ; 95 % CI , 0.32-0 .81 ; P = .004 ) .
We studied , in primary breast tumors through direct cDNA sequencing of exons 2-11 , whether TP53 gene mutations can predict response in patients with Diseaseadvanced disease to either first-line tamoxifen therapy ( 202 patients , of whom 55 % responded ) or up-front ( poly ) chemotherapy ( 41 patients , of whom 46 % responded ) .
BACKGROUND : There is lack of evidence about systemic treatment of Cancerpseudomyxoma peritonei ( PMP ) relapsing after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy .
Consequently , IKZF1 deletion status allowed the prospective identification of 53 % of the relapse-prone NHR classified patients within this subgroup and , therefore , serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for AdverseOutcomefuture risk stratification .
Using exome sequencing , we identified recurrent somatic mutations in EIF1AX and SF3B1 , specifically occurring in Canceruveal melanomas with disomy 3 , which rarely metastasize .
However , few inhibitors for the potential treatment for CancerNRAS mutant neuroblastoma have been investigated so far .
Overall , this methodology may inform the widespread implementation of Cancerprecision cancer medicine .
PURPOSE In the phase III INTEREST trial , 1,466 pretreated patients with Canceradvanced non small cell lung cancer ( NSCLC ) were randomly assigned to receive gefitinib or docetaxel .
RESULTS : Twelve out of 40 ( 30 % ) Canceradenomas harbored RAS mutations .
Recently , we and others identified a single recurrent somatic activating mutation ( JAK2V617F ) in the Janus kinase 2 ( JAK2 ) tyrosine kinase in the Diseasemyeloproliferative disorders ( MPDs ) polycythemia vera , essential thrombocythemia , and myeloid metaplasia with myelofibrosis .
RESULTS : Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas , 4 of 10 invasive lobular carcinomas , 1 of 4 Cancermucinous carcinomas , 2 of 2 squamous carcinomas , and 2 of 2 apocrine carcinomas , but no mutation was found in 12 noninvasive ductal carcinomas .
BACKGROUND : Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia ( CML ) and CancerPhiladelphia chromosome positive acute lymphoblastic leukemia ( Ph positive ALL ) is frequently caused by mutations in the BCR-ABL kinase domain .
EXPERIMENTAL DESIGN : Fifty-three patients were included in the study ; 28 of them had been relapse-free for at least 1 year and 25 had Diseaseprogressive disease or relapsed within 12 months .
CancerAngioimmunoblastic T-cell lymphoma ( AITL ) is a common subtype of peripheral T-cell lymphoma ( PTCL ) with a poor prognosis .
OBJECTIVE : To study the effect of trastuzumab in patients with progressive or Cancerrecurrent metastatic endometrial carcinoma shown by immunohistochemistry to overexpress the HER2 and neu receptor .
Most frequent adverse events were rash , acneiform dermatitis , and Diseasegastrointestinal disorders , mostly grade 1/2 .
A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro B cells was capable of generating CancerB cell leukemia in vivo .
Analysis of all VHL families , excluding germline mutations resulting in Diseasecongenital polycythemias , describes the spectrum of mutation types : 52 % missense , 13 % frameshift , 11 % nonsense , 6 % in-frame deletions and insertions , 11 % large and complete deletions , and 7 % splice mutations .
In addition , there are no reports that analyze overall survival and prognostic factors according to K-ras mutation status and subtypes in only Cancerunresectable pancreatic cancer ( PC ) determined from tissues obtained by endoscopic ultrasound guided fine-needle aspiration .
Thus , BRAF mutations have the highest incidence in non chronic sun damaged ( CSD ) , and are uncommon in acral , mucosal and CancerCSD melanomas .
BACKGROUND : The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously Canceruntreated metastatic melanoma with BRAF V600E or V600K mutations .
Most patients had liver cirrhosis ( 82.9 % ) and Diseasehepatitis B viral infection ( 75.7 % ) .
Here , we identified CH5424802 , a potent , selective , and orally available ALK inhibitor with a unique chemical scaffold , showing preferential antitumor activity against cancers with gene alterations of ALK , such as Cancernonsmall cell lung cancer ( NSCLC ) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma ( ALCL ) cells expressing NPM-ALK fusion in vitro and in vivo .
Uveal melanoma is the most Cancercommon primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung .
BACKGROUND : The molecular causes of Cancermany hematologic cancers remain unclear .
We propose that elevated PRL-3 expression is an important clinical predictive biomarker for Cancerfavorable anti-EGFR cancer therapy .
Collectively , these findings show the recurrence of EML4-ALK fusion in Cancermultiple solid tumors and further substantiate its role in tumorigenesis .
TERT promoter mutations ( C228T , C250T ) were detected in 55 Cancer% glioblastomas analysed .
Advanced Sezary syndrome ( SS ) , an aggressive , exceedingly rare variant of Cancercutaneous T-cell lymphoma ( CTCL ) is a prototypical example of a rare cancer .
Aberrations of AR , ETS genes , TP53 , and PTEN were frequent ( 40 %-60% of cases ) , with TP53 and AR alterations enriched in mCRPC compared to Cancerprimary prostate cancer .
Activating mutations or amplifications in MET have been described in patients with Cancerpapillary renal cell carcinoma ( PRCC ) .
BACKGROUND : All-trans retinoic acid ( ATRA )/anthracycline chemotherapy is beneficial in newly diagnosed acute promyelocytic leukemia ( APL ) ; however , it is important to identify patients with Diseasehigh-risk disease to increase the cure rate .
Angiosarcomas ( AS ) represent a heterogeneous group of Cancermalignant vascular tumors occurring not only in different anatomic locations but also in distinct clinical settings , such as radiation or associated chronic lymphedema .
Germline VHL mutations produced Cancersimilar cancer phenotypes in Caucasian and Japanese VHL families .
These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in Cancerindividual melanomas .
Women homozygotes for arginine had a 2.2-fold increased AdverseOutcomerisk ( 95 % confidence interval : 0.6-7 .6 ) for cervical cancer .
CONCLUSIONS : These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of Diseasemicrometastatic disease in UM .
PURPOSE : The tet oncogene family member 2 ( TET2 ) gene was recently identified to be mutated in Diseasemyeloid disorders including acute myeloid leukemia ( AML ) .
These results show pathological activation of KIT in a substantial number of Cancermetastatic tumors of acral and mucosal melanomas , and suggest a potential therapeutic benefit of sunitinib for these melanomas .
We examined the prognostic and predictive impact of DNA methyltransferase ( DNMT ) 1 and 3b expression in Cancergastric carcinomas ( GC ) treated by neoadjuvant chemotherapy .
METHODS : Previously genotyped ( KRAS , NRAS , BRAF , PIK3CA mutations ) formalin fixed Cancerparaffin embedded tumour biopsies of 226 cetuximab treated CRC patients ( 1st to 3rd line therapy ) were assessed for mRNA expression of epidermal growth factor receptor ( EGFR ) and its ligands EGF , Transofrming Growth Factor-a ( TGFA ) , Amphiregulin ( AREG ) and Epiregulin ( EREG ) with real time quantitative PCR .
Thus , mutations resulting in truncated proteins may lead to a higher AdverseOutcomerisk of RCC in VHL patients .
However , only 102 of the 215 randomized patients ( 47.4 % ) had Cancersufficient tumor samples for HRG mRNA measurement .
Oncogenic BRAF mutations are found in Cancerseveral tumor types , including melanomas and colorectal cancers .
PATIENTS AND METHODS : Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with Cancerlocalized breast cancer .
CONCLUSIONS : Our findings suggest that reappraisal of clinical treatment approaches for patients with Cancerlocalized melanoma harboring tumors with BRAF mutation might be warranted .
These results suggest that Cancerconventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR gamma rearrangement .
For comparison , we analyzed 13 epithelioid hemangiomas , five Cancerepithelioid angiosarcomas , and four epithelioid sarcoma like EHE .
BACKGROUND : Recently , TERT promoter mutations were identified at high frequencies in Cancercutaneous melanoma tumor samples and cell lines .
RESULTS : We identified mutations that affected amino acid 132 of IDH1 in more than 70 % of WHO grade II and III Cancerastrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions .
Because the chromosomal translocation t ( X ; 18 ) has been observed repeatedly in Cancermany synovial sarcomas , it has been heralded as a diagnostic hallmark of synovial sarcoma .
Patients with p53 gene mutations were found to have an aggressive form of DiseaseB-CLL disease characterized by advanced Rai stage , rapid lymphocyte doubling time ( LDT ) , and resistance to chemotherapy .
The genomic events responsible for the pathogenesis of relapsed Canceradult B-lymphoblastic leukemia ( B-ALL ) are not yet clear .
Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or Cancerrenal-cell cancer .
Lynch syndrome ( LS ) is caused by germline mutations in mismatch repair ( MMR ) genes , resulting in Cancermicrosatellite-unstable tumours .
Of note , less than 2 % of Cancerneuroblastoma tumors have a TP53 mutation at diagnosis .
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , Cancerchronic myelomonocytic leukemia ( CMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
Malignant peripheral nerve sheath tumors ( MPNSTs ) are highly Canceraggressive sarcomas that develop sporadically or in neurofibromatosis type 1 ( NF1 ) patients .
Tissue microarray analysis using interphase FISH indicated that hemizygous PTEN losses were present in 42/107 ( 39 % ) of Cancerprostatic adenocarcinomas , with a homozygous PTEN deletion observed in 5/107 ( 5 % ) tumours .
There were anecdotal responses among patients with pleomorphic xanthoastrocytoma , Canceranaplastic thyroid cancer , cholangiocarcinoma , salivary-duct cancer , ovarian cancer , and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab .
In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions , PJS is associated with an AdverseOutcomeincreased risk of tumours at multiple sites .
PURPOSE : This is a noncomparative , randomized , phase II trial of preoperative taxane-anthracycline in combination with trastuzumab , lapatinib , or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive , stage II to CancerIIIA operable breast cancer .
In other histological types , we observed 8 mutations in 7 out of 48 patients ( 15 % ) , 1 mutation in 1 of 6 Canceroncocytoma , 3 mutations in 2 of 7 chromophobe RCC , 2 mutations in 2 of 30 papillary RCC , no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC .
EXPERIMENTAL DESIGN : In the present study , we investigated , both in vitro and in vivo , the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and Cancerorthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors .
Here we demonstrate that inducible expression of the most common HER2 mutant ( HER2 ( YVMA ) ) in mouse lung epithelium causes Cancerinvasive adenosquamous carcinomas restricted to proximal and distal bronchioles .
The mutation analysis may be a useful tool to differentiate particularly between cell rich diffuse granulosa cell tumors and mitotically Canceractive sex cord-stromal tumors .
PURPOSE : Identifying Cancerrectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy .
We evaluated MGMT protein expression in 53 Cancerprimary glioblastomas by the immunohistochemistry ( IHC ) and analyzed the correlation between results of immunostaining and patient outcomes .
Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and isocitrate dehydrogenase 2 ( IDH2 ) occur in most grade 2 and 3 gliomas , secondary glioblastomas , and a subset of Canceracute myelogenous leukemias but have not been detected in other tumor types .
INTRODUCTION : CancerAdvanced stage squamous cell carcinoma of the head and neck carries an overall poor prognosis , and survivorship gains have remained relatively stagnant compared to other malignancies due to its complex tumor biology and lack of proven effective targeting agents .
Furthermore , Cancerhigh EPHB4 tumor levels were associated with decreased median overall survival ( 16 months vs 48 , Log-rank p = 0.012 ) .
BACKGROUND : There have been conflicting data regarding the prevalence and clinicopathological characteristics of BRAF and NRAS mutations in Cancerprimary cutaneous melanoma .
The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the Cancercorresponding pretreatment tumor .
CONCLUSIONS : FGFR1 dependency is frequent across Cancervarious lung cancer histologies , and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN .
We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia ( AML ) , chronic myelomonocytic leukemia ( CancerCMML )/atypical chronic myelogenous leukemia ( aCML ) , myelodysplastic syndrome ( MDS ) , B-lineage acute lymphoblastic leukemia ( ALL ) , T-cell ALL , and chronic lymphocytic leukemia ( CLL ) .
BACKGROUND : CancerMixed fibrolamellar hepatocellular carcinoma ( mFL-HCC ) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components , represents up to 25 % of cases of FL-HCC , and has been associated with worse prognosis .
BACKGROUND : Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in Diseaseleukaemia pathogenesis , including RAS mutation ( RASmut ) in acute myeloid leukaemia ( AML ) , which has been associated with intra-uterine chemical exposures .
CONCLUSIONS : Ponatinib was highly active in heavily pretreated patients with CancerPh positive leukemias with resistance to tyrosine kinase inhibitors , including patients with the BCR-ABL T315I mutation , other mutations , or no mutations .
We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and Cancermucosal melanomas .
METHODS : The methylation status of five DNA damage repair genes ( CHFR , FANCF , MGMT , MLH1 , and RASSF1A ) was detected by nested methylation specific PCR in 102 Cancerparaffin embedded gastric cancer samples .
Here we show that preclinical models of Cancersynovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI and SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2 , the catalytic subunit of PRC2 .
A recent randomized EORTC phase III trial , comparing two doses of imatinib in patients with Canceradvanced gastrointestinal stromal tumours ( GISTs ) , reported dose dependency for progression-free survival .
RESULTS : pRB was overexpressed in pancreatic ductal adenocarcinomas but was hardly detectable in Cancerother pancreatic malignancies , chronic pancreatitis , or nontransformed human pancreatic tissue .
In ARIEL2 Part 1 , patients with recurrent , platinum sensitive , Cancerhigh-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis : BRCA mutant ( deleterious germline or somatic ) , BRCA wild-type and LOH high ( LOH high group ) , or BRCA wild-type and LOH low ( LOH low group ) .
Multivariable analysis distinguished CALR (-) ASXL1 ( + ) mutational status as the most AdverseOutcomesignificant risk factor for survival : HR 3.7 vs 2.8 for age > 65 years vs 2.7 for unfavorable karyotype .
Three patients experienced grade 3/4 Diseasepneumonitis .
We show that mice expressing S47 in homozygous or heterozygous form are susceptible to Cancerspontaneous cancers of diverse histological types .
Again , the test for interaction ( p = 0.46 ) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. CONCLUSION : This meta-analysis demonstrates no significant difference between KRAS G13D and Cancerother KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC .
p16 expression was determined in a subset of 26 Canceroropharynx tumors by immunohistochemistry .
BACKGROUND : CancerSquamous cell lung carcinomas account for approximately 25 % of new lung carcinoma cases and 40,000 deaths per year in the United States .
We report that TG101348 , a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM , shows therapeutic efficacy in a murine model of Diseasemyeloproliferative disease induced by the JAK2V617F mutation .
This work identifies a novel genetic marker for increased AdverseOutcomeheritable risk of melanoma .
BRAF fusions included 3 % ( 14/531 ) of melanomas ; 2 % ( 15/701 ) of gliomas ; 1.0 % ( 3/294 ) of thyroid cancers ; 0.3 % ( 3/1 ,062 ) pancreatic carcinomas ; 0.2 % ( 8/4 ,013 ) Cancernonsmall-cell lung cancers and 0.2 % ( 4/2 ,154 ) of colorectal cancers , and were enriched in pilocytic ( 30 % ) vs. nonpilocytic gliomas ( 1 % ; p < 0.0001 ) , Spitzoid ( 75 % ) vs. nonSpitzoid melanomas ( 1 % ; p = 0.0001 ) , acinar ( 67 % ) vs. nonacinar pancreatic cancers ( < 1 % ; p < 0.0001 ) and papillary ( 3 % ) vs. nonpapillary thyroid cancers ( 0 % ; p < 0.03 ) .
Chronic Myeloid Leukemia ( CML ) is a Diseaseclonal disease characterized by the presence of the Philadelphia ( Ph+ ) chromosome and its oncogenic product , BCR-ABL , a constitutively active tyrosine kinase , that is present in > 90 % of the patients .
Age at first manifestation of VHL disease was significantly earlier ( P = 0.001 ) , and age related risks of Cancerretinal angiomas and RCC were higher ( P = 0.022 and P = 0.0008 , respectively ) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product ( pVHL ) .
CancerFibrolamellar hepatocellular carcinoma ( FL-HCC ) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis .
This may reflect the tendency for patients with SYT-SSX1 tumors to present more often with Diseasemetastatic disease ( P = 0.05 ) .
We identified inactivating biallelic SMARCA4 mutations in 100 % of the 12 CancerSCCOHT tumors examined .
CancerFGFR1 expressing luminal A cancers showed a similar outcome as luminal B cancers .
Our aim was to analyse the Cancerantimyeloma activity of BET inhibitors on U266 cells .
METHODS : Patients with CancerHER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine ( 2,500 mg/m ( 2 ) body-surface area on days 1 through 14 [ 1,250 mg/m ( 2 ) semi-daily ] ) alone or with continuation of trastuzumab ( 6 mg/kg body weight ) in 3-week cycles .
We present the case of a patient with a Cancerleft frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration .
MATERIALS AND METHODS : In this descriptive-analytic , cross-sectional study , paraffin embedded tissues of patients with definitive pathologic diagnosis of Mullerian and Cancernon Mullerian tumors were selected .
In a patient who had Cancermetastatic anaplastic lymphoma kinase ( ALK )-rearranged lung cancer , resistance to crizotinib developed because of a mutation in the ALK kinase domain .
In the cohort with DiseaseErdheim-Chester disease or Langerhans '-cell histiocytosis , the response rate was 43 % ( 95 % CI , 18 to 71 ) ; the median treatment duration was 5.9 months ( range , 0.6 to 18.6 ) , and no patients had disease progression during therapy .
Kaplan-Meier analysis of 39 patients with Cancerlocalized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 ( P = 0.03 by multivariate analysis ; relative risk , 3.0 ) .
In addition , we have stably expressed the HPV oncogenes E6 and E7 in Cancercetuximab sensitive cancer cell lines to specifically investigate their role in the antibody response .
Our biochemical and in vivo data provide the preclinical rationale for fast tracking the development of this agent in children with relapsed and Cancerrefractory ALK-mutant neuroblastoma .
Here , we explore the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with Cancermetastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial .
CancerHigh-risk neuroblastomas are rapidly progressive ; even with intensive myeloablative chemotherapy , relapse is common and almost uniformly fatal .
We classified patients into those with CancerBAP1-mutant tumours and those with tumours exclusively mutated for PBRM1 ( PBRM1-mutant ) .
773 Cancerprimary tumour samples had sufficient quality DNA and were included in mutation frequency analyses ; mass spectrometry genotyping of tumour samples for KRAS , BRAF , NRAS , and PIK3CA was done centrally .
bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all Cancerother brain tumors ( P < .001 ) .
Granulosa cell tumors of the ovary represent ~ 5 % of Cancermalignant ovarian cancers .
Recently , gain-of-function mutations in exon 18 ( activation loop ) and exon 12 ( juxtamembrane domain ) of the PDGFRA were identified in Cancersuch tumors .
METHODS : Twenty Cancersporadic adrenocortical cancers ( ACCs ) and five normal adrenal tissue samples were available for analysis .
This phase II study determined the activity of salirasib in patients with Canceradvanced lung adenocarcinomas with KRAS mutations .
The aim of this study was to establish Cancernew biliary tract carcinoma ( BTC ) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy .
Additionally , there is evidence that temozolomide may be more effective in eradicating CancerGBM cancer cells with PTEN loss and hence , level the outcomes between the PTEN retained and loss groups .
METHODS : HERACLES was a proof-of-concept , multicentre , open-label , phase 2 trial done at four CancerItalian academic cancer centres .
In conclusion , TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with Diseasemetastatic breast disease to tamoxifen therapy .
Doxorubicin treated p53 mutant tumors failed to arrest proliferation , leading to abnormal mitoses and cell death , whereas Cancerp53 wild-type tumors arrested , avoiding mitotic catastrophe .
We have recently shown that genotypes of the single nucleotide polymorphism ( SNP ) T393C in the gene GNAS1 are associated with survival of patients suffering from bladder , renal cell and Cancercolorectal carcinoma .
CancerChildhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia ( BCP-ALL ) has an unfavorable outcome and shows high frequency of IKZF1 deletions .
Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas ( 28 % vs. 31 % , P = 0.6 ) , including clear cell , endometrioid , and Cancercarcinosarcoma .
This phase II , open-label , single-arm study explored afatinib activity in human epidermal growth factor receptor 2 ( CancerHER2 )-positive breast cancer patients progressing after trastuzumab treatment .
Somatic mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) were recently demonstrated in acute myeloid leukemia ( AML ) , but their prevalence and prognostic impact remain to be explored in large extensively characterized AML series , and also in Cancervarious other hematologic malignancies .
EPAS1 expression was inversely associated with Cancerhigh tumor grade ( P = 0.0017 ) and obesity ( body mass index > or = 30 kg/m2 ) ( P = 0.039 ) .
Mutation and loss of Diseasealpha-thalassemia and mental retardation syndrome X linked ( ATRX ) expression has been described in anaplastic gliomas .
Furthermore , we demonstrated that a Cancernon small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth , as treatment of this cell line either with FGFR1 specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition .
BACKGROUND : Biallelic von Hippel-Lindau ( VHL ) gene defects , a rate limiting event in the carcinogenesis , occur in approximately 75 % of Cancersporadic clear-cell Renal Cell Carcinoma ( RCC ) .
This study examined associations between functional variants in ABCB1 , ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian and Cancerprimary peritoneal cancer ( EOC and PPC ) following platinum and taxane based chemotherapy .
Two granulosa cell tumor derived cell lines , COV434 and KGN , three Cancerjuvenile granulosa cell tumors and control tissues were also examined .
To date , most SCLC studies have evaluated patients with surgically Diseaseresectable disease .
PURPOSE : To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 ( FGFR1 ) amplification in patients with surgically Cancerresected squamous cell carcinoma of the lung ( SCCL ) and the association between smoking and FGFR1 amplification .
Thirty-one percent of Cancerprimary HNSCC tumors expressed FGFR1 mRNA , 18 % exhibited FGFR1 CNG , 35 % of amplified tumors were also positive for FGFR1 mRNA .
Inhibition of ALK activity resulted in Cancersustained tumor regression in the xenotransplant tumor model .
Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways , highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease.SIGNIFICANCE : We performed next generation sequencing of Ewing sarcoma , a Cancerpediatric cancer involving bone , characterized by expression of EWS-ETS fusions .
In the validation data set , which included 314 patients , the rate of 5-year disease-free survival was lower among the 38 patients ( 12.1 % ) with CancerCDX2 protein negative colon cancers than among the 276 ( 87.9 % ) with CDX2 protein positive colon cancers ( hazard ratio , 2.42 ; 95 % CI , 1.36 to 4.29 ; P = 0.003 ) .
Dermatofibrosarcoma protuberans ( DFSP ) is an Canceraggressive PDGFB dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences .
PATIENTS AND METHODS : Forty patients with Cancermucinous appendiceal tumors and PMP were clinically eligible and had evaluable tumor samples obtained after CRS and HIPEC .
These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for CancerALK positive neuroblastoma patients alone or in combination with other treatments .
VPA inhibited the growth of CancerUM tumors in vivo .
Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with CancerSYT-SSX1 tumors , but the study groups were too limited to be conclusive .
We show that inhibition of EZH2 has potent effects on the growth of both wild-type and CancerEZH2 mutant human melanoma in vitro particularly in cell lines harboring the EZH2Y646 activating mutation .
This study examines the clinical impact of PTEN genomic deletions using fluorescence in situ hybridisation ( FISH ) analysis of 107 Cancerprostate cancers , with follow-up information covering a period of up to 10 years .
None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with Cancersplenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias .
VHL disease displays marked variation in expression and the presence of Cancerpheochromocytoma has been linked to missense VHL mutations .
Of 17 patients with CancerPD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P = 0.006 ) .
A total of 122 patients with CancerBRAF V600 mutation positive cancer were treated , including 27 patients with colorectal cancer who received vemurafenib and cetuximab .
Triple negative breast cancer ( TNBC ) is currently the Canceronly major breast tumor subtype without effective targeted therapy and , as a consequence , in general has a poor outcome .
Notably aggressive subgroups ( CancerR+M tumors and WHO grade III ) shared a large set of differentially expressed genes ( n = 332 ; p < 0.01 , FC > 1.25 ) .
Clinically , ETV4 overexpression was significantly correlated with Gleason score ( P = 0.045 ) and Cancerpathological tumor stage ( P = 0.041 ) .
In this 3 +3 phase I study , patients with BRAF ( CancerV600E )-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib .
More than 85 % of Ewing 's sarcoma and Cancerperipheral neuroectodermal tumor present a specific t ( 11 ; 22 ) ( q24 ; q12 ) balanced translocation , resulting in the production of a novel chimerical EWS and FLI -1 message .
The overexpression of HIF-1alpha protein has been reported to be associated with a worse prognosis in Cancervarious cancers .
Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group : skin or eye toxicity ( 62 [ 19 % ] of 325 included in safety analyses vs six [ 2 % ] of 325 ) , diarrhoea ( 15 [ 5 % ] vs four [ 1 % ] ) , hypomagnesaemia ( 40 [ 12 % ] vs 12 [ 4 % ] ) , Diseasehypokalaemia ( 33 [ 10 % ] vs 23 [ 7 % ] ) , and dehydration ( 16 [ 5 % ] vs seven [ 2 % ] ) .
Since activated RAS induces cyclooxygenase-2 ( cox-2 ) expression in Cancerother tumor models , we tested a role for cox-2 in mutant RAS containing MM cells .
METHODS : Adults with Canceruntreated metastatic adenocarcinoma of the pancreas were randomised ( 1:1 ) to receive intravenous gemcitabine 1000 mg/m ( 2 ) ( weekly x 7 for 8 weeks , then days 1 , 8 and 15 of 28-day cycles ) plus trametinib or placebo 2mg daily .
A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced Cancerunresectable melanoma arising from acral , mucosal , and chronically sun damaged sites .
A 53-year-old man with metastatic melanoma and dialysis dependent end stage renal failure was treated safely with Vemurafenib for a CancerBRAF V600K mutation positive melanoma and the case was reported elsewhere .
Subgroup analyses confirmed the AdverseOutcomepoor outcomes in BRCA2 patients , whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup .
Here , we test the hypothesis that the KRAS variant can act as a biomarker of outcome in Cancerepithelial ovarian cancer ( EOC ) , and investigate the cause of altered outcome in KRAS variant positive EOC patients .
It has recently been reported that 95-97 % of Canceradult granulosa cell tumors carry a unique somatic mutation in the FOXL2 gene .
PTEN : Cancerhamartoma tumor syndrome ( PHTS ) is a group of syndromes caused by mutations in PTEN .
A comparative analysis of driver genes revealed that the mutation profile of D-MGC was similar to that of Cancerintestinal-type gastric cancer , whereas U-MGC was a distinct entity , harbouring a different mutational profile to intestinal- and diffuse-type gastric cancers .
METHODS : We conducted a phase 3 , open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or Cancermetastatic ALK positive lung cancer who had received one prior platinum based regimen .
PATIENTS AND METHODS : Gene copy number of FGFR1 was investigated in Cancermicroarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available .
Of note , the median survival was only 12.2 months ( 95 % CI , 9.1 to 32.5 months ) in patients with Diseaseadvanced-stage disease .
OBJECTIVES : The aim of the study was to assess whether the genetic polymorphisms were associated with the tumor response in patients treated with platinum based neoadjuvant chemotherapy ( NAC ) for Cancerbulky cervical cancer .
We systematically investigated PD-1 and PD-L1 expression patterns in the Cancerpoor-prognosis tumor entity high-grade serous ovarian carcinoma .
Patients with Cancerstage II-III cancer who received chemotherapy and had large HSP110 T ( 17 ) deletions ( > = 5 bp ; 18 of 77 patients , 23.4 % ) had longer times of relapse-free survival than patients with small or no deletions ( < = 4 bp ; 59 of 77 patients , 76.6 % ) in multivariate analysis ( hazard ratio , 0.16 ; 95 % confidence interval , 0.012-0 .8 ; P = .03 ) .
CancerCutaneous squamous-cell carcinomas ( the majority , keratoacanthoma type ) were diagnosed in 26 % of patients .
PATIENTS AND METHODS : We determined betaIotaIotaIota-tubulin expression in 85 breast cancers , including 41 Cancerlocalized breast cancers treated with primary surgery and 44 treated with neoadjuvant chemotherapy before surgery .
PJS with germline mutations in LKB1 and STK11 are at a very high relative and AdverseOutcomeabsolute risk of multiple gastrointestinal and nongastrointestinal cancers .
We suggest that olaparib would be an appropriate agent for treating Cancerrefractory ATM mutant lymphoid tumors .
Patients with PJS should be offered surveillance from childhood in order to prevent AdverseOutcomemorbidity and reduce mortality .
RESULTS : In a cohort of 144 metastatic melanoma patients we found that patients with CancerN-RAS mutant melanoma had a worse prognosis .
Among these were breast cancer cell lines , with triple negative breast cancer cell lines being more sensitive than cell lines from Cancerother breast cancer subtypes .
Little is known about the sensitivity of subtypes of CancerHER2 mutant lung cancers to targeted agents .
Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while , paradoxically , anti-EGFR antibodies are more effective in colon and head and Cancerneck cancers where EGFR mutations occur less frequently .
Kinase activity has been implicated in the pathophysiology of many tumors , including Cancersmall-cell lung carcinoma ( SCLC ) .
Activating gene rearrangements of anaplastic lymphoma kinase ( ALK ) have been identified as driver mutations in non-small-cell lung cancer , Cancerinflammatory myofibroblastic tumors , and other cancers .
BACKGROUND : In patients with melanoma , ipilimumab ( an antibody against cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] ) prolongs overall survival , and nivolumab ( an antibody against the programmed death 1 [ PD-1 ] receptor ) produced Cancerdurable tumor regression in a phase 1 trial .
Neoantigen prediction bMMRD GBM was compared with Cancerresponsive adult cancers from multiple tissues .
OBJECTIVES : We investigated the relationship between BRCA1 protein expression by immunohistochemistry ( IHC ) and clinical outcome following platinum and platinum and taxane chemotherapy in Cancersporadic epithelial ovarian cancer ( EOC ) .
The majority of uterine sarcomas are leiomyosarcoma and Cancerendometrial stromal sarcoma ( ESS ) .
Adult women with confirmed advanced and Cancermetastatic HER2 positive breast cancer were eligible .
These data indicate that in Cancerthyroid cancer , radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions , whereas in sporadic forms of the disease , effectors along the same pathway are activated predominantly by point mutations .
METHODS : We immunohistochemically investigated the expression of Aurora-A in biopsy specimens of Canceruntreated primary tumors of 78 patients with ESCC and determined the relationship between Aurora-A levels and patient responses to CRT , which consisted of 5-fluorouracil plus cisplatin and 40Gy of radiation .
Poly ( ADP-ribose ) polymerase ( PARP ) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize CancerATM deficient tumor cells to killing .
One member has developed Diseaseacute myeloid leukaemia ( AML ) .
In CancerER+ tumors , the HR for high versus low Ki-67 was similar and significant ( HR = 1.51 , 95 % CI 1.25-1 .81 , P < 0.0001 ) .
RESULTS : After a median follow-up of 48 months , patients with Cancerlocalized melanomas with BRAF-mutant melanomas exhibited poorer disease-free survival than those with BRAF-wt genotype ( hazard ratio 2.2 , 95 % confidence interval 1.1-4 .3 ) even after adjustment for Breslow thickness , tumor ulceration , location , age , sex , and tumor mitotic rate .
CONCLUSIONS : Among patients with Canceradvanced melanoma harboring KIT alterations , treatment with imatinib mesylate results in significant clinical responses in a subset of patients .
These patients with progressive or Diseaserecurrent metastatic disease experienced relief from their symptoms and prolonged survival with no significant toxicity observed .
RESULTS : Despite the very high-mutational background caused by UV exposure , 23 candidate drivers were identified , including the Cancerwell-known cancer associated genes TP53 , CDKN2A , NOTCH1 , AJUBA , HRAS , CASP8 , FAT1 , and KMT2C ( MLL3 ) .
MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom 's macroglobulinemia or non IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma , Cancermarginal-zone lymphoma , or IgM monoclonal gammopathy of unknown significance .
The prognostic relevance of FLT3 D835 and I836 mutations ( FLT3-TKD ) in cytogenetically Cancernormal acute myeloid leukemia ( CN-AML ) remains to be established .
These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this Diseasechallenging disease .
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of Diseasehuman diseases , which provides neoteric insights into disease etiology .
MGMT expression was directly correlated with treatment response in 21 patients who had Canceravailable tumor tissue and response data .
Most importantly , PF-06463922 induces Cancercomplete tumor regression in both crizotinib resistant and crizotinib sensitive xenograft mouse models of neuroblastoma , as well as in patient derived xenografts harboring the crizotinib resistant F1174L or F1245C mutations .
None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant , including 38 patients with splenic marginal-zone lymphomas or Cancerunclassifiable splenic lymphomas or leukemias .
NAPRT1 specific immunohistochemical or DNA methylation assays can be used on Cancerarchival formalin paraffin embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid .
Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract , mucocutaneous pigmentations , and an AdverseOutcomeincreased risk of cancer in the GI tract and at extraintestinal sites .
The Cancersingle medulloblastoma with a mutation was a recurrent tumor that also possessed a p53 mutation .
These data suggest that persistent EGFR signaling is required for tumor maintenance in Cancerhuman lung adenocarcinomas expressing EGFR mutants .
The Sonic Hedgehog ( Shh ) pathway drives a subset of medulloblastomas , a Cancermalignant neuroectodermal brain cancer , and other cancers .
BACKGROUND : The aim of this study was to investigate the patterns of epidermal growth factor receptor ( EGFR ) overexpression , EGFR gene amplification , and the presence of activating mutations in the tyrosine kinase domain of this gene in Cancersquamous cell carcinomas and adenocarcinomas and adenosquamous carcinomas of the uterine cervix .
In 28 patients with BRAF-mutant non melanoma solid tumours , apparent antitumour activity was noted in a gastrointestinal stromal tumour , Cancerpapillary thyroid cancers , non-small-cell lung cancer , ovarian cancer , and colorectal cancer .
In vivo treatment of DFSP105 with PD-0332991 ( 150 mg/kg ) inhibited xenograft growth in mice , in comparison with imatinib treated or Cancer-untreated tumors .
Ewing sarcoma and primitive neuroectodermal tumor ( EWS and PNET ) is a diagnostically Cancerchallenging malignant round cell tumor with signature translocations involving the EWS gene .
If CancerER positive tumors were stratified according to their AIB1 amplification status , there was a significant worse disease specific survival in cases showing AIB1 amplification ( p = 0.0017 ) .
CONCLUSIONS : Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy , with rapid and Cancerdeep tumor regression in a substantial proportion of patients .
We present a patient with CancerHER2 mutant lung cancer with a 12 base pair insertion YVMA ( p.A775 _ G776insYVMA ) , who had a long natural history and durable partial response to afatinib .