tbuckley/cabot-search huggingface dataset:
Outcomes for patients with metastatic solid malignancies who achieve a complete response on an immune checkpoint inhibitor.
Authors: Christopher Eing Wee, Julian R. Molina
Journal: Journal of Clinical Oncology (2020)

82 Background: Use of immune checkpoint inhibitors (ICI) in metastatic solid malignancies can occasionally result in a complete response (CR). There is limited long-term data regarding outcomes for patients who achieve a CR on ICIs. Methods: We screened the Mayo Clinic electronic medical record using an institutional database query program to identify patients whose records contained keywords such as “pembrolizumab” and “complete response” or “no evidence of disease.” Patients were included if they had measurable metastatic solid tumor disease prior to initiation of ICI and if they had a CR defined by two consecutive imaging studies at least twelve weeks apart. Exclusion criteria included oligometastatic disease treated with locoregional therapy or presence of a second confounding malignancy. Results: One-hundred four patients with a CR on pembrolizumab met criteria. Most (71.1%) patients had melanoma and 63/103 (61.2%) received had received the ICI during the first line of metastatic systemic therapy. Additional characteristics are in Table. At a median follow-up of 35.8 months (6.1-87.7), patients had received ICI for a median of 12.1 months (1.5-46.7). The vast majority of patients who stopped ICI did so electively (for reasons other than disease progression). Of 88 elective discontinuations, only 7 patients had disease recurrence after a median follow-up from start of ICI of 40.5 months. Conclusions: Patients with a metastatic solid malignancy who achieve a CR to pembrolizumab appear to maintain remissions off therapy, with low rates of relapse. Further outcomes will be explored, including analyzing and characterizing a sub-group of “hyper-responders” and patients receiving other ICI agents. [Table: see text]
Vitiligo: Mechanisms of Pathogenesis and Treatment
Authors: Michael L. Frisoli, Kingsley Essien, John E. Harris
Journal: Annual Review of Immunology (2020)

Vitiligo is an autoimmune disease of the skin that targets pigment-producing melanocytes and results in patches of depigmentation that are visible as white spots. Recent research studies have yielded a strong mechanistic understanding of this disease. Autoreactive cytotoxic CD8 + T cells engage melanocytes and promote disease progression through the local production of IFN-γ, and IFN-γ-induced chemokines are then secreted from surrounding keratinocytes to further recruit T cells to the skin through a positive-feedback loop. Both topical and systemic treatments that block IFN-γ signaling can effectively reverse vitiligo in humans; however, disease relapse is common after stopping treatments. Autoreactive resident memory T cells are responsible for relapse, and new treatment strategies focus on eliminating these cells to promote long-lasting benefit. Here, we discuss basic, translational, and clinical research studies that provide insight into the pathogenesis of vitiligo, and how this insight has been utilized to create new targeted treatment strategies.
Cell types and cell circuits in human and non-human primate retina
Authors: Ulrike Grünert, Paul R. Martin
Journal: Progress in Retinal and Eye Research (2020)

This review summarizes our current knowledge of primate including human retina focusing on bipolar, amacrine and ganglion cells and their connectivity. We have two main motivations in writing. Firstly, recent progress in non-invasive imaging methods to study retinal diseases mean that better understanding of the primate retina is becoming an important goal both for basic and for clinical sciences. Secondly, genetically modified mice are increasingly used as animal models for human retinal diseases. Thus, it is important to understand to which extent the retinas of primates and rodents are comparable. We first compare cell populations in primate and rodent retinas, with emphasis on how the fovea (despite its small size) dominates the neural landscape of primate retina. We next summarise what is known, and what is not known, about the postreceptoral neurone populations in primate retina. The inventories of bipolar and ganglion cells in primates are now nearing completion, comprising ~12 types of bipolar cell and at least 17 types of ganglion cell. Primate ganglion cells show clear differences in dendritic field size across the retina, and their morphology differs clearly from that of mouse retinal ganglion cells. Compared to bipolar and ganglion cells, amacrine cells show even higher morphological diversity: they could comprise over 40 types. Many amacrine types appear conserved between primates and mice, but functions of only a few types are understood in any primate or non-primate retina. Amacrine cells appear as the final frontier for retinal research in monkeys and mice alike.
The impact of primary tumor location (PTL) and age on the risk of developing noncolonic second primary malignancy (SPM) in colon cancer (CC) patients (PTS).
Authors: Charles Chu, Albert Y. Lin
Journal: Journal of Clinical Oncology (2020)

67 Background: Colon cancer remains one of the leading causes of cancer death worldwide. There has been a renewing interest in the role of PTL (right- or RS vs. left-sided or LS) in CC for their differences in biology, prognostic and predictive features. Given the increasing incidence of early-onset (age 20-49) CC, coupled with their longer life expectancy, we seek to examine the effects of PTL and age in the development of SPM in a population-based cohort. Methods: Surveillance, Epidemiology, and End Results (SEER) Program data were queried to identify CC PTS diagnosed between 1973-2015 with complete follow-up information and available data on SPM. Using SEER*Stat, we calculated standardized incidence ratios (SIRs) -- the ratio of observed to expected cases of SPM based on incidence data in the general US population and compared by PTL (RS vs. LS) and age of diagnosis (20-49 vs. &gt;49). Results: A total of 269,442 (RS/LS=46.4%/53.6%) CC PTS were obtained. Overall RS, compared with LS, CC PTS have a higher likelihood of developing SPM in all sites (OR: 1.09, 95% CI: 1.08- 1.11 vs. 1.03, 1.02-1.04). RS CC PTS and age 20-49 group, compared with other subgroups, has a much greater likelihood of being diagnosed with the following SPM:small intestine, urinary tract, bile duct, gynecologic (GYN), and stomach cancers, as shown in the Table below. Conclusions: Our results show that the increased risk in non-colonic SPMs in CC PTS is associated with RS CC and age less than 49, suggesting the implications on survivorship care and surveillance of SPMs. Furthermore, there may be a possible overlap with Lynch syndrome in these PTS with SPM given the overlap in the presentation of cancer patterns and early-onset of CC, suggesting the indication for MMR testing. [Table: see text]
healed IEによる高度三尖弁閉鎖不全症の1例 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: 李哲民, 磯部光章, 平尾見三, 畑明宏, 鈴木淳一, 蜂谷仁, 川端美穂子, 稲垣裕, 櫻井馨, 佐々木毅, 植島大輔, 小西裕二
Journal: Circulation (2007)
Role of hepatologists in management of hepatocellular carcinoma in the new era of transplant oncology.
Authors: Divya Ashat, Mark Karwal, Shiliang Sun, Sandeep Laroia, Tomohiro Tanaka
Journal: Journal of Clinical Oncology (2020)

501 Background: There have been global efforts to manage hepatobiliary malignancies such as hepatocellular carcinoma (HCC) in a multidisciplinary setting under the concept of transplant oncology. We published preliminary data of hepatology-directed treatment of HCC (Ann Hepatol 2019). However, the actual role of hepatologists in this setting is not well defined. Methods: We evaluated 107 patients with newly diagnosed HCC, undergoing locoregional therapy (LRT) as a first therapy (microwave ablation, TACE, TARE or SBRT) in our institution between 1/2017 to 2/2019 and being followed until 8/2019. Patients were divided into three groups based on referral pathways: outside referral directly to oncologists (O-group, n=24), internal referral from hepatologists to oncologists (H/O-group, n=62) and hepatologist directed HCC treatment (H-group, n=21). The hepatologist performed all microwave ablations in H-group; rest of the LRTs were performed by either interventional radiology or radiation oncology. Results: The baseline gender, etiology of liver disease, MELD score, Child-Pugh score, BCLC stage, CLIP score, AFP and proportion of patients within Milan criteria were similar between 3 groups ( p=n.s.). However, O-group included older patients (median 70 vs 63/62 y.o., p&lt;0.01), and had larger HCC size (median diameter 41 vs 26/28mm, p&lt;0.01). In H-group, there were more cases discussed in multidisciplinary tumor boards (77% vs 46%, p=0.012) and referrals for liver transplantation (71% versus 50%, p=0.046). Time between the diagnosis and the first procedure was shorter in H-group than others (median 53 vs 69 days, p=0.048). The rate of complete response/partial response per mRECIST criteria was highest in H-group (91 vs 66%, p=0.024). The 2-year cumulative survival was comparable among three groups (70, 74 and 76% in O-group, H/O-group and H-group, respectively, p=0.4). Conclusions: Hepatologists are often the first point of contact and can play a key (and even more direct) role in subsequent management of HCC. To further accomplish the concept of multidisciplinary approach and transplant oncology, primary/secondary care institutions might be a potential target for intervention for outreach.
Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).
Authors: J. Randolph Hecht, Sara Lonardi, Johanna C. Bendell, Hao-Wen Sim, Teresa Macarulla, Charles D. Lopez, Eric Van Cutsem, Andres J. Munoz Martin, Joon Oh Park, Richard Greil, Yong Lin, Sujata Rao, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2020)

637 Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1 st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m 2 ], oxaliplatin [85 mg/m 2 ] followed by bolus 5-FU [400 mg/m 2 ], and a 46-48 hr infusion of 5-FU [2400 mg/m 2 ]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if &gt; 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if &gt; 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1 st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.
Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers.
Authors: Thierry Andre, Dominique Berton, Filippo G. De Braud, Giuseppe Curigliano, Wei Guo, Hadi Danaee, Sharon Lu, Ellie Im, Naureen Starling
Journal: Journal of Clinical Oncology (2020)

218 Background: Dostarlimab (TSR-042) is an investigational humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking the interaction with ligands PD-L1 and PD-L2. The ongoing GARNET trial (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F in the GARNET trial enrolled pts with dMMR or microsatellite instability high (MSI-H) non-endometrial solid tumors, the majority of which were GI in origin. Pts must have progressed following prior systemic therapy for advanced disease, assessed by independent central review (ICR). Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W thereafter. Objective response rate (ORR) and duration of response (DOR) were assessed by ICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and ≥24 weeks of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 109 pts were included in the safety analysis, with 48 dMMR pts in the efficacy analysis. Of the 48 pts, 42 (88%) had GI tumors. Confirmed ORR in dMMR pts was 43.8% (95% CI: 29.5, 58.8), with a complete response rate of 8.3%. ORR was consistent across tumor type (Table). Median DOR was not reached. The probability of maintaining response at 12 months was 85.9%. Treatment-related adverse events (TRAEs) were reported in 55% of pts; 7.3% of pts experienced grade ≥3 TRAEs, including 1 each of adrenal insufficiency, rash, diarrhea, and fatigue. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No treatment-related deaths were reported. Conclusions: Dostarlimab demonstrated robust, durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers, with an acceptable safety profile. Clinical trial information: NCT02715284. [Table: see text]
Encyclopedic liquid biopsies for guideline-compliant diagnostic work-up in gastrointestinal cancers.
Authors: Revati Patil, Dadasaheb Akolkar, Darshana Patil, Sewanti Limaye, Raymond Page, Timothy Crook, Vineet Datta, Stefan Schuster, Cynthe Sims, Navin Srivastava, Pradip Devhare, Pradip Fulmali, Sanket Patil, Shoeb Patel, Pooja Fulmali, Shabista Khan, Rohit Chougule, Raja Dhasarathan, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2020)

799 Background: Definitive diagnosis of gastrointestinal (GI) malignancies is reliant on histopathological examination of tumor tissue obtained by invasive biopsies. However, invasive biopsies are associated with procedural risks, complications and expenses. A non-invasive technique for diagnosis of GI cancers is presently unavailable. Here we present a non-invasive diagnostic approach for GI cancers based on immunocytochemical (ICC) profiling of Circulating Tumor Associated Cells (C-TAC) enriched from peripheral blood. Methods: We collected 15 mL peripheral blood from 1052 patients with known diagnosis of Ca Oesophagus (244), Ca Stomach (170) and Ca Colorectum (638) and with histopathological information available from prior tissue analysis. CTACs were harvested following negative enrichment. C-TACs were identified by immunostaining with EpCAM and panCK. Deep ICC characterization was carried out in a subset of 203 samples (100 colorectal, 19 Gastric and 84 Esophageal) using organ specific markers. A subset of 19 samples from Gastric and 94 samples Esophageal cancers were profiled for Her2 and PD-L1 status. Results: C-TACs could be identified and enriched in 1012 out of 1052 patients (96.2% overall sensitivity). Immunostaining for organ-specific markers was possible in all 203 (100%) samples. Her2 positivity was observed in 2/19 Gastric and 19/84 Esophageal samples. PD-L1 (22C3) positivity was observed in 5/19 Gastric and 32/84 Esophageal samples while PD-L1 (28-8) positivity was observed in 2/19 Gastric and 16/84 Esophageal samples. Conclusions: Our results show that ICC profiling of C-TACs can provide necessary diagnostic information non-invasively to substitute conventional procedures dependent on tissue extraction. This approach fulfils most clinical decision-making requirements in GI malignancies.
Variations in surgical treatment of stage I gallbladder carcinoma impacts survival.
Authors: Anthony Joseph Scholer, Mary Garland-Kledzik, Mansen Wang, Adam Khader, Juan Santamaria-Barria, Zeljka Jutric, Ronald Wolf, Melanie Goldfarb
Journal: Journal of Clinical Oncology (2020)

495 Background: Variations in surgical care for stage I gallbladder carcinoma (GBC) may be associated with inferior outcomes. The aim of this study was to identify the variations in surgical treatment of GBC. Methods: All patients diagnosed with stage I GBC by AJCC 8 criteria from 2004-2013 were identified in the NCDB. Surgical treatment was categorized as cholecystectomy (C), cholecystectomy with lymph node dissection (C+LND), or radical cholecystectomy (RC). Independent predictors of improved overall survival (OS) and extent of surgery were identified by multinomial regression analyses. Results: Of 1756 patients with stage I GBC, 26% were T1a, 56% T1b, and 18.5% T1NOS. The majority were White non-Hispanic (61.8%) and female (68.5%), with 55.1% &gt; 70 years of age. Two-thirds of T1a tumors were treated with more aggressive surgery (28% C+LND, 4.2% RC), which did not differ by age. However, only 44.4% of patients with T1b tumors had more aggressive surgery, which was significantly less likely in patients &gt; 70 years, even after controlling for other factors (C+LND (OR:0.60; CI:0.44-0.81), RC (OR:0.52; CI:0.29-0.91)). Five-year OS was 54.34% for T1a and 43.05% for T1b (p = 0.02). After controlling for other factors, both C+LND (HR:0.46, CI:0.26-0.81) and RC (HR:0.31, CI:0.16-0.62) significantly improved 5-year OS for T1b tumors, whereas RC also improved 5-year OS for all patients &gt; 70 years old (p = 0.04). Conclusions: A majority of patients with T1b GBC had less than adequate surgery by the current AJCC staging, which significantly decreased survival in all patients. This was especially evident in older patients who were also the least likely to receive more aggressive surgery.
Timing and location of palliative care consultation in metastatic pancreatic cancer: A retrospective, single-center observational study.
Authors: Timil Patel, Joseph Anthony Miccio, Thejal Srikumar, Elizabeth Horn Prsic, Kerin B. Adelson, Dmitry Kozhevnikov, Komal Patel, Jill Lacy, Michael Cecchini
Journal: Journal of Clinical Oncology (2020)

770 Background: Patients (pts) receiving treatment for metastatic pancreatic cancer (MPC) experience significant symptoms, treatment related side effects and psychosocial burdens. The ASCO guidelines recommend early palliative care consultation (PCC) to improve quality of life and survival. However, limited real-world data is available regarding the timing of PCC, hospice enrollment and location of death (LOD) in pts with MPC. Methods: We conducted a retrospective observational analysis of pts treated with chemotherapy for MPC at the Yale Smilow Cancer Hospital and affiliated community care centers (CCC) from January 2011 to April 2019. Patient demographics, treatment dates, initial PCC, enrollment of hospice at the time of death and LOD were manually abstracted from the electronic medical record. Univariate and multivariable logistic regression analyses were conducted to predict for PCC and death outside the hospital. Results: Of 363 pts identified with MPC who received chemotherapy, 38% (138) had a PCC. 67% (93) of patients’ initial PCC was in the hospital versus 33% (45) in the outpatient setting. The median time from the start of first-line chemotherapy to the first PCC was 5.2 months (interquartile range [IQR] 1.2 – 12.9). The median time from the first PCC to death was 1.5 months (IQR 0.5 – 4.42). At the time of our analysis, 300 pts had died and of those 76% (229) were enrolled on hospice at the time of death while 24% (71) were not. With respect to LOD, 47% (139) of pts died at home with hospice, 31% (94) at an inpatient hospice facility and 22% (67) died in the hospital. Female gender was associated with an increased likelihood of a PCC (HR 1.78, 95% CI 1.07-2.94, P = 0.026). Pts treated at a CCC were less likely to have a PCC (HR 0.21, 95% CI 0.12-0.36, P &lt; 0.001). A PCC was not associated with a higher likelihood of death outside the hospital (HR 1.31, 95% CI 0.75-2.29, P = 0.346). Conclusions: Although most pts with MPC enroll in hospice, PCC is generally underutilized. In fact, many pts receive PCC near the end of life and in the hospital. Further studies are warranted to determine how best to incorporate early PCC to maximize supportive care for pts with MPC.
Circulating Tumor Cells and Early Relapse in Node-positive Melanoma
Authors: Anthony Lucci, Carolyn S. Hall, Sapna P. Patel, Boomadevi Narendran, Jessica B. Bauldry, Richard E. Royal, Mandar Karhade, Joshua R. Upshaw, Jennifer A. Wargo, Isabella C. Glitza, Michael K.K. Wong, Rodabe N. Amaria, Hussein A. Tawbi, Adi Diab, Michael A. Davies, Jeffrey E. Gershenwald, Jeffrey E. Lee, Patrick Hwu, Merrick I. Ross
Journal: Clinical Cancer Research (2020)

Abstract Purpose: There is a need for sensitive, reproducible biomarkers for patients with stage III melanoma to guide clinical decision making. Circulating tumor cells (CTCs) can be detected in patients with melanoma; however, there are limited data regarding their significance in stage III disease. The aim of this study was to determine whether CTCs are associated with early relapse in stage III melanoma. Experimental Design: We prospectively assessed CTCs at first presentation in clinic (baseline) for 243 patients with stage III melanoma. CTCs were measured using the CellSearch System. Relapse-free survival (RFS) was compared between patients with one or more baseline CTC versus those with no CTCs. Log-rank test and Cox regression analysis were applied to establish associations of CTCs with RFS. Results: At least one baseline CTC was identified in 90 of 243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. CTC detection was not associated with substage, or primary tumor characteristics. Multivariable analysis demonstrated that the detection of ≥1 baseline CTC was significantly associated with decreased 6-month RFS [log-rank, P &amp;lt; 0.0001; HR, 3.62, 95% confidence interval (CI), 1.78–7.36; P &amp;lt; 0.0001] and 54-month RFS (log-rank, P = 0.01; HR, 1.69; 95% CI, 1.13–2.54; P = 0.01). Conclusions: ≥1 CTC was independently associated with melanoma relapse, suggesting that CTC assessment may be useful to identify patients at risk for relapse who could derive benefit from adjuvant therapy.
A New Rho(d) Map to Diffuse Gastric Cancer
Authors: Dorothy Benton, Jonathan Chernoff
Journal: Cancer Discovery (2020)

Abstract Summary: Diffuse gastric cancer (DGC) is characterized by frequent missense mutations in the small GTPase RHOA, but the effects of this mutation on enzyme activity and signaling have been widely debated. In this issue, Zhang and colleagues show that the most common RHOA mutation in DGC, encoding RHOAY42C, represents a gain of function; that a mouse model incorporating this mutation in association with loss of the E-cadherin gene CDH1 recapitulates many aspects of DGC; and that rationally designed therapeutics based on our understanding of RHOA signaling are promising agents for treating DGC. See related article by Zhang et al., p. 288.