tbuckley/cabot-search huggingface dataset:
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of LBH589, a novel deacetylase (DAC) inhibitor given intravenously on a new once weekly schedule
Authors: S. Sharma, N. J. Vogelzang, J. Beck, A. Patnaik, M. Mita, M. Dugan, A. Hwang, E. Masson, K. W. Culver, H. Prince
Journal: Journal of Clinical Oncology (2007)

14019 Background: LBH589 is a novel deacetylase inhibitor that inhibits proliferation of tumor cells at nanomolar levels. This phase I study tested the safety and tolerability of IV LBH589 once each week for 3 of 4 wks in pts with advanced solid tumors or lymphoma. Methods: LBH589 was administered IV over 30 min. on days 1, 8 and 15 of a 28-day cycle. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 8. Results: Thirty five pts (median age: 70 yrs; 23M, 12F) have been treated on 3 dose levels [10 mg/m 2 (8pts), 15 mg/m 2 (8 pts), 20 mg/m 2 (19 pts)] with the following tumor types: Cutaneous and peripheral T cell lymphoma (7 pts), prostate (6 pts), mesothelioma (4 pts), colon (3 pts) and other (15 pts). There was one dose-limiting toxicity (transient grade 4 thrombocytopenia) at 20 mg/m 2 , none at the lower doses. Other G3/G4 toxicities (all cycles) include: transient thrombocytopenia (G4–5 pts, G3–5 pts), neutropenia (G3–2 pts), anemia (G3–5 pts), G3 hypophosphatemia (1 pt), G3 hypokalemia (1 pt), G3 nausea (1 pt) and G3 pruritus (1 pt). Thrombocytopenia was transient. Of 2,042 ECGs, 1 pt had an increase in QTcF from baseline of &gt; 60 msec another with a QTcF &gt;500 msec, both at 20 mg/m 2 . There was a dose-dependent increase in HA 7 days after one dose with 43% (10 mg/m 2 ), 50% (15 mg/m 2 ) and 60% (20 mg/m 2 ) of pts with increased acetylation. The LBH589 plasma conc. peaked at the end of the 0.5 hr infusion with a mean terminal half-life of 16 hr. Median Cmax achieved with 20 mg/m 2 was 1,000 ng/mL (2.86 μM). The AUC0-inf increased linearly with IV doses of 10–20 mg/m 2 . One pt with CTCL achieved a complete response (CR) on cycle 3, Day 1; this pt had previously received oral LBH589 at 20 mg MWF, achieving a CR on cycle 6, Day 28 that lasted for 7 months. One peripheral T-Cell lymphoma pt achieved a partial response that has persisted for &gt;7 months. One pt with prostate cancer has had a 26% reduction in nodal disease and &gt; 50% drop in PSA in the first 2 cycles. Conclusions: The maximum tolerated dose of LBH589 given IV wkly on a 3 of 4 wk schedule is 20 mg/m 2 . This dose produced sustained PD effects and higher systemic exposure compared to oral LBH589. Preliminary evidence of antitumor activity has been observed. No significant financial relationships to disclose.
US abortion gag: clinics that leave family planning programme may have to destroy contraceptives
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Family planning clinics that leave the US government’s Title X programme may have to return or destroy any contraceptives they bought at a discount rate.1

Many clinics throughout the US are currently deciding whether to remain part of Title X, after Donald Trump’s government announced a “domestic gag rule” earlier this year.

Title X clinics already cannot provide abortion services, but this new rule would mean that they cannot refer patients to another service for an abortion and would ban them from discussing abortion with service users.

While the new gag rule on Title X is still tied up in the US …
A phase II randomized study of CMB305 and atezolizumab versus atezolizumab in NY-ESO-1<sup>+</sup> soft tissue sarcoma: Analysis of immunogenicity, tumor control, and patient survival.
Authors: Sant P. Chawla, Brian Andrew Van Tine, Seth Pollack, Kristen N. Ganjoo, Anthony D. Elias, Richard F. Riedel, Steven Attia, Edwin Choy, Scott H. Okuno, Mark Agulnik, Margaret von Mehren, Michael B. Livingston, Vicki Leigh Keedy, Claire F. Verschraegen, Tony Philip, Gerry C. Bohac, Sergey Yurasov, Hailing Lu, Michael Chen, Robert G. Maki
Journal: Journal of Clinical Oncology (2019)

11011 Background: CMB305 (C) is an immunotherapy designed to generate an anti-NY-ESO-1 immune response (IR). C consists of a dendritic cell-targeting lentiviral vector encoding NY-ESO-1 gene (LV305), and a TLR-4 agonist NY-ESO-1 recombinant protein plus GLA-SE (G305). A Phase 1 study demonstrated C is safe, generates IR and conveys a median overall survival (mOS) of 23.7 months (15.5, not reached [NR]) for soft tissue sarcomas &amp; 29.2 months (12.2, NR) for synovial sarcoma (SS) (ESMO 2018). We evaluated efficacy and safety of C and atezolizumab (A) vs A alone in NY-ESO-1 + SS and myxoid round cell liposarcoma (MRCL). Methods: A prospective randomized open label phase 2 study of C (LV305 Intradermal Days 0, 14, 42, 70 + G305 Intramuscular Days 28, 56, 84 then q 6wk up to one year (yr)) + A (1200mg IV q3wk) vs A alone in advanced NY-ESO-1+ SS/MRCL. Primary endpoints of OS and progression-free survival (PFS); secondary endpoints of safety, IR, and response rate and post hoc analysis by line of therapy. Results: 88 patients (pts) were enrolled and dosed. Arm C+A: median age 48 yrs, 73% SS, 98% relapsed metastatic, 73% ≥2 prior lines chemotherapy; Arm A: 47 yrs, 67% SS, 84% relapsed metastatic, 53% ≥2 prior lines chemotherapy. Most treatment-related adverse events (TRAE) Grade 1/2, no treatment related deaths. Summary of clinical outcomes. Conclusions: Despite no major differences in PFS and OS between the treatment arms (Arm C+A had more advanced disease and more prior lines of chemotherapy), Arm A +C achieved PRs, a higher level of anti-NY-ESO-1 IR, and pts with IR had numerically superior outcomes. Moreover, the clinical benefit of C+A in earlier lines of therapy warrant further study. Clinical trial information: NCT02609984. [Table: see text]
Palliative benefit of novel cell-free and concentrated ascites reinfusion therapy (CART) for refractory ascites associated with cancerous peritonitis.
Authors: Keisuke Matsusaki, Akitaka Yoshizawa, Keiichiro Ohta
Journal: Journal of Clinical Oncology (2013)

e20591 Background: Refractory ascites associated with cancerous peritonitis causes severe abdominal distention, dyspnea and appetite loss, resulting in loss of patients’ activities of daily living (ADL) and discontinuation of their treatment for cancer such as chemotherapy. To improve the symptoms, we have developed a novel cell-free and concentrated ascites reinfusion therapy (CART) which is modified from a conventional CART approved by the Ministry of Health, Labor and Welfare in Japan and examined the efficacy in a pilot study. Methods: 87 patients with cancerous ascites were enrolled and subjected to novel CART from April 2012 to November 2012. The response was assessed by improvement of their ADL. Patients were asked in the form of questionnaires about general malaise, abdominal distention, abdominal pain, nausea, dyspnea, sleep disturbance, appetite loss, disturbance in gait, discomfort and frustration before and after treatment and each point was scored on a scale of zero to ten (ten being severe). Abdominal and thigh circumferences were also examined before and after treatment to evaluate efficacy. This study was approved by the ethics review committee of Kaname-cho hospital. Results: On average, 8.3 ± 4.4 L (range 2.3-27.0) of cancerous ascites was filtrated and concentrated to 0.69 ± 0.28 L (range 0.2-1.6) by novel CART. Any severe adverse events except fever were not observed. After treatment, the scores of all points were significantly improved. For example, abdominal distention was improved by 8.1 ± 2.4 vs. 2.0 ± 2.4 (p&lt;0.0001), dyspnea by 3.7 ± 3.3 vs. 1.3 ± 2.1 (p&lt;0.0001), and appetite loss by 5.3 ± 4.3 vs. 3.1 ± 3.4 (p&lt;0.0001). Abdominal and thigh circumferences were also decreased by -13.3 ± 7.5 cm (p&lt;0.0001) and -2.7 ± 2.6 cm (p&lt;0.0001), respectively. Conclusions: This novel CART system is capable to process over 20 L of cancerous ascites and immediately improve their ADL and edematous lesions. Some patients also restarted anticancer treatment such as chemotherapy. Taken together, this CART is safe and effective for palliative care of patients with cancerous ascites.
Incidence of severe nephrotoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with sub-group analyses based on renal eligibility criteria.
Authors: Arati Dahal, Brandon Kyle Bellows, Guru Sonpavde, Matt D. Galsky, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2013)

e15549 Background: Serum Creatinine (SCr) is commonly used to screen patients for eligibility in trials of the nephrotoxic drug cisplatin despite the fact that glomerular filtration rate (GFR) is known to better estimate renal function. The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin for treatment of solid tumors when renal function was assessed using SCr or GFR for eligibility criteria. Methods: A literature search was conducted in PubMed to identify randomized trials comparing cisplatin to non-cisplatin containing chemotherapy regimens. Studies were included if they were performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events for both treatment arms. Review articles, non-randomized trials, observational, phase I, studies without a comparator group, or not reported in English were excluded. The relative risk (RR) of grade ≥3 nephrotoxicity associated with cisplatin vs. non-cisplatin regimens was examined using inverse variance weighted fixed effects (FE) and random effects (RE) methods. Subgroup analyses of studies using SCr, GFR, and either SCr or GFR for screening were performed. Results: The literature search identified 2,359 studies, and 42 studies met all inclusion and exclusion criterion (N=9,521 patients). SCr was used as eligibility criteria in 20 studies (N=4,704), GFR was used by 9 studies (N=1,650), and either SCr or GFR was used by 13 studies (N=3,167). The overall RR for developing nephrotoxicity with cisplatin vs. non-cisplatin treatment was 1.75 (95%CI 1.18-2.58, p=0.005). Results from subgroup analyses showed the RR was 2.60 (95%CI 1.34-5.03, p=0.005) when SCr was used as eligibility criteria compared to 1.50 (95%CI 0.82-2.74, p=0.19) when GFR was used and 1.26 (95%CI 0.55-2.85, p=0.59) when either SCr or GFR was used. Results did not vary between FE and RE methods. Conclusions: Cisplatin based therapy is associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity is higher in trials that utilize SCr as eligibility criteria compared to those that utilize GFR.
Multicentric ipilimumab experience in Turkish patients with metastatic melanoma: MIPI-TURK.
Authors: Alper Sevinc, Hande Turna, Mustafa Ozdogan, Suleyman Buyukberber, Gokhan Demir, Erhan Gokmen, Nil Molinas Mandel, Semra Paydas, Hakan Akbulut, Ismail Celik
Journal: Journal of Clinical Oncology (2012)

e19024 Background: Ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen) monoclonal antibody has been shown to enhance immune responses and induce durable clinical responses in patients with metastatic melanoma. The authors report retrospectively on metastatic melanoma patients treated under Expanded Access Program in Turkey among 13 centers. Methods: Patients with metastatic melanoma were treated with ipilimumab 3 mg/kg for 4 doses on weeks 1, 4, 7, 10 as induction. Response evaluation was done on week 12. Patients with complete response (CR), partial response (PR) and stable disease (SD) at week 12 were eligible for re-induction. Results: A total of 75 patients enrolled with 70 evaluable. Ipilumumab treatment was given as 2nd, 3rd and 4th line in 20.0%, 64.3% and 15.7% of patients respectively. The numbers of patients receiving ipilimumab for 1, 2, 3 and 4 doses were 9, 12, 13 and 36, respectively. Seven of 70 patients were eligible for re-induction. G1/2 adverse events were reported in 32.8% (23/70) of patients whereas G3/4 was 14.3% (10/70). The most common G1/2 immune related adverse event was skin rash (14.3%) followed by muscle weakness (10.0%) and gastrointestinal side effects (8.6%). There were seven G3 side effects (diarrhea in 4, muscle weakness in 1, hypothyroidism in 1 and GI bleeding in 1 patient). There was one reversible G4 thrompocytopenia and two deaths were associated with hepatic AEs. Thirty-six of 70 patients (51.4%) completed 4 doses ipilimumab treatment were available for response evaluation. There was no CR. The disease control rate (DCR) was 36.1% (PR: 8.3% and SD 27.8%). Median time to progression (TTP) was 2.7 months (95% CI, 2.1-4.2 months). Median overall survival was not reached with 61.3% of patients surviving within 12 months of follow up period. Conclusions: As a conclusion, ipilimumab treatment resulted in favorable clinical benefit for metastatic melanoma patients. Data generated by our 13 centers revealed an efficacy and safety profile consistent with the currently avaliable knowledge.
Triple-Negative Myeloproliferative Neoplasms Vs. Calr, JAK2 or MPL-Mutated Myeloproliferative Neoplasms: Distinct Molecular Characteristics
Authors: Jiwon Yun, Jung-Ah Kim, Byungjin Hwang, Hee Sue Park, Kyongok Im, Sung-Min Kim, Dajeong Jeong, Kyu Min Lim, Duhee Bang, Dong Soon Lee
Journal: Blood (2018)
Emerging Multimodality Approaches to Treat Localized Esophageal Cancer
Authors: Ronan J. Kelly
Journal: Journal of the National Comprehensive Cancer Network (2019)

Esophageal cancer has a poor prognosis, with 5-year survival rates ranging from 20% to 35% in the nonmetastatic setting. Despite advances in surgical techniques and optimization of chemoradiotherapy regimens, overall survival benefits have been incremental at best. Esophageal cancer requires a concerted multidisciplinary approach, perhaps more so than any other tumor type given the integral role played by the esophagus in maintaining calorific intake and the propensity for early spread through the lymphatics. This review describes the latest in surgical techniques to minimize postoperative complications and examines previous and ongoing systemic therapy approaches. Strategies that harness a patient’s own immune system hold great promise, and shifting checkpoint inhibitors from the metastatic setting to the neoadjuvant/adjuvant setting is currently being evaluated in phase II and III clinical trials. In addition, a much better understanding of the interplay between tumors and their immune microenvironment is clearly needed to better judge how best to engage each patient’s immune system, and there will be likely demonstrable differences between early-stage tumors and metastatic disease. This review highlights emerging data, which demonstrate that, in addition to The Cancer Genome Atlas classification of esophageal squamous cell carcinoma having a distinct molecular makeup compared with esophageal adenocarcinoma, there are also differing responses to PD-1 inhibitors. Histology and the underlying immune milieu may have important ramifications for the management of localized disease in the future, above and beyond PD-L1 expression, microsatellite instability status, and tumor mutational burden.
Nuclear SMAD4 as a predictor of survival in patientes with extremity soft tissue sarcomas submitted to neoadjuvant chemotherapy.
Authors: Isabela Werneck Cunha, Ranyell Spencer Sobreira Batista, Paulo Roberto Stevanato, Samuel Aguiar, Ademar Lopes, Celso Abdon Mello, Wilson Luiz da Costa
Journal: Journal of Clinical Oncology (2013)

10586 Background: Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas, although not standard, represents a promising option for resectable tumours. The discovery of biological predictors of chemotherapy response highlights the possibility to develop individualised therapeutic approaches in selected group of patients or predict survival also. The SMAD4 protein, a member of TGFβ superfamily has a role in progression and tumor metastasis and may be involved sarcomas recurrence. Methods: 30 patients with soft tissue sarcomas (STS) of high-grade located in extremities treated with neoadjuvant doxorubicin and ifosfamide chemotherapy were observed prospectively since January 2005 to June 2011. All patients were submitted to radiation therapy adjuvant. Surgical specimens after neoadjuvant treatment were evaluated of SMAD4 nuclear expression by immuno-histochemistry and percentage of viable cells Results: The median follow-up time was 42 months. The overall survival (OS) was 91.7% in patients with low expression SMAD4 nuclear protein associated with ≤10% of viable cells (n=12) in the surgical specimen and 68.9% in the remaining patients. Likewise, the disease free survival (DSF) was 91.7% versus 38.6% (p 0.01) respectively. Conclusions: The combination of nuclear SMAD4 low expression and 10% or less of viable cells in the surgical specimen was statistically significant in better DFS in patients with locally advanced extremity STS treated with neoajuvant chemotherapy with benefit in OS.
Definition of Synchronous Oligometastatic Non–Small Cell Lung Cancer—A Consensus Report
Authors: Anne-Marie C. Dingemans, Lizza E.L. Hendriks, Thierry Berghmans, Antonin Levy, Baktiar Hasan, Corinne Faivre-Finn, Matteo Giaj-Levra, Niccolò Giaj-Levra, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, John Edwards, Mary O’Brien, Martin Reck, Egbert F. Smit, Paul Van Schil, Pieter E. Postmus, Sara Ramella, Yolande Lievens, Mina Gaga, Nir Peled, Giorgio V. Scagliotti, Suresh Senan, Luiz Paz-Ares, Matthias Guckenberger, Fiona McDonald, Simon Ekman, Tanja Cufer, Hester Gietema, Maurizio Infante, Rafal Dziadziuszko, Solange Peters, Ramon Rami Porta, Johan Vansteenkiste, Christophe Dooms, Dirk de Ruysscher, Benjamin Besse, Silvia Novello
Journal: Journal of Thoracic Oncology (2019)

IntroductionImproved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.MethodsA pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.ResultsIt was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography–computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography–computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.ConclusionA multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.
Cognitions Associated With Hypoglycemia Awareness Status and Severe Hypoglycemia Experience in Adults With Type 1 Diabetes
Authors: Amelia J. Cook, Stephanie N. DuBose, Nicole Foster, Emma L. Smith, Mengdi Wu, Georgina Margiotta, Michael R. Rickels, Jane Speight, Nicole de Zoysa, Stephanie A. Amiel
Journal: Diabetes Care (2019)

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and recurrent severe hypoglycemia (RSH) remain problematic for people with type 1 diabetes (T1D), despite major therapeutic advances. We explored beliefs around hypo- and hyperglycemia in adults with T1D with, and without, IAH and RSH. RESEARCH DESIGN AND METHODS A cross-sectional U.S. multicenter survey included Attitudes to Awareness of Hypoglycemia (A2A; a 19-item questionnaire concerning beliefs about hypoglycemia), the Gold score (single item: awareness of hypoglycemia), and a question about severe hypoglycemia over the preceding year. The survey was emailed to 6,200 adult participants of the annual T1D Exchange clinic registry data collection. A2A data were subjected to principal component analysis with varimax rotation. RESULTS Among 1,978 respondents (response rate 32%), 61.7% were women, mean ± SD age was 39.6 ± 16.3 years, and T1D duration was 23.1 ± 13.8 years. Thirty-seven percent reported IAH, 16% RSH, and 9% both. A2A items segregated into three factors, differently distributed by hypoglycemia experience. Respondents with IAH or RSH expressed appropriate concern about hypoglycemia, but those with IAH were more likely to prioritize hyperglycemia concerns than those with intact awareness (P = 0.002). Those with RSH showed greater normalization of asymptomatic hypoglycemia than those without (P = 0.019) and trended toward prioritizing hyperglycemia concerns (P = 0.097), driven by those with both IAH and RSH. CONCLUSIONS Adults with T1D with IAH and RSH report specific cognitions about hypoglycemia and hyperglycemia, which may act as barriers to hypoglycemia avoidance and recovery of awareness. These may be modifiable and present a target for enhancing engagement of vulnerable people with strategies to avoid future hypoglycemia.