tbuckley/cabot-search huggingface dataset:
Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer
Authors: Michael Brandon Ware, Bassel F El-Rayes, Gregory B Lesinski
Journal: Journal for ImmunoTherapy of Cancer (2020)

Pancreatic ductal adenocarcinoma (PDAC) is plagued by a dismal 5-year survival rate, early onset of metastasis and limited efficacy of systemic therapies. This scenario highlights the need to fervently pursue novel therapeutic strategies to treat this disease. Recent research has uncovered complicated dynamics within the tumor microenvironment (TME) of PDAC. An abundant stroma provides a framework for interactions between cancer-associated fibroblasts, suppressive myeloid cells and regulatory lymphocytes, which together create an inhospitable environment for adaptive immune responses. This accounts for the poor infiltration and exhausted phenotypes of effector T cells within pancreatic tumors. Innovative studies in genetically engineered mouse models have established that with appropriate pharmacological modulation of suppressive elements in the TME, T cells can be prompted to regress pancreatic tumors. In light of this knowledge, innovative combinatorial strategies involving immunotherapy and targeted therapies working in concert are rapidly emerging. This review will highlight recent advances in the field related to immune suppression in PDAC, emerging preclinical data and rationale for ongoing immunotherapy clinical trials. In particular, we draw attention to foundational findings involving T-cell activity in PDAC and encourage development of novel therapeutics to improve T-cell responses in this challenging disease.
Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients
Authors: Erika Morsia, Kristen McCullough, Maansi Joshi, Joselle Cook, Hassan B. Alkhateeb, Aref Al‐Kali, Kebede Begna, Michelle Elliott, William Hogan, Mark Litzow, Mithun Shah, Animesh Pardanani, Mrinal Patnaik, Ayalew Tefferi, Naseema Gangat
Journal: American Journal of Hematology (2020)

Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.
Ritonavir blocks the growth of breast cancer line MDA-MB-231 in a mammary fat pad xenograft model, in part through calpain inhibition of cell cycle progression
Authors: Anjaiah Srirangam, Ranjana Mitra, Christopher Gorski, Lang Li, George W. Sledge, Hiromitsu Kishimoto, Harikrishna Nakshatri, David A. Potter
Journal: Cancer Research (2004)

534  The growth of the breast cancer line MDA-MB-231 is inhibited by the HIV protease inhibitor ritonavir, with an IC50 of 45 μM. Cell cycle arrest occurs at Go/G1 at the IC50 for proliferation by Hoechst 33342 dye/pyronine flow cytometry and there is induction of apoptosis, measured by propidium iodide/annexin V flow cytometry. Fluorometric analysis of protease inhibition in the MDA-MB-231 line reveals that ritonavir inhibits greater than 90% of calpain activity, but inhibits proteasome activity by only 10-20%, at the IC50 concentration for growth of 45 μM. Surface EGFR levels are down-regulated by 25% at the ritonavir IC90. Phospho-Akt is reduced by 70% after 48 h exposure to ritonavir. Calpain’s physiological inhibitor, calpastatin, also down-regulates phospho-Akt. Pharmacokinetic analysis was used to determine a dosing route and schedule for ritonavir in mice. Gavage did not result in adequate blood levels 1 h following administration and this approach was abandoned. IP injection of 40 mg/kg was found to result in ritonavir Cmax levels of 12-67 μM, measured 1 h following drug administration. The Tween 80 vehicle was well tolerated. A mouse mammary fat pad model was used to test the hypothesis that ritonavir will block the growth of solid tumors in a xenograft model. Tumors were established for 21 days before treatment. Daily ritonavir treatment, 40 mg/kg ip, resulted in arrest of growth of the MDA-MB-231 xenografts, with a plateau of tumor size, 300 + 20 mm3, compared to 800 + 200 mm3 for vehicle, by day 52 of treatment (P=0.002, by Gompertzian curve fitting). The ritonavir treatment was well tolerated and the mouse weights were 23 + 2 g at the beginning of drug treatment and 25 + 2 g on day 52. No effects of ritonavir on angiogenesis or EGFR levels were observed by immunohistochemical (IHC) analysis of tumors harvested at the end of the study. Data on phospho-Akt IHC and dose dense treatment will be presented. These results point to the development of ritonavir for treatment of solid tumors, because tumor growth inhibition is observed at well tolerated ritonavir doses.
A rare skin burn during endoscopic submucosal dissection
Authors: De-feng Li, Zhi-yuan Zou, Sha Nie, Zheng-lei Xu, Li-sheng Wang
Journal: Endoscopy (2020)

A 54-year-old woman was diagnosed with early gastric cancer (EGC) in the gastric antrum during screening examination ([Fig. 1 a]). The EGC was successfully removed using an insulated-tip knife (Endocut I, Effect 3, Duration 2, Interval 4; ERBE Elektromedizin, Tübingen, Germany) ([Fig. 2]). Unfortunately, we noticed after the procedure that the skin on the patient’s back, where the electrode pad had been placed, was severely burnt ([Fig. 3], [Video 1]). The patient recovered in a week after applying recombinant human epidermal growth factor gel to the burn.
Paclitaxel versus oral vinorelbine in patients with advanced non-small cell lung cancer (NSCLC) with performance status (PS) 2: A randomized phase II study
Authors: K. N. Syrigos, C. Bacoyiannis, T. Makatsoris, A. Bamias, G. Klouvas, C. Nicolaides, I. Boukovinas, E. Linardou, G. Fountzilas, P. Kosmidis
Journal: Journal of Clinical Oncology (2009)

e19035 Background: The optimal treatment of patients with advanced NSCLC and PS 2 is not well established. Our group has shown that single agent is equally effective to doublets. Purpose of this study was to compare efficacy and toxicity of two single agents Paclitaxel and oral Vinorelbine. Methods: 75 stage IIIb wet and IV chemotherapy-naïve for metastatic disease patients with PS 2 were randomized to either Paclitaxel 90mg/m 2 weekly (group A: 36pts) or Vinorelbine 60mg/m 2 weekly (group B: 34pts). Both agents were given for three weeks on and one week off. Results: A total of 70 out of 75 patients were eligible for analysis. All patient and disease characteristics were well balanced. Partial response rate (PR) was 14% (95% CI, 4.7%-29.5%) and 6% (95% CI, 0.7%- 19.7%) for groups A and B respectively. Stable disease (SD) was 17% (95% CI, 6.4%-32.8%) and 12% (95% CI, 3.3%-27.5%) respectively. These rates did not differ significantly. Median survival (OS) was 5.3m (95% CI, 3.1–7.5 m) and 3.5m (95% CI, 1.6 - 5.4 m) respectively (P=0.6). Progression free survival (PFS) was 3.2m (95% CI, 1.9 - 4.6 m) and 2.1m (95% CI, 1.8 - 2.3 m) respectively (P=0.2). There was a non-statistically significant trend for more myelotoxicity in the vinorelbine group. Conclusions: A trend for higher efficacy and less toxicity of Paclitaxel in comparison to oral Vinorelbine was observed, without however reaching statistical significance. No significant financial relationships to disclose.
Successful treatment of anastomotic leakage by endoscopic stenting after esophageal atresia repair in an infant
Authors: Yu-Wei Fu, Yao-Jen Hsu, Hsu-Heng Yen
Journal: Endoscopy (2020)

A 1-day-old infant was admitted with dyspnea and increased oral secretion following birth. Chest X-ray obtained after failure of nasogastric tube placement revealed tube curling in the upper esophagus. The diagnosis was esophageal atresia with tracheoesophageal fistula, requiring thoracoscopic repair of the fistula and atresia on Day 3 after birth.
The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies
Authors: Subhabrata Chaudhury, Bradley M. Keegan, Brian S. J. Blagg
Journal: Medicinal Research Reviews (2020)

Abstract Heat shock proteins (Hsps) are molecular chaperones that also play important roles in the activation of the heat shock response (HSR). The HSR is an evolutionary conserved and protective mechanism that is used to counter abnormal physiological conditions, stressors, and disease states, such as those exemplified in cancer and/or neurodegeneration. In normal cells, heat shock factor‐1 (HSF‐1), the transcription factor that regulates the HSR, remains in a dormant multiprotein complex that is formed upon association with chaperones (Hsp90, Hsp70, etc.), co‐chaperones, and client proteins. However, under cellular stress, HSF‐1 dissociates from Hsp90 and induces the transcriptional upregulation of Hsp70 to afford protection against the encountered cellular stress. As a consequence of both peripheral and central neuropathies, cellular stress occurs and results in the accumulation of unfolded and/or misfolded proteins, which can be counterbalanced by activation of the HSR. Since Hsp90 is the primary regulator of the HSR, modulation of Hsp90 by small molecules represents an attractive therapeutic approach against both peripheral and central neuropathies.
Clinical Implications of Detection and Clearance of Post-Induction Residual Disease in 2119 Children and Young Adults with AML: Children's Oncology Group Studies AAML0531 and AAML1031
Authors: Lisa E. Brodersen, Todd A Alonzo, Robert B Gerbing, Anders Kolb, Alan S Gamis, Richard Aplenc, Soheil Meshinchi, Michael R. Loken
Journal: Blood (2017)
Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy
Authors: Yuefei Zhu, Xiangrong Yu, Soracha D. Thamphiwatana, Ying Zheng, Zhiqing Pang
Journal: Acta Pharmaceutica Sinica B (2020)

Cancer immunotherapy has veered the paradigm of cancer treatment. Despite recent advances in immunotherapy for improved antitumor efficacy, the complicated tumor microenvironment (TME) is highly immunosuppressive, yielding both astounding and unsatisfactory clinical successes. In this regard, clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME. Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME. The immunosuppressive TME may even dampen the efficacy of antitumor immunity. Recently, some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment (TIME) for robust immunotherapeutic responses. In this review, we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy, especially those unique classes associated with the immunosuppressive effect. The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation. After introducing the various strategies, we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.
A Shift Toward a Plant-Centered Diet From Young to Middle Adulthood and Subsequent Risk of Type 2 Diabetes and Weight Gain: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Yuni Choi, Nicole Larson, Daniel D. Gallaher, Andrew O. Odegaard, Jamal S. Rana, James M. Shikany, Lyn M. Steffen, David R. Jacobs
Journal: Diabetes Care (2020)

To examine the associations between change in plant-centered diet quality and type 2 diabetes risk and change in body size.A prospective study conducted in the U.S. enrolled adults ages 18-30 years in 1985-1986 (examination year [Y0]) and followed them through 2015-2016. We analyzed the associations between change in plant-centered diet quality over 20 years (Y0-Y20) and diabetes (Y20-30; n = 2,534) and change (Y0-Y20 and Y20-30) in BMI, waist circumference (WC), and weight (n > 2,434). Plant-centered diet quality was measured using the A Priori Diet Quality Score (APDQS); a higher score favors nutritionally rich plant foods. Cox regression models were used to assess diabetes risk, and linear regression models were used to examine change in body size.During a mean follow-up of 9.3 (± 1.7) years, 206 case subjects with incident diabetes were observed. In multivariable analysis, participants with the largest increase in APDQS over 20 years had a 48% (95% CI 0.31-0.85; Ptrend < 0.001) lower risk of diabetes over the subsequent 10 years compared with participants whose score remained stable. Each 1-SD increment in APDQS over 20 years was associated with lower gains in BMI (-0.39 kg/m2; SE 0.14; P = 0.004), WC (-0.90 cm; SE 0.27; P < 0.001) and weight (-1.14 kg; SE 0.33; P < 0.001) during the same period, but not with subsequent changes.Young adults who increased plant-centered diet quality had a lower diabetes risk and gained less weight by middle adulthood.
Randomized Phase II Trial of Nivolumab With Stereotactic Body Radiotherapy Versus Nivolumab Alone in Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Sean McBride, Eric Sherman, C. Jillian Tsai, Shrujal Baxi, Jahan Aghalar, Juliana Eng, Wanqing Iris Zhi, Daniel McFarland, Loren Scott Michel, Robert Young, Robert Lefkowitz, Daniel Spielsinger, Zhigang Zhang, Jessica Flynn, Lara Dunn, Alan Ho, Nadeem Riaz, David Pfister, Nancy Lee
Journal: Journal of Clinical Oncology (2020)

The objective response rate (ORR) for single-agent anti-programmed death receptor 1 (anti-PD-1) therapy is modest in patients with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). We aimed to test whether radiotherapy may act synergistically with anti-PD-1 therapy to improve response through the abscopal effect.We conducted a single-center, randomized, phase II trial of nivolumab (anti-PD-1 therapy) versus nivolumab plus stereotactic body radiotherapy (SBRT) in patients with metastatic HNSCC. Patients had at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Patients were randomly assigned (1:1), stratified by human papillomavirus status, to nivolumab (3 mg/kg intravenously every 2 weeks) or nivolumab (same dose) plus SBRT (9 Gy × 3) to 1 lesion. The primary end point was ORR in nonirradiated lesions, which was assessed by RECIST in patients with at least one available set of on-treatment images; safety was assessed in a per-protocol population.Between March 11, 2016, and June 22, 2018, 62 patients were randomly assigned to nivolumab (n = 30) or nivolumab plus SBRT (n = 32). There was no statistically significant ORR difference between arms (34.5% [95% CI, 19.9% to 52.7%] v 29.0% [95% CI, 16.1% to 46.6%]; P = .86). There was no significant difference in overall survival (P = .75), progression-free survival (P = .79), or response duration (P = .26). Grade 3-5 toxicities were similar (13.3% v 9.7%; P = .70).We found no improvement in response and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.
Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study
Authors: Viktor Grünwald, Annika Karch, Markus Schuler, Patrick Schöffski, Hans-Georg Kopp, Sebastian Bauer, Bernd Kasper, Lars H. Lindner, Jens-Marcus Chemnitz, Martina Crysandt, Alexander Stein, Björn Steffen, Stephan Richter, Gerlinde Egerer, Philipp Ivanyi, Silke Zimmermann, Xiaofei Liu, Annegret Kunitz
Journal: Journal of Clinical Oncology (2020)

PURPOSE Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m 2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.
Phase I dose escalation trial of tremelimumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: M. S. Gordon, M. Stein, P. Shannon, S. Eddy, A. Tyler, L. Catlett, P. Hsyu, B. Huang, D. Healey, B. I. Rini
Journal: Journal of Clinical Oncology (2009)

5115 Background: Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor that has antitumor activity in mRCC. Recent data show sunitinib reduces levels of myeloid-derived suppressor cells and prevents T-cell suppression in pts with mRCC. CTLA4 blockade with tremelimumab is an immunotherapy that enhances T-cell activation and proliferation, and is associated with durable objective responses in metastatic melanoma. It was hypothesized that combination therapy could safely be administered. Methods: The primary endpoint was to assess maximum tolerated dose (MTD) of tremelimumab Q12W in combination with 2 schedules of SU (50 mg/day for 4 weeks followed by 2 weeks off or 37.5 mg QD continuous) in pts with ≤1 prior treatment. Tremelimumab doses were 6, 10, and 15 mg/kg. Secondary objectives included best overall response (RECIST), duration of response, safety, and pharmacokinetics. Results: Twenty-one pts were enrolled. Two of 5 pts in the SU 50 mg (4/2 schedule) plus tremelimumab 6 mg/kg cohort experienced dose-limiting toxicities (DLTs): 1) G5 ruptured diverticula; 2) prolonged G3 mucositis and fatigue. Further exploration of this schedule for SU was excluded. In the SU 37.5 mg QD continuous cohorts, no DLTs were observed at 6 mg/kg tremelimumab (n = 3), 1 of 6 pts treated with 10 mg/kg tremelimumab in the protocol-defined cohort suffered sudden death, and 3 of 6 pts treated with 15 mg/kg tremelimumab + SU experienced DLTs, including: 1 pt with G3 acute renal failure and G3 lymphopenia, 1 pt with G3 elevated creatinine, and 1 pt with worsening G3 dyspnea. Therefore, SU 37.5 QD + tremelimumab 10 mg/kg Q12W was considered the MTD. Five pts achieved partial response: 1 at SU 50 (4/2) + tremelimumab 6 mg/kg; 3 at SU 37.5 + tremelimumab 10 mg/kg; and 1 at SU 37.5 QD + tremelimumab 15 mg/kg. Six pts stayed on study ≥11 mo. An expansion cohort is enrolling another 12 patients at the MTD to further define toxicity and clinical activity. Conclusions: Tremelimumab 10 mg/kg Q12W + SU 37.5 mg QD was tolerable and associated with antitumor activity in pts with mRCC. Further exploration of this combination is warranted. [Table: see text]
Suppression of peritoneal metastasis of pancreatic cancer by Id1 and 3 double-knockdown.
Authors: Yasutaka Shuno, Nelson Tsuno, Takeshi Tsuchiya, Satomi Yoneyama, Jun Yamada, Junichiro Tanaka, Takeshi Nishikawa, Yurai Okaji, Giichiro Tsurita, Joji Kitayama, Koki Takahashi, Hirokazu Nagawa
Journal: Cancer Research (2008)

333  Objective: The Id (inhibitor of DNA binding/differentiation) proteins are transcriptional regulatory factors, and play important roles in tumor growth. Id are necessary for cell differentiation, proliferation, cell-cycle progression, migration, invasion, cell fate, and angiogenesis in many cell types. In the present study, we aimed to investigate the effect of Id1, 3 double-knockdown in human pancreatic cancer cells.  Methods: MIA-PaCa2, the human pancreatic cancer cell line, was used. The Id1, 3 double-knockdown MIA-PaCa2 cells were obtained by the RNA interference technique. Parental MIA-PaCa2 cells and empty vector (mock) transfectants were used as control.  The proliferative ability, the migrative capacity and the surface expression of transmembrane receptors were evaluated, in vitro. In vivo, the effects of Id1, 3 double-knockdown on the ability of MIA-PaCa2 to form metastatic peritoneal nodules was investigated in a mouse model of peritoneal metastasis.  Results: Cell proliferation and migration capabilities were significantly decreased in the double-knockdown MIA-PaCa2 cells, compared to control mock transfectants and the parental cells. Also, the expressions of integrins α3β1 and α6β1 were decreased in the double-knockdown cells. In vivo, the volume of peritoneal metastatic nodules were significantly reduced in the double-knockdown MIA-PaCa2, compared to mock transfectants and the parental cells.  Conclusions: Id1, 3 double-knockdown resulted in decreased ability of pancreatic cancer cells to proliferate and migrate, which can partly be explained by the decreased expression of integrins, molecules involved in the interaction with the extracellular matrix proteins. Moreover, development of peritoneal metastasis was reduced in vivo. From these results, we concluded that Id proteins play an important role in the development of peritoneal metastasis of pancreatic cancer. And, consequently, Id should be considered an ideal target for the treatment and prevention of pancreatic cancer.