tbuckley/cabot-search huggingface dataset:
Identification and validation of a 24-gene expression signature for subtype classification of medulloblastoma.
Authors: Qinghua Xu, Qifeng WANG, Jinying Chen, Chengshu Chen, Yifeng Sun, Lei Chen, Xiang Du
Journal: Journal of Clinical Oncology (2018)

10553 Background: Medulloblastoma is the most common malignant brain tumor in children accounting for about 10% of all pediatric cancer deaths. According to the 2016 WHO Classification, four molecular subtypes of medulloblastoma including WNT, SHH, Group 3 and Group 4 were characterized by high-throughput gene expression profiling. These molecular subtypes display distinct clinical, demographic and genetic features that are associated with prognostic and therapeutic differences. Because it is currently impractical to perform microarray analysis in clinical settings, distinguishing the four molecular subgroups of medulloblastoma in the daily treatment of patients, as well in the setting of clinical trials, remains an important challenge. Methods: Three medulloblastoma microarray datasets were curated to perform integrative analysis. To identify a reliable biomarker, a training - validating approach were adopted in this study. The gene expression profiles of 103 samples were selected as a training set for signature identification. Additional 358 samples were used for signature validation.The Gene Ontology and KEGG pathway analysis were performed to reveal the biological features of candidate genes. Results: A 24-gene expression signature derived from the training set was strongly associated with the molecular subtypes of medulloblastoma. The 24-gene expression signature was validated in 8 WNT, 61 SHH, 62 Group 3 and 227 Group 4 samples. With the 24-gene expression signature, 8 samples were classified as WNT, 63 as SHH, 73 as Group 3 and 214 as Group 4. The gene expression-based assignments reached a 95.5% overall agreement with the reference diagnoses (342 of 358; 95% CI: 0.928 to 0.974). Sensitivity ranged from 94% to 100%, while specificity ranged from 96% to 100%. The functional enrichment analysis showed that 24 genes were significantly associated with signal transduction and WNT signaling pathway. Conclusions: A 24-gene expression signature that could accurately discriminate molecular subtypes of medulloblastoma was identified in this study. Our results may prompt further development of this gene expression signature into a molecular assay amenable to routine clinical practice.
What is the role of the decrease in M-protein after the first cycle in patient with multiple myeloma?
Authors: Mehmet Turgut, Elif Akyazı, Engin Kelkitli, Memis Hilmi Atay, Bahiddin Yilmaz
Journal: Journal of Clinical Oncology (2016)

e19502 Background: There are limited data about whether the role of the decrease in M protein after he first cycle is independent prognostic value in newly diagnosis multiple myeloma (MM). Our aim is to investigate the association of the M protein decrease in the first cycle with response rates. Methods: In this study we included 30 patients diagnosed as multiple myeloma according to the international working group between January 2010 and December 2015. We retrospectively analyzed patients with newly diagnosed MM (n = 30). The demographic data of patients were recorded. M protein level were measured at the diagnosis and after the first dose. The amount of reduction in M protein were recorded. Response rates were recorded after the first cure. The amount of the decrease of M protein were compared by the response rates. Results: 8 patients were women (25.8%), 22 were males (74.2%), mean age was 66 (SS:8.3) between 49 and 81. Response analysis of 30 patients was done after treatment according to IMWG criteria of response. 15 patients were treated with VAD regimen as first line, and other 15 pateints were treated with bortezomib containing regimen as first line. Median decrease in M protein was 16,2 gr/dl in patients with VAD arm, and 29,6 gr/dl in patients with bortezomib arm. When we investigate response rates ; complete response (CR) in 8 (25,8%) patients, very good partial response (VGPR) in 16 (51,6%) patients, partial response (PR) in 5 (12,9%) patients, and progressive disease (PD) in 1 (3,2%) patients were observed. Relationship between decrease rate in M protein and response rates were statistically significant in both VAD arm and bortezomib arm (p = 0.023) Conclusions: Nowadays different parameters are used for estimating response rate and prognosis in patients diagnosed as multiple myeloma. Some of these parameters are ISS, comorbid conditions and cytogenetics . Our study showed that decrease rate in M protein after first course of treatment can be used to estimate prognosis and response to treatment. But multicenter studies with large patient population should be done.
Lung cancer: EGFR-ALK mutation in the high lands.
Authors: Leonardo David Villacrés, Nelson Villarroel, Pablo Moreno, Edison A. Carrasco, José Castillo, María José Muñoz, Henry Caballero, Tannia Soria
Journal: Journal of Clinical Oncology (2018)

e24248 Background: It has been shown that oxygen is a driver of damage forming free radicals, at higher areas of altitude the risk of developing lung cancer decreases, the primary endpoint was to identify the incidence of EGFR-ALK mutation in the high lands and as a secondary endpoint was to determine the relationship among a pulmonary lobe location, EGFR-ALK mutation and tobacco use. Methods: All patients with lung cancer living at an altitude between 2500( meters above sea level) masl to 3000 masl treated at the Hospital Solon Espinosa Ayala
Incidence of soft tissue sarcoma in China.
Authors: Rongshou Zheng, Siwei Zhang, Hongmei Zeng, Wanqing Chen
Journal: Journal of Clinical Oncology (2018)

e23560 Background: Soft tissue sarcoma (STSs) may arise in various organs and those are rare malignant tumors with different heterogeneous. The incidence of STSs and non-gastrointestinal stromal sarcoma (non-GISTs) were estimated to provide valuable information for cancer control. Methods: Data from 339 cancer registries were selected for this study, covered about 288 243 347 population in China in 2014. The data coded in accordance with the WHO classification of STSs (including GISTs and non-GISTs) were extracted. Incidence rates stratified by area, gender and age groups were calculated and then multiplied by nationwide population to estimate the number of new cases. Results: It was estimated about 43400 new cases of STSs (21400 in male and 22000 in female) in China in 2014. The crude incidence rate was 3.17/105 and the ASRW was 2.38/105. The incidence rates for STSs were higher in urban areas (3.74/105) than in rural areas (2.49/105). It was estimated about 36000 new cases of non-GISTs (17100 in male and 18900 in female) in China in 2014, accounting for about 82.9% of all STSs. The crude incidence rate was 2.63/105 and the ASRW was 2.01/105. The incidence rates of non-GISTs were higher in urban (3.03 /105) than in rural (2.15/105) both in men and in women. ASRW: Age –standardized rate by Segi’s Population Conclusions: STSs and non-GISTs are rare malignancy tumor in China, but remains as unmet medical needs because limited treatments are available. This study provides a systematic analysis on STSs and non-GISTs in China, which may serve as a baseline for the future assessment. Table 1 Estimated number of new cases for STSs and non-GISTs in China in 2014 Areas Sex new cases Incidence ASRW Cumulative rate(0-74) 1/105 1/105 % All areas Both sexes 43400 3.17 2.38 0.25 Male 21400 3.05 2.35 0.25 Female 22000 3.31 2.41 0.24 Urban areas Both sexes 28000 3.74 2.68 0.28 Male 13800 3.63 2.65 0.28 Female 14200 3.85 2.71 0.27 Rural areas Both sexes 15400 2.49 1.99 0.20 Male 7600 2.36 1.96 0.20 Female 7800 2.63 2.02 0.21 non-GISTs All areas Both sexes 36000 2.63 2.01 0.20 Male 17100 2.44 1.92 0.19 Female 18900 2.83 2.10 0.21 Urban areas Both sexes 22700 3.03 2.21 0.22 Male 10700 2.82 2.10 0.21 Female 12000 3.25 2.32 0.23 Rural areas Both sexes 13300 2.15 1.74 0.17 Male 6400 2.00 1.67 0.17 Female 6900 2.32 1.80 0.18
Notch1 mutations in head and neck adenoid cystic carcinoma (HNAdCC) may define an aggressive genetic subtype.
Authors: John F. Deeken, Haresh Mani, Gopal Krishna Bajaj, Arjun Joshi, Moin Ahmad, Ramaswamy K Iyer
Journal: Journal of Clinical Oncology (2016)

e17520 Background: HNAdCC is a rare cancer commonly treated with surgery and adjuvant radiation, and typically displays an indolent course. Overall survival rates at 5 and 15 yrs are 89% and 40%, respectively, but some patients (pts) have a more aggressive phenotype. The molecular landscape of HNAdCC was recently published (Ho 2013) but these authors did not report on prognosis by genomic profile. We profiled pts with an aggressive HDAdCC clinical course to investigate potential prognostic markers. Methods: Pts with HNAdCC who had disease progression less than two years after radiation and whose tumors were resected less than 24 months from study start were identified. Tumors were profiled using the Ion AmpliSeq Oncomine Comprehensive Panel which tests for for 2,530 mutation hotspots in 73 oncogenes, 49 copy number variant targets, and full exon coverage for 26 tumor suppressor genes, as well as 183 breakpoint fusion genes. Results: Three patients were identified. Primary tumors were available for all 3 pts; 2 pts had resected metastatic tumors also available for profiling. The average age at diagnosis was 51 years, median progression free survival after radiation was 11 months, and median overall survival from diagnosis was 20 months. Pt 1 had mutations in Notch1 (Pro2514fs), PIK3CA (Gly1049Arg), and ATM (Arg337His); these identical mutations were found in later resected lung and liver metastases, with no other new genomic alterations detected. Pt 2 had only a mutation in Notch1 (Val1721Gly) in the primary tumor, but that mutation as well as a mutation in FGFR2 (Lys659Glu) and a GOPC(8)-ROS1(35) fusion in a later liver metastases. Pt 3 had a mutation in NRAS(Gln61Lys) in his primary tumor. Conclusions: Tumor profiling of HNAdCC may define aggressive vs indolent genotypes and help influence therapeutic decisions. While Ho found that 13% of HNAdCCs had mutations in Notch1, in our series 2 of 3 pts with an aggressive course had Notch1 driver mutations. HRAS murations have been reported in HNAdCC but this is the first report of an NRAS mutation in this disease.
Characterizing the tumor microenvironment (TME) in primary melanomas using multiplex immunohistochemistry (mIHC).
Authors: Robyn Denise Gartrell, Douglas Kanter Marks, Thomas Hart, Edward Stack, Yan Lu, Camden Esancy, Camille Gerard, Danielle Rose Davari, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Margueritta El Asmar, Zoe Blake, Yichun Fu, Basil Horst, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2017)

9580 Background: Biomarkers are needed in primary melanoma to risk stratify for adjuvant trials. High levels of infiltrating cytotoxic (CD8+) T lymphocytes (CTLs) and low levels of CD68+ macrophages (MΦ) may correlate with prolonged survival but quantification methods are not standardized for clinical practice. HLA-DR is a marker of MΦ activation not expressed by suppressor myeloid cells. A novel pathology technique using mIHC allows for quantitative and spatial analysis of immune cell subsets. Methods: In a pilot set of stage II/III primary melanomas from Columbia University Medical Center (n = 94), clinical follow up is available for 51 cases. 32 had no evidence of recurrence at last follow up (minimum 2 years) while 19 died of melanoma. 5µm slides were stained using Opal multiplexed IHC (mIHC) for DAPI, CD3, CD8, CD68, SOX10, HLA-DR and Ki67. Tumor areas were pre-selected by a dermatopathologist, visualized using Mantra (Perkin Elmer) and analyzed using inForm (Perkin Elmer) and Spotfire (TIBCO). Results: In all patients (n = 94), CTLs are farther from tumor (SOX10+) cells when they are proliferating (Ki67+) (p &lt; 0.0001***), while they are closer to MΦ when they are activated (HLA-DR+) (p = 0.0002***). Next, we evaluated impact on prognosis using disease specific survival (DSS) as an outcome based on median value (n = 51). In this exploratory study no correction for multiple comparisons was made. We find that CTL density correlates with prolonged DSS in tumor (p = 0.0185*) but not in stroma (p = 0.1630 ns). Ratio of density of CD8/CD68+HLA-DR- correlates with DSS in both tumor (p = 0.027*) and stroma (p = 0.017*). Finally, distance from CTLs to HLA-DR- MΦ was significantly greater in non-recurrent melanomas as compared to recurrent ones (p = 0.0167*). Conclusions: HLA-DR expression on MΦ and Ki67 expression on tumor cells correlate with position of CTLs in TME in primary melanoma. CTL density is a favorable prognostic marker while HLA-DR non-expressing MΦ may favor tumor progression. Quantitative mIHC allows for accurate spatial analysis of immune subsets within the TME and the development of novel, more accurate and potentially clinically relevant biomarkers.
Development and temporal validation of a practical prognostic scoring system (ONCOGERIATRIC INDEX -OGI) based on the comprehensive geriatric assessment to predict early death in elderly cancer patients: A 892 patients cohort study.
Authors: Jurema Telles O Lima, Mirella Rebello Bezerra, Maria Julia Gonçalves Mello, José Natal Figueiroa, Anke Bergmann, Zilda Cavalcanti, Raissa Viana, Letícia telles Sales, Luiz Claudio Santos Thuler
Journal: Journal of Clinical Oncology (2018)

10049 Background: Recognizing prognostic factors is important when evaluating elderly people with cancer to decide the appropriate treatment. The Oncogeriatric Index (OGI) was developed to predict early death (in 6 months) among elderly people with cancer, based on the Karnofsky Performance Status Scale, the Mini Nutritional Assessment and the Charlson Comorbidity Index. OBJECTIVES: To temporarily validate the OGI.Methods: We used a prospective cohort of cancer patients aged 60 or + years for GA n 605 (2015-2017) [training set]; 2016–2017: n 291 [validation set]) was performed during a six-month follow-up. Epidemiologic data and CGA (using 12 scales) before oncologic treatment were collected. The outcome was ED (within first 180 days). Cox’s proportional hazards model was used for the selection of prognostic factors. A prognostic score, the Onco Geriatric Index (OGI), was constituted of the number of abnormal CGA scales. Overall survival was estimated using the Kaplan–Meier method, and survival curves were compared using the log rank test. Predictive performance (calibration and discrimination) was determined. Results: There were 41 deaths among the 291 admitted patients. Patients who had three altered scales had 23.5 times higher risk of dying, adjusted for age, primary site of cancer and tumor staging (HR = 23.5, 95% CI 7.0-78.4, p < 0.001); those with two, 6.9 times (HR = 6.8, 95% CI 2.4-40.1, p < 0.001); and those with one, 3.1 fold (HR = 3.1, 95% CI 1.2-7.9, p = 0.020). The numbers of deaths predicted by the OGI were similar to those occurred, as well as a 6-month overlap of survival curves for each of the groups in the derivation and validation cohort, demonstrating that this prognostic model had an adequate predictive performance. Conclusions: Geriatric Index (OGI) is valid to evaluate elderly people with cancer in order to identify those at higher risk for early death.
Inclusion Across the Lifespan
Authors: Marie A. Bernard, Janine A. Clayton, Michael S. Lauer
Journal: JAMA (2018)

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Dysregulation of nuclear factor-kappaB pathway in multiple myeloma patients at diagnosis and relapse.
Authors: Shivali Jasrotia, Ritu Gupta, Sobuhi Iqbal, Atul Sharma, Ashutosh Halder, Lalit Kumar
Journal: Journal of Clinical Oncology (2016)

8050 Background: In multiple myeloma (MM), a variety of genetic events have been described to be associated with disease progression. Besides, the activation of the NF-κB (nuclear factor-kappa B) pathway is suggested of paramount importance for the survival of healthy plasma cells and for MM tumors. The present study hypothesized the possible distinction in the disease biology of new and relapse/progressive MM patients especially in context to dysregulation of NF-κB pathway. Methods: Expression levels of NF-κB pathway genes (NFKB2, NIK, IKB, BCL3, and CCND1) were studied in total bone marrow samples of MM patients using real-time quantitative PCR with SYBRGreen chemistry and fold change values were calculated by comparative ΔΔCT method. Results: Total of 54 newly diagnosed, 14 relapse/progressive patients and 11 healthy controls were included in the study. The median age for newly diagnosed and relapse patients was 57.8 (Range 31-76) and 56.7 (Range 46- 65) years respectively. We found higher expression levels (as fold-change values) of genes in both cohorts of MM patients, however, the difference was non- significant (p > 0.05). In newly diagnosed MM patients, overexpression of NIK and IKB showed a significant association with hemoglobin (p-value = 0.05 and 0.02 respectively) whereas BCL3 and IKB mRNA over expression was significantly associated with serum albumin levels (p = 0.02) and plasma cells percentage (p = 0.04) respectively. Also, overexpression of IKB was found to be associated with International Staging System (ISS) (p = 0.05). On the other hand, in relapse MM patients, CCND1 and NFKB2 showed significant association with hemoglobin (p-value of 0.006 and 0.02 respectively) whereas BCL3 again showed significant association with serum albumin levels (p = 0.04). Conclusions: We suggest that the genetic architecture in new and relapse MM patients is aligned and regulated in a similar way. Also, we might say that certain mutations in the putative genes leads to the constitutive activation of NF-κB pathway by either inhibiting or bypassing the function of the IKB and NIK regulatory complexes. Apparently, there is also a need to further explore the nuclear components that regulate the NF-κB signaling cascade.
Correlation of low CT attenuation and necrotic features of tumor in contrast-enhanced CT with nivolumab response.
Authors: Ryo Ariyasu, Atsushi Horiike, Junji Koyama, Masafumi Saiki, Tomoaki Sonoda, Natsuki Takano, Yosuke Kawashima, Tomoyo Oguri, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Fumiyoshi Ohyanagi, Katsunori Oikado, Makoto Nishio
Journal: Journal of Clinical Oncology (2017)

e23105 Background: Anti-PD1/PD-L1 antibodies, including nivolumab, produce durable responses in non-small cell lung cancer (NSCLC), but the response rate is about 20% in unselected NSCLC. Identifying predictive markers of response is necessary. Although PD-L1 expression may be a potential biomarker, evaluating whole tumors based on a small sample is difficult. Identifying radiographic features of responders can be very useful. We hypothesized that low attenuation on computed tomography (CT), considered to represent necrosis, correlates with nivolumab response. Methods: We retrospectively evaluated contrast-enhanced CT images before treatment and tumor response in 60 patients receiving nivolumab. The largest tumor lesion was characterized in each patient. CT attenuation (CTA) of whole tumor areas was measured; the presence of radiological findings of necrosis (necrotic features), presenting cavitation or ring- or patchy-enhancement in tumors, were assessed. We evaluated the association between CT imaging characteristics and nivolumab response and that between CT imaging characteristics and PD-L1 expression in tumors. Results: Thirty-nine target lesions in lung, 12 in lymph node, and 9 in other organs were chosen. The mean CTA was 58.5 ± 15.3 HU. Necrotic feature were observed in 24 (40%) of 60 lesions.Twenty of 60 lesions (33%) shrank to &gt; 30% with nivolumab treatment. Mean CTA in responding lesions was 48.6 HU, significantly lower than that in nonresponding lesions (63.4 HU) (p &lt; 0.001). The response rate of lesions with/without necrotic features was 45% and 28%, respectively (p = 0.246).Systemic tumor response, assessed by RECIST v1.1, was confirmed in 20 (33%) patients. Mean CTA of target lesions was lower in responders than patients with stable disease or progressive disease (51.4 vs. 62.0 HU, p = 0.011). The systemic response rate of lesions with/without necrotic features was 50% and 25%, respectively (p = 0.081).Mean CTA of target lesions was lower in tumors with high PD-L1 expression than in tumors with low PD-L1 expression (54.8 vs. 64.4 HU, p = 0.045). Conclusions: Low CTA and necrotic features in CT may correlate with nivolumab response. Tumors with low CTA may have high PD-L1 expression.
Detecting KRAS and NRAS resistance mutations in plasma of lung cancer patients.
Authors: Gary Potikyan, Magdalena Falat, Fabienne Duchoud, Matthew Maland, Sanjay Adhikari
Journal: Journal of Clinical Oncology (2017)

e20511 Background: Mutations in KRAS and NRAS have been found in a number of malignancies, particularly metastatic colorectal cancer, lung adenocarcinoma, and thyroid cancer. Several studies have shown that specific mutations in KRAS and NRAS are less likely to respond to anti-EGFR therapies. Several diagnostics have been developed to identify such mutations. However, in a large number of cancer patients, tumor biopsy poses a significant health risk thereby limiting the tissue available for current molecular diagnostics. Non-invasive liquid biopsy diagnostics are revolutionizing cancer treatment selection, patient prognosis, and monitoring. Low abundance circulating tumor DNA (ctDNA) is purified from patient plasma and used as an alternative source of genomic material for detecting tumor mutations. Currently available qPCR kits for detecting RAS mutations have a limited sensitivity and coverage since they are not optimized for liquid biopsy purposes. Methods: We have developed a two-step PCR to qPCR method to identify down to single mutant copies of KRAS or NRAS in ctDNA isolated from plasma. The mutant copies are first enriched by a novel multiplexed formula of primers and wildtype (WT) allele blockers. The mutations are then identified by EntroGen’s RAS Mutation Screening Panel or next generation sequencing (NGS). Synthetic mutant DNA was spiked in a background of WT DNA purified from plasma to yield a range of mutant allelic burden over WT background. The dilutions were analyzed to determine the method’s sensitivity. We subsequently used the method to screen 53 non-small cell lung cancer (NSCLC) patient samples. Results: Our two-step method detects single digit mutant copies of 35 clinically significant KRAS and NRAS mutations. Furthermore, NGS experiments demonstrated the two-step method can enrich mutations more than 52-fold. KRAS 12/13 mutations were identified in 6 out of 53 (11%) NSCLC patients. Conclusions: ctDNA-based liquid biopsy tests have been employed by few laboratories but are generally available only as a service. EntroGen’s platform agnostic liquid biopsy RAS assay provides clinicians the tools necessary to determine cancer treatment and monitor patients using most PCR and qPCR instruments.