tbuckley/cabot-search huggingface dataset:
Time from first symptoms to diagnosis in GEP-NET patients: Results from a large German tertiary referral center.
Authors: Esra Koca, Christine Koch, Gabriele Husmann, Jörg Bojunga
Journal: Journal of Clinical Oncology (2020)

610 Background: Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Methods: Retrospective analysis of 486 patients with GEP-NET (488 tumors) at tertiary referral center from 1984-2019; inclusion criteria: Patients &gt; 18 years, diagnosis of GEP-NET; descriptive analysis using SPSS; Cox regression, Log rank test. Results: Demographics: Male 54% / 52.9% (all/GEP-NET), median age at first diagnosis 63y/58y (all /GEP-NET). Localizations: small intestine 145/488 (29.7%), pancreas 143/488 (29.3%), CUP 53/488 (10.9%), colon 49/488 (10%), stomach 45/488 (9.2%), rectum 27/488 (5.5%), other digestive organs 11/488 (2.3%), esophagus 5/488 (1%), other 10/488 (2%). Ki67 in 330/488 (67.6%) evaluable patients: &lt; 3%: 155/330; 46.9%; ≥ 3%: 111/330; 33.6%; &gt; 20%: 64/330;19.3%. 128/488 (26.2%) of patients had NET specific symptoms (abdominal pain 77/128; 60.2%, diarrhea 51/128; 39.8%, flush 19/128; 14.8%, carcinoid syndrome 8/128; 6.3% tachycardia 6/128; 4.7%). 122/488 (25%) patients showed other tumor-specific symptoms (weight loss 48/122; 39.3%, stool irregularity 21/122; 17.2%, hypoglycemia 10/122; 8.2%, painless jaundice 8/122; 6.6%). 154/ 488 (32%) of NET were incidental findings (imaging 39.6%, endoscopy 23.4%, surgery for other causes 18.8%, appendectomy 15.6%). 221/279 (initial diagnosis/any time; 79.2%) patients had distant metastases at initial diagnosis (187/221 liver metastases). Time from tumor manifestation to initial diagnosis: pNET 360 ± 116 days, siNET 309 ± 87 days, gastric NET 66 ± 47 days, colonic NET 98 ± 67 days. Time from onset of symptoms to diagnosis in symptomatic patients was significantly longer than in asymptomatic patients (388 ± 86 days vs. 174 ± 58 days, p = 0.001). No significant difference in patients with or without distant metastases (223 ± 78 days vs. 259 ± 57 days, p = 0.355). Conclusions: A large proportion of NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. Diagnosis for symptomatic patients takes significantly longer than for asymptomatic, which might be due to mainly unspecific symptoms. Presence of metastases has no influence on time to diagnosis.
Venous thromboembolism (VTE) in melanoma patients (pts) on immunotherapy (IO).
Authors: Tamara A. Sussman, Joanna Roopkumar, Hong Li, Brian Hobbs, Alok A. Khorana, Pauline Funchain
Journal: Journal of Clinical Oncology (2020)

94 Background: VTE in cancer significantly contributes to morbidity and a worse overall prognosis. Little is known about the incidence of VTE in melanoma pts receiving IO. This study aims to assess the incidence of VTE in melanoma pts on IO, interrogate potential association with specific therapies, and ascertain its prognostic utility. Methods: We conducted a retrospective cohort study of melanoma pts who received any IO including ipilimumab (ipi), nivolumab (nivo) or pembrolizumab (pembro) from July 2015 to December 2017 at the Cleveland Clinic. VTE including deep venous thrombosis and pulmonary embolism were identified by chart review. VTE-free survival and overall survival (OS) were estimated by Kaplan-Meier and Cox proportional hazard models; association between VTE and IO was examined using the Pearson’s chi-squared test. Results: This cohort comprised 219 pts with median age of 65 years (range 24-92) and 66.7% male. Pembro was most common (36.5%), followed by ipi/nivo (26.9%), ipi (21.9%), and nivo (14.6%). Most had distant metastatic disease (79.9%), and 16.4% had brain metastases. VTE occurred in 14.2% (n = 31) of pts on therapy. Of those with VTE, 12 (38.7%) were receiving ipi/nivo and 19 (61.3%) single agent IO. Median VTE-free time was 4.9 months on ipi/nivo compared to 9.2 months on single agent IO (p = 0.05). The 6-month VTE-free survival was 18.5% for ipi/nivo and 71.8% for single agent IO. Among pts with distant metastatic disease, ipi/nivo was significantly associated with earlier time to VTE when adjusted for age, gender, and presence of brain metastases, (median VTE-free time 4.9 months vs. 9.3; p = 0.024; HR 2.96 [95% CI, 1.15-7.59]). Among pts without brain metastases, VTE was associated with worse OS (median OS 1.3 years vs. NR; p&lt;0.001; HR 3.47 [95% CI, 1.66-7.24]). Conclusions: VTE risk may be elevated for melanoma pts on IO, specifically those receiving ipi/nivo. Further studies are needed to identify pathophysiology, risk factors, and benefit of thromboprophylaxis in this setting. [Table: see text]
Depression among older adults with gastrointestinal (GI) malignancies: Results from the Cancer and Aging Resilience Evaluation (CARE) registry.
Authors: Richard Godby, Mustafa Al-Obaidi, Crystal Young Smith, Kelly Kenzik, Andrew Michael McDonald, Ravi Kumar Paluri, Olumide B. Gbolahan, Smita Bhatia, Grant Richard Williams
Journal: Journal of Clinical Oncology (2020)

92 Background: Depression among older adults with cancer is often under recognized and under treated. This study characterizes the burden of depression in older adults with GI malignancies and its relationship with geriatric assessment (GA) impairments, health-related quality of life (HRQOL), and healthcare utilization. Methods: Since September 2017, patients ≥60 years in GI oncology clinics at UAB were asked to complete a CARE GA questionnaire. We examined depression using the Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 4 item short form; moderate/severe (mod/sev) depression was defined by a T-score ≥60. GA impairments, HRQOL (PROMIS Global-10), and healthcare utilization were compared between those with and without mod/sev depression using a Chi-squared or t-test. Results: A total of 462 enrolled; mean age was 69 (range 60-96), majority white (72%), males (52%), and with advanced stage (III/IV, 69.1%). Most common cancers were colorectal (36%), pancreatic (23%), or hepatobiliary (15%). Overall, 55 patients reported mild depressive symptoms (12%) and 60 (13%) were found to have mod/sev depression. Depressed participants did not differ in demographics or GI cancer type/stage. Those reporting mod/sev depression were more likely to report falls (44 v 19%, p&lt;.001), impaired performance status (63 v 27%, p&lt;.001), dependence in activities of daily living (ADL; 45 v 14%, p&lt;.001), dependence in instrumental ADL (84 v 45%, p&lt;.001), cognitive dysfunction (40 v 5%, p&lt;.001), financial distress (37 v 23%, p=.03), anxiety (76 v 10%, p&lt;.001), fatigue (88 v 54%, p&lt;.001), and pain (70 v 32%, p&lt;.001). Depressed patients reported lower physical (32 v 45%, p&lt;.001) and mental (36 v 50%, p&lt;.001) HRQOL sub-scores, as well as more emergency room visits (67 v 49%, p=.009), but no difference in hospitalizations. Conclusions: More than one out of eight older adults with a GI malignancy reported mod/sev depression, which was associated with impairment in several geriatric domains and overall quality of life. As depression is a pleiotropic yet treatable comorbidity, oncologists should prioritize its screening and treatment.
Platinum-based therapy of patients with gastrointestinal cancers that harbor homologous recombination DNA damage response (HR-DDR) mutations: A single institutional retrospective analysis.
Authors: Bhavana Pendurthi Singh, Madison Ballman, Evan Drake, Ashish Khanchandani, Petra Prins, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2020)

836 Background: HR-DDR deficiencies have been described across cancer types and associated with response to specific therapies, including platinum (Pt)-based drugs and poly ADP-ribose polymerase (PARP) inhibitors. We sought to estimate the frequency of HR-DDR gene mutations in gastrointestinal (GI) cancers and determine if these patients (pts) benefit from Pt-based therapy. Methods: A retrospective chart review was performed on 421 pts with GI cancers treated at our institution. Tumors were categorized as colorectal (CRC), gastroesophageal (GE), pancreatic (PDA), hepatobiliary (HB), or other. All had next-generation sequencing with mutations in one or more of the following HR-DDR genes: BRCA1, BRCA2, PALB2, CHEK2, ATM, ARID1A, MRE11A, NBN, BARD1, and BL M. Overall survival (OS) of pts was analyzed using Log-rank test. Results: Of those analyzed, 127 pts (84 women and 43 men) met the inclusion criteria. Forty-eight percent had primary CRC tumors, and the remainder had primary GE (17%), PDA (14%), HB (10%), and other GI (11%) tumors. Fifty-four percent had stage IV disease. Sixty-five percent received Pt-based therapy at some point during their disease course. HR-DDR analysis revealed the following mutation rates: 34% ARID1A; 16% ATM; 19% BRCA2; and 9% BRCA1. OS analysis showed no significant survival advantage based on stage or mutation type for any of the disease-specific cohorts. There was no significant OS benefit in pts who received Pt-based therapy vs. those who did not, although pts with ARID1A-mutated tumors did show a trend towards improved OS (P = 0.09). Conclusions: Despite our limited cohort, our data suggest that pts with GI tumors harboring certain HR-DDR gene mutations might benefit from Pt-based therapy, supporting the development of mutation-specific Pt-based clinical trials.
B-Cell–Specific CXCR4 Protects Against Atherosclerosis Development and Increases Plasma IgM Levels
Authors: Yvonne Döring, Yvonne Jansen, Ismail Cimen, Maria Aslani, Selin Gencer, Linsey J.F. Peters, Johan Duchene, Christian Weber, Emiel P.C. van der Vorst
Journal: Circulation Research (2020)
Palliative systemic chemotherapy with or without pressurized intraperitoneal aerosol chemotherapy with cisplatin and doxorubicin (PIPAC C/D) for gastric cancer with peritoneal metastasis: A propensity score analysis.
Authors: Vladimir Khomiakov, Christoph Meisner, Andrey Ryabov, Larisa Bolotina, Anna Utkina, Ilia Kolobaev, Dmitry Sobolev, Anna Chayka
Journal: Journal of Clinical Oncology (2020)

380 Background: Gastric cancer (GC) with peritoneal metastasis (PM) has a dismal prognosis. Palliative systemic chemotherapy (SC), usually doublet combinations of platinum and fluoropyrimidines, is the standard of care. Pressurized IntraPeritoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin (PIPAC C/D) yields promising results. Here we aimed to compare overall survival (OS) between SC + PIPAC C/D vs. SC alone in patients with PM from GC. Methods: Prospective cohort of 95 consecutive patients with PM from GC treated in palliative intent at our institution from 2010 to 2018. Of these patients, 69 received SC + PIPAC C/D („PIPAC“), 26 SC alone („control“). Choice of treatment was not dictated by medical criteria, but by (non-) availability of the single-use medical devices needed for PIPAC in Russia. All patients received doublet or triplet chemotherapy with platinum together with fluoropyrimidines or capecitabin. A Cox proportional hazard model based on propensity score (PS) was used to assess the effect of PIPAC on OS and account for confounding factors. Results: The HR adjusted for PS for PIPAC vs. control was 0.396 (CI 5- 95% = 0.224-0.700, p-value 0.001). In the simple (unadjusted) Kaplan-Meier, median survival in the control group was 7.0 months (CI: 4.51 - 9.49) and in the PIPAC group 14.0 months (CI: 11.46-16.54). In the control group, all 26 patients died after 1-25 months. In the PIPAC group, 36 of 69 patients died after 4 to 20 months. The longest observed survival time in the PIPAC group was 27 months. Significance for the log-rank test after Mantel-Cox (not adjusted) was p &lt; 0.0001. Conclusions: Compared with SC alone, intensified chemotherapy combining PIPAC C/D and SC doubled OS. These promising results need to be confirmed in a randomized trial.
An overview of precision oncology basket and umbrella trials for clinicians
Authors: Jay J. H. Park, Grace Hsu, Ellie G. Siden, Kristian Thorlund, Edward J. Mills
Journal: CA A Cancer Journal for Clinicians (2020)

Abstract With advancements in biomarkers and momentum in precision medicine, biomarker‐guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.
Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody.
Authors: Hirofumi Ohmura, Kyoko Yamaguchi, Fumiyasu Hanamura, Tanoue Kenrou, Shiho Kawagoe, Kohei Arimizu, Yuzo Matsushita, Tatsuhiro Kajitani, Shingo Tamura, Hozumi Shimokawa, Keita Uchino, Hisanobu Oda, Yudai Shinohara, Mamoru Ito, Kenji Tsuchihashi, Taichi Isobe, Hiroshi Ariyama, Hitoshi Kusaba, Koichi Akashi, Eishi Baba
Journal: Journal of Clinical Oncology (2020)

35 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.
A case series of tardive expansion congenital hemangioma: A variation of noninvoluting congenital hemangioma or a new hemangiomatous entity?
Authors: Chen Hua, Lizhen Wang, Yunbo Jin, Hui Chen, Gang Ma, Xia Gong, Yajing Qiu, Xi Yang, Hanru Ying, Xiaoxi Lin
Journal: Journal of the American Academy of Dermatology (2020)
Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).
Authors: Ibrahim Halil Sahin, Subir Goyal, Yoanna S Pumpalova, Mohamad Bassam Sonbol, Satya Das, Sigurdis Haraldsdottir, Zhengjia Chen, Mehmet Akce, Olatunji B. Alese, Walid Labib Shaib, Daniel H. Ahn, Kristen Keon Ciombor, Jordan Berlin, Tanios S. Bekaii-Saab, Amber Draper, Gregory B. Lesinski, Bassel F. El-Rayes, Christina Wu
Journal: Journal of Clinical Oncology (2020)

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P &lt; 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P &lt; 0.001). Notably pts &lt; 65 had better 2-year disease control rates when compared to &gt; 65 (71.1% and 41.5% respectively; P &lt; 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.
Conditional survival of patients with rectal cancer undergoing Watch and Wait: The risk of recurrence over time.
Authors: Laura Melina Fernandez, Nuno Figueiredo, Geerard Beets, Maxime Van Der Valk, Renu Bahadoer, Denise Hilling, Andrew Renehan, Cornelis J. H. Van De Velde, Angelita Habr-Gama, Rodrigo O Perez
Journal: Journal of Clinical Oncology (2020)

30 Background: Patients with rectal cancer and complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) have been offered non-operative management (W&amp;W). Risk factors for local regrowth (RG) include baseline cT and type of nCRT. However, the influence of risk factors for RG over time and the extent in time that patients need to be followed with the rectum in situ after a cCR are unknown. Objective: Analyze the risk of recurrence over time through conditional survival (cDFS/cLRFS) estimates for rectal cancer patients under W&amp;W. Methods: Retrospective analysis of all patients from the largest multicenter database of patients managed non-operatively (International Watch and Wait Database–IWWD). Only patients with cCR after nCRT and W&amp;W with a median of &gt;3 years of follow-up were included. cDFS was used to investigate the evolution of recurrence-odds, as patients remain disease-free after nCRT. 2-year cDFS was estimated at “x” years after nCRT based on the formula cDFS 2 =DFS (x+2) /DFS (x) . Results: 768 patients treated between 1991-2015 were included. Using cDFSestimates, the probability of remaining disease-free for 2 additional years once cCR was achieved and sustained for 1, 3, and 5 years, were 85%, 97%, and 95%, respectively. These contrast with the actuarial DFS for similar intervals of 70%, 68% and 65% respectively. Baseline cT was associated with the risk of RG at 1 year after a cCR (cT2 aLRFS 89% vs. cT3 82%; p=0.004). However, after sustaining a cCR for 1 year, baseline cT becomes irrelevant at 2 years (cLRFS; 94% vs. 90%; |d| 0.14). Also, total dose of RT (≤50 vs &gt;50Gy) was associated with the risk of RG (aLRFS 76% vs 85%; p=0.03) at 1 year. Dose of RT becomes irrelevant (at 2 years; cLRFS 93% vs. 90%; |d| 0.10) once patients sustained a cCR for 1 year. Conclusions: Conditional survival estimates suggests that patients have significantly lower risks (≤5%) of developing late RG (at 5 years) after sustaining cCR for 3 years. A sustained cCR over time may be more relevant for long-term risk of RG than cT-stage or RT dose. The present data can have significant consequences for the recommendation of intensive surveillance after sustaining 3ys of cCR.
Dietary Modification and Breast Cancer Mortality: Long-Term Follow-Up of the Women’s Health Initiative Randomized Trial
Authors: Rowan T. Chlebowski, Aaron K. Aragaki, Garnet L. Anderson, Kathy Pan, Marian L. Neuhouser, JoAnn E. Manson, Cynthia A. Thomson, Yasmin Mossavar-Rahmani, Dorothy S. Lane, Karen C. Johnson, Jean Wactawski-Wende, Linda Snetselaar, Thomas E. Rohan, Juhua Luo, Ana Barac, Ross L. Prentice
Journal: Journal of Clinical Oncology (2020)

PURPOSE Observational studies of dietary fat intake and breast cancer have reported inconsistent findings. This topic was addressed in additional analyses of the Women’s Health Initiative (WHI) Dietary Modification (DM) clinical trial that evaluated a low-fat dietary pattern influence on breast cancer incidence. METHODS In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer, and a dietary fat intake of ≥ 32% of energy were randomly assigned at 40 US centers to a usual diet comparison group (60%) or dietary intervention group (40%). The goals were to reduce fat intake to 20% of energy and increase vegetable, fruit, and grain intake. Breast cancers were confirmed after central medical record review and serial National Death Index linkages to enhance mortality findings. RESULTS During 8.5 years of dietary intervention, breast cancer incidence and deaths as a result of breast cancer were nonsignificantly lower in the intervention group, while deaths after breast cancer were statistically significantly lower both during intervention and through a 16.1-year (median) follow-up. Now, after a long-term, cumulative 19.6-year (median) follow-up, the significant reduction in deaths after breast cancer persists (359 [0.12%] v 652 [0.14%] deaths; hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.96; P = .01), and a statistically significant reduction in deaths as a result of breast cancer (breast cancer followed by death attributed to the breast cancer) emerged (132 [0.037%, annualized risk] v 251 [0.047%] deaths, respectively; HR, 0.79; 95% CI, 0.64 to 0.97; P = .02). CONCLUSION Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, may reduce the risk of death as a result of breast cancer in postmenopausal women.