tbuckley/cabot-search huggingface dataset:
Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy
Authors: Song Xue, Man Hu, Veena Iyer, Jinming Yu
Journal: Journal of Hematology & Oncology (2017)

Gliomas are the most common type of primary brain tumor in adults. High-grade neoplasms are associated with poor prognoses, whereas low-grade neoplasms are associated with 5-year overall survival rates of approximately 85%. Despite considerable progress in treatment modalities, the outcomes remain dismal. As is the case with many other tumors, gliomas express or secrete several immunosuppressive molecules that regulate immune cell function. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand that is predominantly expressed by tumor cells. The binding of PD-L1 to its receptor PD-1 has been demonstrated to induce an immune escape mechanism and to play a critical role in tumor initiation and development. Encouraging results following the blockade of the PD-1/PD-L1 pathway have validated PD-L1 or PD-1 as a target for cancer immunotherapy. Studies have reported that the PD-1/PD-L1 pathway plays a key role in glioma progression and in the efficacy of immunotherapies. Thus, progress in research into PD-L1 will enable us to develop a more effective and individualized immunotherapeutic strategy for gliomas. In this paper, we review PD-L1 expression, PD-L1-mediated immunosuppressive mechanisms, and the clinical applications of PD-1/PD-L1 inhibitors in gliomas. Potential treatment strategies and the challenges that may occur during the clinical development of these agents for gliomas are also reviewed.
Ischemic Cerebroprotection Conferred by Myeloid Lineage-Restricted or Global CD39 Transgene Expression
Authors: Amy E. Baek, Nadia R. Sutton, Danica Petrovic-Djergovic, Hui Liao, Jessica J. Ray, Joan Park, Yogendra Kanthi, David J. Pinsky
Journal: Circulation (2017)

Cerebral tissue damage after an ischemic event can be exacerbated by inflammation and thrombosis. Elevated extracellular ATP and ADP levels are associated with cellular injury, inflammation, and thrombosis. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39), an enzyme expressed on the plasmalemma of leukocytes and endothelial cells, suppresses platelet activation and leukocyte infiltration by phosphohydrolyzing ATP/ADP. To investigate the effects of increased CD39 in an in vivo cerebral ischemia model, we developed a transgenic mouse expressing human CD39 (hCD39).A floxed-stop sequence was inserted between the promoter and the hCD39 transcriptional start site, generating a mouse in which the expression of hCD39 can be controlled tissue-specifically using Cre recombinase mice. We generated mice that express hCD39 globally or in myeloid-lineage cells only. Cerebral ischemia was induced by middle cerebral artery occlusion. Infarct volumes were quantified by MRI after 48 hours.Both global and transgenic hCD39- and myeloid lineage CD39-overexpressing mice (transgenic, n=9; myeloid lineage, n=6) demonstrated significantly smaller cerebral infarct volumes compared with wild-type mice. Leukocytes from ischemic and contralateral hemispheres were analyzed by flow cytometry. Although contralateral hemispheres had equal numbers of macrophages and neutrophils, ischemic hemispheres from transgenic mice had less infiltration (n=4). Transgenic mice showed less neurological deficit compared with wild-type mice (n=6).This is the first report of transgenic overexpression of CD39 in mice imparting a protective phenotype after stroke, with reduced leukocyte infiltration, smaller infarct volumes, and decreased neurological deficit. CD39 overexpression, either globally or in myeloid lineage cells, quenches postischemic leukosequestration and reduces stroke-induced neurological injury.
William John Reilly
Authors: Antony Fulford-Smith
Journal: BMJ (2017)

Born in County Cavern, Ireland, William John Reilly (“Bill”) was brought up in Coatbridge, Glasgow, by his aunt and uncle after his widowed mother went to the US to fund her two sons (Bill and Paul). Bill went to medical school in Glasgow and did house jobs in Bury St Edmunds. National service with the Royal Army Medical Corps took him to Germany and Africa. In 1952 he started as a general practitioner in Dawley, Shropshire. He stayed with the practice until he retired in 1990 and was a member of the Shropshire local medical committee for many years.

During the 1970s he published several Personal View articles in The BMJ and was a …
Anatomic segmentectomy versus lobectomy for clinical stage I non-small cell lung cancer: A propensity-matched analysis.
Authors: Matthew J. Schuchert, Daniel Paul Normolle, Kristen N. McCormick, David O Wilson, Jill Siegfried, Joshua P Landreneau, Margaret Reamer, James D. Luketich, Rodney Jerome Landreneau
Journal: Journal of Clinical Oncology (2012)

7071 Background: Although anatomic segmentectomy is considered a “compromised” procedure by many surgeons, new information from several retrospective, single-institution series has countered negative premises regarding tumor recurrence and patient survival. The primary objective of this study was to utilize propensity score matching to compare outcomes following these anatomic resection approaches for stage I NSCLC. Methods: Patients undergoing lobectomy (n=392) vs. segmentectomy (n=793) for clinical stage I NSCLC were matched 1:1 using a propensity score that accounted for the potential confounding effects of pre-operative patient variables. Matching based on propensity scores produced 312 patients in each group. Primary outcome variables included recurrence-free and overall survival. Factors affecting survival were assessed by proportional hazards (Cox) regression and Kaplan-Meier survival function estimates. Results: Peri-operative mortality was 1.2% in the segmentectomy group and 2.5% in the lobectomy group (p=0.38). Ninety-day mortality was 2.6% and 4.8% (p=0.20), respectively. At a mean follow-up of 5.4 years, no differences were noted in locoregional (5.5% vs. 5.1%, p=1.00), distant (14.8% vs. 11.6%, p=0.29) or overall recurrence rates (20.2% vs. 16.7%, p=0.30) when comparing segmentectomy with lobectomy. Furthermore, no significant differences were noted in time to recurrence (p=0.415) or overall survival (p=0.258) when comparing the matched groups. Five year freedom from recurrence (95% CI) was: Segment 0.70 [95% CI: (0.63, 0.78) vs. Lobe 0.71 [95% CI: 0.64, 0.78]. Overall survival (95% CI) was: Segment 0.54 [95% CI: (0.47, 0.51) vs. Lobe 0.60 [95% CI: 0.54, 0.67]. Segmentectomy was not found to be an independent predictor of recurrence (HR: 1.11, 95% CI: 0.87, 1.40) or overall survival (HR = 1.17, 95% CI: 0.89.1.52). Conclusions: In this large propensity-matched comparison, anatomic segmentectomy is associated with similar time to recurrence and overall survival rates when compared to lobectomy for clinical stage I NSCLC. These results will need further validation by prospective, randomized trials (CALGB 140503).
A bleeding socket after tooth extraction
Authors: Isabelle J Moran, Libby Richardson, Manolis Heliotis, Alex Bewick
Journal: BMJ (2017)

#### What you need to know

A fit and well 25 year old man attends his local emergency department concerned about a bleeding tooth socket after having had a lower wisdom tooth extracted earlier that morning.

Postoperative bleeding is a recognised complication after tooth extraction, with an incidence of up to 1.4% of patients undergoing lower wisdom tooth surgery.1 It can be difficult to achieve complete haemostasis within the oral cavity because of the highly vascular nature of the tissues and exposure of the open socket to the patient’s exploring tongue and fingers.2

In healthy patients, a low level ooze for 12-24 hours after extraction is normal as an organised clot forms in the tooth socket.23 The patient will have mildly bloodstained saliva that will decrease over time. Any active bleeding beyond this point often indicates a haemostatic problem and requires investigations and treatment.4

Significant, active haemorrhage must be addressed before taking a comprehensive history. It …
Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial
Authors: Gerd R Burmester, William F Rigby, Ronald F van Vollenhoven, Jonathan Kay, Andrea Rubbert-Roth, Ricardo Blanco, Alysha Kadva, Sophie Dimonaco
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objective</h3> Investigate whether the efficacy and safety of intravenous tocilizumab (TCZ) demonstrated at week 52 in patients with early rheumatoid arthritis (RA) are maintained to week 104. <h3>Methods</h3> Methotrexate (MTX)-naive patients with early progressive RA were randomly assigned to double-blind 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo or placebo+MTX for 104 weeks. Patients not receiving 8 mg/kg TCZ and not achieving Disease Activity Score-28 joints (DAS28-erythrocyte sedimentation rate (ESR)) ≤3.2 at week 52 switched to escape therapy (8 mg/kg TCZ+MTX). Analyses were exploratory. <h3>Results</h3> Intent-to-treat and safety populations included 1157 and 1153 patients, respectively. DAS28-ESR remission (&lt;2.6) rates were maintained from weeks 52 to 104 (eg, 8 mg/kg TCZ+MTX, 49.3% to 47.6%). Placebo+MTX and 4 mg/kg TCZ+MTX escape patients9 week 104 response rates were 51.4% and 30.5%, respectively. Inhibition of radiographic progression was maintained with 8 mg/kg TCZ (eg, 8 mg/kg TCZ+MTX mean (SD) change from baseline in modified total Sharp score: 0.13 (1.28), week 52; 0.19 (2.08), week 104). The safety profile of TCZ was consistent with that of previous reports. <h3>Conclusions</h3> Patients with early RA treated with TCZ monotherapy or TCZ+MTX maintained clinical benefits during their second year of treatment with no new safety signals. <h3>Trial registration number:</h3> NCT01007435; Results.
The role of surgery in limited-disease small cell lung cancer (SCLC); a retrospective comparative study
Authors: A. Badzio, K. Kurowski, H. Karnicka-Mlodkowska, J. Jassem
Journal: Journal of Clinical Oncology (2004)

7221 Background: Despite very high response rates to chemotherapy, prognosis of SCLC patients has remained poor with a median survival of only 12–14 months for limited disease. High incidence of local relapses after chemotherapy in limited-stage SCLC led to reassessment of the role of local treatment in the multimodality management of this tumor Methods: We performed retrospective analysis of survival in two groups of limited-stage patients treated with either complete resection followed by chemotherapy (67 patients) or with conventional non–surgical management (67 patients). In all patients managed with the resection, the diagnosis of SCLC was established only postoperatively. The control group was selected using “pair-matched case-control” methodology, out of 176 limited-stage patients potentially suitable for surgery, but treated without resection. The major prognostic factors were well balanced between these two groups. Total series included 109 males and 25 females, 20 patients with T1 and 114 patients with T2 disease, 51 N0, 43 N1 and 40 N2 disease. In the surgical group, 23 patients received elective cranial irradiation and in the non-surgical group 39 pts received thoracic irradiation. Results: : Median survival in patients treated with and without surgery was 22 months and 11 months, respectively (p<0.001). The two-year and five-year survival probabilities were 43% and 27%, respectively in the surgical group, and 17% and 4%, respectively in the non-surgical group. Subset analysis confirmed significantly longer survival with surgery in all T and N categories, except for N2 disease. Local relapse occurred in 15% and 55% of patients treated with and without surgery, respectively (p<0.001). Distant relapse rates were similar in both groups (36% and 40%, respectively). Conclusions: These data suggest that improved local control may possibly be translated into prolonged survival in selected limited-stage SCLC patients. A randomised study assessing the role of surgery in combined modality treatment of those patients seems to be justified No significant financial relationships to disclose.
Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose interleukin-2: Interim analysis data.
Authors: Laura Ridolfi, Francesco De Rosa, Anna Maria Granato, Elena Pancisi, Jenny Bulgarelli, Antonino Romeo, Elisabetta Parisi, Massimiliano Petrini, Laura Fiammenghi, Valentina Ancarani, Valentina Soldati, Giorgia Gentili, Ugo De Giorgi, Salvatore Luca Burgio, Angela Riccobon, Alice Rossi, Serena Cassan, Massimo Guidoboni
Journal: Journal of Clinical Oncology (2015)

e14007 Background: Ashigh-dose Interleukin-2 (HDIL2) is a necessary component of a curative treatment strategy in melanoma and renal cell carcinoma (RCC), it is imperative to improve its therapeutic index. Radiotherapy (XRT) strongly synergizes with immunotherapy and may boost the effects of HDIL2 allowing for less toxic schedules. Methods: In this proof-of-principle phase II study, biological markers and immune response were considered as primary endpoints in pre-treated metastatic melanoma (MM) o RCC patients. Three daily doses of boosted XRT (6-12 Gy) were delivered to one lesion before the first and third IL-2 cycles (dose 18 MIU/m2/day by continuous IV infusion for 72 h).Cycles were repeated every 3 weeks for a maximum of 6. A minimax two-stage Simon design was used: 7 patients were enrolled during the first stage and if an immune response was observed in at least 3, a further 12 patients were recruited. PBMCs were evaluated for tyrosinase, gp100, Mart-1, 5T4, CAIX/G250, EGFR, survivin, MAGEA3 and NYESO1 in IFNgamma ELISPOT assay. Enhancement of at least 10% of antigen-specific spot-forming cells (SFC) for at least one antigen after treatment with respect to baseline was considered as positive. Results: From September 2012, we enrolled 5 RCC and 5 MM patients. Median age was 44 years. All MM patients were BRAF wild type. Four (2 MM and 2 RCC) of the 7 patients evaluable for immunological response showed a tumor antigen-specific immune response. One MM patient had T-cell reactivity against Mart1, MAGEA3, NYESO1, survivin; the other to gp100 and survivin. One RCC patient had reactivity against MAGEA3, survivin, CAIX, 5T4, EGFR, and 5T4; the second to survivin, NYESO, and MAGEA3. In 9 patients evaluable for clinical response we observed 1 CR (24+ months), 1 PR (3+ months), 1 SD (6 months), all in RCC patients, and 5 PD. Median daily dose of IL2 was 35.8 MIU. Most toxicities by CTCAE 4.0 were grade 1-2. Grade 3 toxicities were 1 acute renal failure, 1 lymphopenia and 1 venous thrombosis. The IL2 dose was never reduced, nor was the infusion interrupted. Conclusions: This schedule of HDIL2+XRT is well tolerated and fairly active in this setting of MM and RCC. Clinical trial information: NCT01884961.
Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among BRCA mutation “previvors.”
Authors: Laura L. Holman, Molly S Daniels, Amanda C. Brandt, Banu Arun, Elizabeth Keeler, David Marc Gershenson, Charlotte C. Sun, Karen H. Lu
Journal: Journal of Clinical Oncology (2012)

1518 Background: We prospectively evaluated the timing and uptake of risk-reducing surgery in a cohort of female BRCA mutation carriers that have no personal cancer history (“previvors”). Methods: Patients at high risk of breast and ovarian cancer were enrolled between 2007 and 2011 and followed in a high-risk ovarian cancer screening clinic. Women were offered risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy (PM) per guidelines. Their clinical data were recorded and analyzed using descriptive statistics. Results: Of 260 BRCA mutation carriers enrolled, 73 have no personal history of cancer and are “previvors.” Patients have been followed for a median of 26.5 months (1-50 months). The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2% of participants and 55.4% have a BRCA2 mutation. The majority of patients (77.6%) presented for ovarian cancer screening &lt;1 year after their BRCA testing. In all, 60.8% of women underwent prophylactic surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both procedures. Postmenopausal women were more likely to choose RRSO, while uptake for both procedures was common for premenopausal women (Table, p=0.04). RRSO was also more likely in parous than nulliparous premenopausal women (35.2% vs 9% p=0.001). PM was not associated with parity (p=0.79). Of women that had both surgeries, 20% had them concurrently and 20% had PM first. Of the 60% that underwent RRSO first, all had their second surgery within 14 months. Conclusions: BRCA mutation “previvors” have a high overall uptake of prophylactic surgery. Premenopausal women are more likely to choose PM than postmenopausal women; reasons for this are unclear. “Previvors” that choose RRSO and PM typically have both surgeries within a fairly short timeframe. With the growing population of “previvors” in the US, further study of patient preferences regarding preventative surgery and long-term consequences is needed. [Table: see text]
Adherence (adh) to and beliefs about oral anticancer medications (OAMs) in metastatic renal cell carcinoma (mRCC) patients (pts): A single-center pilot study in the United States.
Authors: Daniel M. Geynisman, Fay J. Hlubocky, Masha Kocherginsky, Sarah M. Duster, Joseline X. Gomez, Walter Michael Stadler, Christopher Daugherty
Journal: Journal of Clinical Oncology (2013)

e17511 Background: Suboptimal adh to drugs is a problem in chronic diseases. In mRCC, OAMs are the mainstay of treatment (tx). Adh and its determinants in exclusively mRCC pts has not been studied in the US. This study aimed to evaluate adh to OAMs in mRCC pts, and describe pts understanding and beliefs about OAMs and their disease. Methods: Single center, cross-sectional study of pts on OAMs for at least 60 days. Planned study size is 50 pts. Standardized assessment instruments used: Adh—MMAS-8 questionnaire (Q); beliefs and expectations regarding OAMs—Beliefs about Medicines Q (BMQ) and Brief-Illness Perception Q (IPQ); Quality of Life (QOL)—BSI-18, FKSI. Semi-structured interviews assessed financial burden, barriers to adh, understanding of prognosis and goals of therapy. Results: To date, 40 pts have been studied. Median age 66 (range 36-85), 75% male, 78% Caucasian, 43% college graduates, 58% with income ≤ 60K. OAMs used: 43% sunitinib, 25% pazopanib, 23% everolimus, 8% axitinib. 1 st line tx: 45%; 2 nd line tx: 30%; 3 rd or beyond: 25%. MMAS-8: 7.4 ± 1.1 (range 3-8); 10% low adheres, 30% intermediate, 60% high. 36% reported not receiving counseling on taking OAMs. BMQ-Necessity: 20 ± 4 (range 8-25); BMQ-Concern: 12 ± 4 (range 5-24). IPQ: 40 ± 13 (range 6-71). QOL: BSI 10 ± 9 (range 0-38); FKSI 44 ± 8 (range 26-60). 18% reported financial difficulty paying for OAMs; 25% paid ≥ $100/mo. No significant difference between adherers and non-adherers in regard to demographic, QOL or belief variables was detected. 23% did not believe OAMs are chemotherapy. 67% believed mRCC is a chronic disease, 46% believed that their OAM may be able to cure them and 44% strongly agreed or agreed with “I expect to be free of cancer in the future.” 52% reported not discussing prognosis with their MD. Conclusions: Our data suggest that self-reported adh in mRCC is much better than in other diseases. Most pts felt mRCC was a chronic disease and almost 50% believed they could be cured. Further research is needed addressing the development of an oncology-specific adh tool and defining an optimal adh benchmark for OAMs via prospective studies of self-reported adh, serum drug levels and outcomes.
How well is interdependent care managed across specialties in breast cancer? Metrics and pre-implementation data from the 4R in Oncology Project.
Authors: Christine B. Weldon, Julia Rachel Trosman, Claudia B. Perez, Swati Kulkarni, Seema Ahsan Khan, Nora Hansen, Valerie Nelson, Jennifer Stein, Melissa A. Simon, Jonathan Blake Strauss, Sasa M. Espino, Mikele Bunce, Wayne Pan, Sarah M. Friedewald, William John Gradishar
Journal: Journal of Clinical Oncology (2017)

171 Background: The “NCI ASCO Teams” Project emphasized management of interdependent cancer care across specialties as crucial to teamwork, yet a considerable challenge (Taplin JOP 2015). Interdependent care requires well-managed timing and sequencing of events across specialties. We developed the 4R model (Right Information / Care / Patient / Time) to manage interdependent care and facilitate teamwork (Trosman JOP 2016). 4R is being implemented at 3 centers: academic, community and safety net. Pre-implementation, we identified guideline recommended interdependent care whose timing / sequencing is challenging, developed relevant adherence metrics and gathered current state data. Methods: Interviews with 42 clinicians across breast cancer (BC) specialties at the 3 sites, using theme analysis to identify challenging interdependent care. Guidelines and literature were used to define adherence metrics. Clinical data were reviewed for 162 Stage I-III patients at 3 sites to measure adherence. Results: We identified 7 interdependent BC care events for which timing / sequencing is a challenge - Table. Adherence ranged from 0% to 100%, and was &lt; = 50% for 6 of the 7 care events. Preoperative BRCA 1/2 results and neoadjuvant consult showed highest adherence, yet were most frequently noted as a challenge: interviewees reported substantial ad-hoc efforts applied to managing timeliness of these events. Conclusions: Identified challenges and adherence gaps support the need for the 4R implementation for systematic, consistent and timely delivery of interdependent care. Established metrics will allow pre / post 4R implementation comparison and may inform broader adoption of the 4R model. [Table: see text]
Opening the door of your patient’s medicine cabinet: Unexpected outcomes of cancer pain management.
Authors: Alison Wiesenthal, Natalie Moryl, Paul A. Glare
Journal: Journal of Clinical Oncology (2014)

e20629 Background: Most victims of the current epidemic of prescription pain medicine (PPM) overdoses are non-patients, with 75% of overdoses attributed to opioids prescribed to someone else. Responsible prescribing of PPM should include monitoring the amount of unused PPM and reducing refills accordingly. The aim of this exploratory study was to estimate the amount of unused opioids prescribed for cancer pain at a comprehensive cancer center (CCC). Methods: At each clinical encounter in one Palliative Medicine clinic at a CCC over a 3 month period, we documented consecutive patients’ self-reports of adequacy of pain relief and the number of short-acting opioids consumed. The amount dispensed was obtained from the state’s mandatory Prescription Monitoring Program (PMP), and was compared to the patient’s report of the amount of short-acting opioid used, categorized by analgesic adequacy. Results: Out of the 7 of 33 (21%) patients reporting adequate analgesia, 3 patients (43%) reported using all of their short-acting opioids. Of the 26 patients reporting suboptimal analgesia, 16 patients (61%) reported using the entirety of that month’s dispensed opioids. The number of unused pills left in the medicine cabinets of patients with controlled pain ranged from 90 to 333 tablets of short-acting opioids. The remaining patients with uncontrolled pain reported unused opioids ranging from 33-100% of the amount prescribed that month. Fear of side effects was cited as the main reason for underuse. Conclusions: Prescription adherence is methodologically challenging to research, but for controlled substances, PMP may be leveraged for this purpose. These preliminary data highlight the importance of reconciling the number of PPM taken by cancer patients with the amount prescribed. Other strategies to reduce risk of diversion to non-patients e.g. returning unused pills also need to be developed.