tbuckley/cabot-search huggingface dataset:
New biomarkers to predict platinum resistance in ovarian cancer patients.
Authors: Oana Trifanescu, Laurentia Minea Gales, Maria Iuliana Gruia, Bianca Andreea Gusoiu, Florina Torliceanu, Anghel Rodica Maricela
Journal: Journal of Clinical Oncology (2019)

e17085 Background: Epithelial ovarian cancer is the second most common gynecologic malignancy and is characterized by the highest mortality of all gynecological cancers. Despite of initial response, platinum resistance develops and contributes to the poor outcome of advanced stage ovarian cancer patients. The aim of the study was to identify biomarkers helpful in predicting treatment response to platinum salts. Methods: Forty eight patients with advanced ovarian (stage II, III and IV) cancer were prospectively enrolled between 2014 and 2017. All patients underwent surgery followed by platinum-based chemotherapy. Serum reactive oxygen species parameters such as malondialdehyde, ceruloplasmine, and serum VEGF were measured before each cycle of chemotherapy. Results: Mean age at diagnostic was 51.3 +/- 8.1 years, (range 42 - 78). Median follow up was 39 months (range 12-56). Twenty tree percent were platinum resistance. Median progression free survival was 22 months and estimated median overall survival was 84 months, 77% of patients being alive at 3 years. VEGF levels were significantly higher in patients with platinum resistance disease (1210 pg/ml) compare to platinum sensitive (mean VEGF levels 945pg/ml, p = 0.0003). We used a ROC curve to estimate the sensitivity and specificity of VEGF as a predictor to platinum response and find out that the aria under the curve (AUC) was 0.874, p = 0.003, 95% CI 0.734-1 and cut-off value (80% sensibility, 80% specificity) was 1085pg/ml. Malondialdehyde levels were statistically significant higher in patients with platinum resistance disease (mean value 11.1 μmol/100 ml vs. 7.4 μmol/100 ml in platinum sensitive, p = 0.02. The ROC curve for malondialdehyde identify an aria under the curve of 0.818, p = 0.0001 and CI 95% (0.744-0.893) and a cut-off value of 7.74 μmol/100 ml to estimate with 81.3% sensitivity and 64% specificity platinum response validating this bio markers as predicting platinum response. For Ceruloplasmine AUC was 0.706, p = 0.0001, 95% CI (0.617,-0.796). Conclusions: Malondialdehyde, ceruloplasmine and VEGF can estimate with precision the resistance to platinum salts in advanced ovarian cancer patients.
Circulating free DNA as a prognostic biomarker in patients with advanced <i>ALK</i>+ NSCLC treated with alectinib from the global phase III ALEX trial.
Authors: Rafal Dziadziuszko, Solange Peters, Tony S. K. Mok, D. Ross Camidge, Johannes Noé, Malgorzata Nowicka, Walter Bordogna, Peter N. Morcos, Vlatka Smoljanovic, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2019)

9053 Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK inhibitor treatment is poorly understood. Here, we examine the prognostic potential of cfDNA in the phase III ALEX trial of alectinib versus crizotinib in previously untreated patients with advanced ALK+ NSCLC. Methods: Data cutoff was December 1, 2017. Median cfDNA was determined from 276 baseline samples; patients were stratified into ‘≤median’ and ‘ &gt; median’ biomarker-evaluable populations (BEP). Results: Median cfDNA was 11.5ng/mL. Baseline characteristics were mostly balanced between the crizotinib (≤median, n = 72; &gt; median, n = 67) and alectinib (≤median, n = 66; &gt; median n = 71) BEPs. However, the alectinib &gt; median BEP had more active smokers (7.0% vs crizotinib 1.5%), more measurable/non-measurable CNS lesions (47.9% vs 41.8%) and more patients with TP53 short-variant (SV) (44.8% vs 32.8%); the alectinib ≤median BEP had more active smokers (7.6% vs crizotinib 2.8%). Alectinib exposure was not substantially different between relevant BEPs. Higher cfDNA amount was associated with measurable/non-measurable CNS lesions and TP53 SV. Tumor burden positively correlated with normalized cfDNA amount (Pearson correlation 0.204; p &lt; 0.001). Median PFS by investigator in the ≤median BEP was 34.9 months alectinib vs 14.8 crizotinib (HR 0.37, 95% CI 0.22–0.61, p &lt; 0.0001); in the &gt; median BEP it was 14.8 months alectinib vs 8.6 crizotinib (HR 0.43, 95% CI 0.28–0.64, p &lt; 0.0001). Response rates in the ≤median BEP were 82.3% alectinib vs 70.4% crizotinib; in the &gt; median BEP, 70.2% alectinib vs 55.4% crizotinib. Median duration of response in the ≤median BEP was not reached for alectinib vs 21.0 months for crizotinib; in the &gt; median BEP, 33.1 months alectinib vs 7.3 crizotinib. Conclusions: Tumor burden positively correlated with cfDNA amount; patients with ≤median cfDNA at baseline had better prognosis than those with &gt; median cfDNA. Alectinib consistently improved PFS, DOR and ORR versus crizotinib across BEPs, reducing the risk of tumor progression by &gt; 50% compared with crizotinib. Clinical trial information: NCT02075840.
A retrospective series of centralized reviewed GEP MANECs receiving a first-line adenocarcinoma-oriented chemotherapy.
Authors: Francesca Spada, Massimo Milione, Patrick Maisonneuve, Natalie Prinzi, Valeria Smiroldo, Elena Bolzacchini, Carlo Carnaghi, Stefano La Rosa, Carlo Capella, Fausto Sessa, Nicola Fazio
Journal: Journal of Clinical Oncology (2019)

e15695 Background: Mixed adeno-neuroendocrine carcinomas (MANECs) are very rare malignancies. Due to their biological and clinical heterogeneity, there is not a universally shared clinical approach. Methods: We retrospectively analyzed clinical records of 22 patients from 4 Italian referral centers with advanced MANEC of the gastro-entero-pancreatic (GEP) tract who received a first line chemotherapy and were part of a previously published series of 160 patients (M. Milione et al, Endocrine Related Cancer 2018). Surgical specimens were centrally reviewed by a team of 7 expert pathologists. Clinical and biological data were correlated with outcomes. Results: All patients developed distant metastases (32% synchronous, 68% metachronous). Primary sites were colorectal in 13 patients, esophago-gastro-duodenal in 6, and pancreato-biliary in 3. Ki-67 index in the NEC component was ≥55% in 77% of the patients. Three patients (2 colorectal) received neo-adjuvant chemotherapy, 4 adjuvant (2 colorectal), and 2 peri-operative (one colorectal, one pancreas). The most common regimen was adenocarcinoma-oriented (59% fluoropyrimidines /oxaliplatin). Overall, 14% of patients had a partial response (PR) and 18% stable disease (SD). The median OS in the whole cohort was 0.9 years (95% CI 0.3-1.4). It was longer in patients with Ki-67 &lt; 55% in the NEC component (median 2.5 years; 95% CI 0.5-2.5) than in those with Ki-67 ≥ 55% (median 0.9 years; 95% CI 0.3-1.0) (Wilcoxon P =0.10), regardless of the type of therapy. Mutations in either KRAS (codons 12 and 13) or TP53 (exons 5-8) genes performed by NGS were observed in 9 (8 colorectal, one pancreas) out of 19 patients. Only one of them, (colon primary site), experienced SD. Conclusions: This analysis suggested that an adenocarcinoma-oriented regimen could be active as first line chemotherapy in patients with advanced GEP-MANECs especially with Ki-67 index &lt; 55% in the NEC component. Since its descriptive design and various clinical management, this study cannot either suggest a specific therapy or a real impact of chemotherapy on prognosis. However, it produced solid hypotheses for future prospective-interventional studies in selected populations.
Early case ascertainment and prospective multidisciplinary review for management of new melanoma diagnoses within an integrated healthcare system: The Kaiser Permanente Northern California experience.
Authors: Thach-Giao Truong, Kirun Chohan, Angeles Price, Helene B Fevrier, Peter D Peng, Maihgan A Kavanagh, Maris S Jones, Alpana X Soni, Mark A Price, Barry M Rasgon, Basil Adad, Paul A Martin, Javier Rangel, Juraj Kavecansky, Mala N. Reddy, Stephen E. Wang, Lisa J. Herrinton, Tatjana Kolevska, James P Morris, Ching-Kuo Chang
Journal: Journal of Clinical Oncology (2019)

6523 Background: Appropriate surgical treatment of early-stage melanoma yields a high cure rate, but this management can be nuanced. In particular, surgical management, including sentinel lymph node biopsy (SLNB), of thin melanoma (≤1.0mm) is not well-defined. Methods: Biopsies with new melanoma diagnoses were identified electronically and manually reviewed. In a community oncology setting, we organized a review panel of physicians specialized in melanoma from dermatology, medical oncology, nuclear medicine, radiation oncology, and surgical subspecialties (oncology, plastics, head and neck). Patients were assigned to care pathways based on NCCN and ASCO guidelines, including guidance on SLNB for thin melanomas with high-risk features like lymphovascular invasion, high mitotic rate, positive deep margin, and ulceration. These recommendations were documented in the chart and communicated directly to the patients care team. Results: From 11/2016 through 10/2018, our multidisciplinary committee reviewed 3626 patients with new melanoma from 22 sites in our integrated, regional hospital system. Median age was 66 (range 19-99); 60% were male. cT2N0 tumors comprised 7%, cT3 3%, and cT4 2%. Thin melanomas ≤1.0mm represented 71% of cases, of which 34% were ≤0.5mm. SLNB was performed in 9.8% of thin melanomas, and 18% were positive, much higher than historical positive rates of 3-4%. Conclusions: Early case ascertainment and prospective multidisciplinary review in a community oncology setting resulted in increased identification of high-risk thin melanoma, and consequently increased identification of nodal disease through SLNB. Positive SLNB triggers important clinical decision-making regarding need for node dissection versus clinical surveillance, and need for adjuvant therapy, which have been shown to improve survival. This clinical practice structure improved risk-stratification and adherence to national guidelines. We plan to further study the impact of these improvements to melanoma care on disease-free survival and overall survival.
Extracellular vesicles in the tumor microenvironment: old stories, but new tales
Authors: Liu Han, Eric W.-F. Lam, Yu Sun
Journal: Molecular Cancer (2019)

Mammalian cells synthesize and release heterogeneous extracellular vesicles (EVs) which can be generally recognized as subclasses including exosomes, microvesicles (MVs), and apoptotic bodies (ABs), each differing in their biogenesis, composition and biological functions from others. EVs can originate from normal or cancer cells, transfer bioactive cargoes to both adjacent and distant sites, and orchestrate multiple key pathophysiological events such as carcinogenesis and malignant progression. Emerging as key messengers that mediate intercellular communications, EVs are being paid substantial attention in various disciplines including but not limited to cancer biology and immunology. Increasing lines of research advances have revealed the critical role of EVs in the establishment and maintenance of the tumor microenvironment (TME), including sustaining cell proliferation, evading growth suppression, resisting cell death, acquiring genomic instability and reprogramming stromal cell lineages, together contributing to the generation of a functionally remodeled TME. In this article, we present updates on major topics that document how EVs are implicated in proliferative expansion of cancer cells, promotion of drug resistance, reprogramming of metabolic activity, enhancement of metastatic potential, induction of angiogenesis, and escape from immune surveillance. Appropriate and insightful understanding of EVs and their contribution to cancer progression can lead to new avenues in the prevention, diagnosis and treatment of human malignancies in future medicine.
Projecting overall survival data for health-economic models in oncology: Do maturity levels impact uncertainty?
Authors: Stéphane Roze, Nicolas Bertrand, Lauriane Eberst, Isabelle Borget
Journal: Journal of Clinical Oncology (2019)

e18350 Background: A lifetime horizon is recommended for health-economic evaluation of anticancer drugs. If overall survival (OS) data is immature, extrapolation of the Kaplan-Meier (KM) curve using distributions is done to obtain long-term data. Depending on OS maturity, the distribution chosen may impact estimation of life expectancy (LE) and of life years gained (LYG) between treatments. This study aimed to estimate the error (on LE and LYG) induced by the choice of extrapolation distributions, for 2 levels of OS maturity (30% and 50%), as compared to LE and LYG at full maturity. Methods: Fifteen phase 3 trials published between 2013 and 2017 containing OS KM curves were selected if maturity &gt; 70% (Full). To test 2 maturity levels, each KM curve was truncated at 30% and 50%. A 3-step process was performed: 1) KM was digitalized, 2) individual patient-data was reproduced using the Guyot algorithm, and 3) 5 parametric survival distributions were fit using the R-Survival package. For each study, the process was done for each treatment arm and each of the 3 maturity levels on the same time horizon, equal to the maximum follow-up of the study. For each curve, the best distribution was chosen by a board of 2 oncologists and 2 health-economists, based on visual inspection, Akaike/Bayesian Information criteria and external validity. Results: Based on the board review of the 90 KM curves, main chosen distributions were Weibull (33%), Log-logistic (32%) and Log-normal (27%). As compared to LE at full maturity, LE was overestimated in 23% and 40% at 30% and 50% maturity, respectively. Mean absolute error was 0.88 at 30% maturity, and decreased to 2.12 at 50% maturity, i.e. estimation was 2.4 times better from 30% to 50% maturity. On average, at 30% maturity versus full, mean percentage of error in LYG was 126.4% and 62.4% at 50% maturity versus full. Conclusions: The use of immature OS data increases the risk of error when projecting long-term LE. Even marginal gains in OS maturity can be translated in more accurate estimations and guide health-economist in developing models.
Case 10-1964
Authors: Allan I. Sandler, Richard B. Cohen
Journal: New England Journal of Medicine (1964)

Presentation of Case First admission. A seventy-nine-year-old man entered the hospital because of pain in the leg.Six months previously he experienced an episode of pain in the chest with radiation to the left arm. He believed that he had been admitted to another hospital at that time but could recall no details. Two weeks before admission the right leg became cold and painful and did not improve.Physical examination revealed an elderly, confused man. The heart was slightly enlarged, with no murmur or gallop; the lungs were clear. The liver and spleen were not palpable. The prostate gland was . . .
Association between<i>BRCA1</i> and <i>BRCA2</i> mutations and prognosis in women with endometrial carcinoma.
Authors: Aifen Wang, Robert W. Holloway, Lijuan Cui, Yan Sun, Zihan Zhao
Journal: Journal of Clinical Oncology (2019)

e17115 Background: To evaluate the prognosis of BRCA mutation carriers compared to non-carriers and to demonstrate whether BRCA1 and BRCA2 mutation carriers present similar survival patterns among endometrial carcinomas. Methods: This data was from NCI Cancer Genome Atlas endometrial cancer database (TCGA) with pathogenic mutations in BRCA1 (58) or BRCA2 (77) or BRCA1and BRCA2 coexisted mutation (40) and non-mutation (461). We compared clinicopathologic features and prognosis of patients with BRCA1 or BRCA2 or BRCA1and BRCA2 coexisted mutation. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1and BRCA2 as time-varying covariates. Results: We found histologic types of patients with BRCA1 or BRCA2 mutation presented more progressive than non-carriers ( p = 0.029, p= 0.029, respectively). BRCA1 or BRCA2 mutations were detected to be associated with younger patients at diagnosis ( p = 0.036, p = 0.001, respectively). BRCA2 mutation carrier was identified more advanced stage than BRCA non-carriers. Compared to patients with BRCA1 mutation, the body mass index is higher in non-carriers. Before around 100 months survival, BRCA2 mutation carriers had the most favorable overall survival (OS). OS rate of all patients with BRCA1 or BRCA2 mutation was higher than non-carriers. BRCA1 and BRCA2 mutation carriers had similar OS. Around 100 months later, BRCA1 carriers had more favorable OS than patients with BRCA2 mutation, BRCA1 / BRCA2 coexisted mutation and non-carriers ( p &lt; 0.001). Patients with BRCA2 mutation had the most favorable progression-free survival (PFS), following by BRCA1 and BRCA2 coexisted mutation and BRCA2 alteration carriers ( p= 0.011). BRCA non-carriers had the worst PFS and OS all the time. Conclusions: BRCA1 or BRCA2 mutation carriers have favorable overall survival and progression-free survival among patients with endometrial carcinoma. [Table: see text]
Does adding claims to EMR data improve comorbidity burden capture? A Concerto Health AI Definitive Oncology Dataset and Symphony Linkage Study.
Authors: William Bruce Wong, Navdeep Pal, Ning Wu, Li Chen, Daniel Sheinson, Laura Kay Chu
Journal: Journal of Clinical Oncology (2019)

e18186 Background: Current commercially available oncology electronic medical record (EMR) databases typically have limited data on patient comorbidities which may limit the ability to accurately include/exclude these patients or adjust for these factors in health outcomes research. The objective of this study was to investigate the impact of identifying comorbidities using both EMR and claims data. Methods: The Concerto Health AI Definitive Oncology Dataset is a deeply curated cohort of patients (pts) derived from a wide range of oncology practices throughout the United States. Concerto Health AI has a co-exclusive partnership with ASCO CancerLinQ and collects data from multiple other sources. These data were deterministically linked to US Symphony Health’s (SH) Integrated Dataverse, an anonymized, HIPAA-compliant data set. Advanced (stage IIIb/IV) non-small cell lung cancer (aNSCLC) pts with data curated via manual review by nurse practitioners and diagnosed after 2011 were included. Comorbidities within 1 year prior to advanced diagnosis were categorized using the Charlson Comorbidity Index (CCI). The impact of the claims linkage on inclusion/exclusion (I/E) criteria was assessed by applying criteria from the IMpower150 clinical study and exploring changes to survival estimates, as calculated using Kaplan-Meier method. Results: A total of 11,373 aNSCLC pts were identified, of which 7,887 pts were linked to SH. Using only Concerto, 278 pts (3.5%) had a CCI score ≥1, whereas 3,033 pts (38.4%) had a CCI score ≥1 using linked Concerto and SH. After applying I/E criteria from IMpower150 using available data elements from Concerto only, 88 pts were identified matching the trial criteria, with a median survival of 15.8 mths (95% CI: 14.4, 21.0). When leveraging Concerto and SH, 8 (9.1%) more patients were excluded (n = 80) based on comorbidities (6 pts) and oral medications (2 pts), with a median survival of 16.6 mths (95% CI: 14.6, 23.4). Conclusions: The addition of claims to EMR enhanced the ability to identify patient comorbidities given the longer history and broader physician specialty of claims data. Future real-world studies should explore linkages across datasets to better capture comorbidities for patient selection and adjustment.
Non-invasive assessment of chemotherapy-induced peripheral neuropathy using neuromuscular ultrasound in breast cancer patients.
Authors: Thomas Lycan, Alexandra Thomas, Fang-Chi Hsu, Michael Stephen Cartwright, Francis O Walker, Christine Ahn, Omar P Sangueza, Yusuke Shiozawa, Sun Hee Park, Christopher Michael Peters, Edgar Alfonso Romero-Sandoval, Susan Anitra Melin, Steven Sorscher, Katherine Cox Ansley, Glenn Jay Lesser, Roy E. Strowd
Journal: Journal of Clinical Oncology (2019)

e23152 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity for breast cancer patients that leads to early treatment discontinuation and worse outcomes. Neuromuscular ultrasound (NMUS) is a non-invasive assessment of peripheral nerves that has not been studied in taxane CIPN. Methods: This cross-sectional study enrolled breast cancer patients with subjective complaints of CIPN symptoms during or after taxane chemotherapy and compared nerve cross-sectional area (CSA) by NMUS with historical values in 120 healthy adults. Findings were correlated with self-reported symptom scale (EORTC-QLQ CIPN20, range 0-72, higher more severe); nerve conduction studies; and skin biopsies for intraepidermal nerve fiber density (IENF). Results: We evaluated 20 participants (mean 55.4 ± 10.5 yrs) with NMUS at 74 nerve sites after median 3.7 months (IQR 1.0-6.1) since last taxane (paclitaxel 10, docetaxel 8, nab-paclitaxel 2). Participants reported moderate-to-severe CIPN symptoms which were predominantly sensory (19.1 ±4.9, max 32) as opposed to motor (15.6 ±5.8, max 32) or autonomic (3.3 ±1.6, max 8). Sural sensory nerve CSA was 1.2 mm 2 smaller than in historical controls (4.1 vs. 5.3 mm 2 , 2-sample t-test p = 0.005) and decreased with more days from last taxane (Spearman’s r -0.46, p = 0.04). Tibial motor nerve was not significantly different from controls (p = 0.35). Median nerve CSA was enlarged at the distal wrist crease entrapment site (12.5 vs 10.1, p = 0.03). Older age was associated with smaller sural CSA (r = -0.72, p &lt; 0.001). When controlling for age and days from last taxane, for each 1mm 2 decrease in sural CSA, distal IENF reduced by 2.1 nerve/mm 2 (p = 0.04, R 2 = 0.30). Conclusions: NMUS showed expected sensory predominant distal axonopathy in taxane CIPN. Evaluation of nerve CSA by non-invasive NMUS may serve as an objective point-of-care assessment to risk-stratify women with taxane CIPN prior to the development of debilitating symptoms. Clinical trial information: NCT03139435. [Table: see text]
Case 18-1984
Authors: Robert S. Brown, Robert T. McCluskey
Journal: New England Journal of Medicine (1984)

Presentation of CaseA 32-year-old woman was admitted to the hospital because of proteinuria and impaired renal function.There was a history of episodic flank pain and fever in childhood that resolved spontaneously. As a teenager the patient experienced her first bout of documented urinary-tract infection and was treated with sulfisoxazole. Nine years before admission she entered another hospital because of cystitis and flank pain. An automated scan of 12 blood-chemical determinations was normal. A culture of urine yielded Escherichia coli. An intravenous urographic examination showed that the right kidney was 9 cm, with small calyxes and pelvis, and . . .
Tumor-Stroma Proportion as a Predictive Biomarker of Resistance to Platinum-Based Chemotherapy in Patients With Ovarian Cancer
Authors: Emil Lou, Rachel I. Vogel, Spencer Hoostal, Molly Klein, Michael A. Linden, Deanna Teoh, Melissa A. Geller
Journal: JAMA Oncology (2019)

This study assesses tumor-stroma proportion and compares this finding with the development of resistance to platinum-based chemotherapy in women newly diagnosed with ovarian carcinoma.