tbuckley/cabot-search huggingface dataset:
Melanoma-specific MHC-II expression to predict response to α-PD-1 therapy.
Authors: Justin M. Balko, Douglas Buckner Johnson, Monica Valeria Estrada, Violeta Sanchez, Melinda Sanders, Mark C. Kelley, Christine Marie Lovly, Jeffrey Alan Sosman
Journal: Journal of Clinical Oncology (2015)

9041 Background: αPD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma (MEL) patients (pts). While promising, many pts do not benefit clinically. Predictive biomarkers to guide pt selection are needed. We hypothesized that tumor antigen presentation (MHC-I or MHC-II expression) is a requirement of αPD-1 benefit, and presence of these cell surface markers would predict benefit. Methods: We profiled MHC-I/II mRNA across 60 MEL cell lines. The transcriptional characteristics of MHC-II+ cell lines were analyzed by Gene Set Analysis. Cell surface expression of MHC-I and MHC-II was confirmed by flow cytometry (FC) in a subset of cell lines under basal and stimulated (IFNγ) conditions. In 26 tumor samples from αPD-1 treated MEL pts, immunohistochemistry (IHC) was performed for HLA-DR (MHC-II) or HLA-A (MHC-I), SOX10, CD4 and CD8. IHC results were correlated with response and progression-free survival (PFS). Results: MHC-I mRNA was expressed in all cell lines while MHC-II expression was bimodal (60% positive). MHC-II+ cell lines had transcriptional signatures of the PD-1 signaling, allograft rejection, and T-cell receptor signaling. By FC, MHC-II+ (mRNA) cell lines were constitutive and inducible (IFNγ stimulation) for HLA-DR while MHC-II- cells did not express or induce HLA-DR. In contrast, all tested cell lines significantly upregulated PD-L1 with IFNγ stimulation. Of 26 pts treated with αPD-1, 10 were MHC-II+. All 10 MHC-II+ (100%) pts had partial, complete, or mixed responses (MR), while only 7/16 (44%) of MHC-II- pts benefited (Fisher’s exact p = 0.004). Excluding MR pts (n = 2), median PFS for MHC-II+ was 728 days (d), while the median PFS for MHC-II- tumors was 98d (log-rank p = 0.01) . MHC-II+tumors had enhanced CD4 and CD8 infiltrate (Pearson’s correlation p = 0.000002 and p = 0.03, respectively). MHC-I positivity was ubiquitous and not associated with response. Conclusions: A subset of MEL demonstrates an MHC-II signature that correlates with αPD-1 response and enhanced CD4/CD8 T-cell infiltrate. MHC-II+ tumors can be robustly identified by routine melanoma-specific IHC for HLA-DR to guide pt selection. Combining HLA-DR IHC with other biomarkers, including PD-L1 expression may further improve pt selection.
Circadian Clock Boosts Stress-Response Genes During Aging
Authors: Tracy Hampton
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Impact of positron emission tomography (PET) in a prospective cohort of cancer patients: The Powdermilk Biscuit effect
Authors: B. E. Hillner, M. Fratkin, R. Tunuguntla
Journal: Journal of Clinical Oncology (2004)

6035 Background: Physicians (MDs) commonly use single or serial tests with the intent of crossing uncertainty thresholds in diagnosis, staging or treatment. In 2001, Medicare approved for reimbursement positron emission tomography (PET) for a variety of cancers (CA). PET has been observed to be more accurate than other imaging, but PET's impact on management in routine practice is uncertain. Methods: A prospective cohort of 250 patients (pts) having non-research PET at one academic center. Before and after PET, a questionnaire solicited from each MD his or her preceding actions, intended management (PLAN), and probability estimates. Results: 71 MDs provided >90% data on 248 pts. 40% had suspected or new CA and 60% restaging or suspected recurrence. 86% had at least one prior CT or MRI. Lung, lymphoma and head/neck CA accounted for two-thirds of cases. MDs impression of CA extent after PET increased in 43% and decreased in 11% cases. The table shows that MDs changed their intended PLAN in 66% (60–72%, 95% C.I.) of pts. MDs most often changed if their pre-PET PLAN was imaging, testing or biopsy (79%, 90 of 114). Changes to a treatment (RX) from a non-RX were more common than it's opposite. In 22 (7%) pts the goal and in 21 (8%) the mode of RX changed post-PET. In 12 of 22 pts, surgery was abandoned. The pre-PET MD probability estimates of metastases were associated only with changes to a non-RX. The only pre-PET predictor of a PLAN change was a pre-PET plan of testing or biopsy. Conclusions:In over half of pts having extensive preceding imaging, the PLAN changed after PET. This impact is likely due to combined effects of PET's improved accuracy that are intertwined with changes in MDs confidence or reduced uncertainty. The 80% change from further data strategies to action or non-action with PET, we suggest is a medicinal 'Powdermilk Biscuit™' effect–using PET to give MDs 'strength to do what needs to be done.' No significant financial relationships to disclose.
Vulvar Squamous Cell Carcinoma (VSCC) as Two Diseases: HPV Status Identifies Distinct Mutational Profiles Including Oncogenic Fibroblast Growth Factor Receptor 3
Authors: Johanne I. Weberpals, Bryan Lo, Marc M. Duciaume, Johanna N. Spaans, Aisling A. Clancy, Jim Dimitroulakos, Glenwood D. Goss, Harman S. Sekhon
Journal: Clinical Cancer Research (2017)

Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes.Experimental Design: A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics.Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%), and PTEN (9%), whereas HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%), and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (P = 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC.Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women. Clin Cancer Res; 23(15); 4501-10. ©2017 AACR.
Clinical trials in Ontario’s quality-based funding model.
Authors: Leta Forbes, William K. Evans, Thomas Eduard Kais-Prial, Ron Fung, Carlin Lalonde, Charlotte Hoskin, Lisa Milgram, Vanessa Cho, Vicky Simanovski, Scott Gavura, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2017)

186 Background: Clinical trials (CTs) are a key component of a quality cancer care system. When funding for systemic therapy services in Ontario transitioned in 2014 from a one-time payment for new cases to bundled payments for specific care activities (consultation, therapy, well follow-up, supportive care), a policy was developed to address public funding for systemic therapy in CTs. Methods: Treatment facilities receive funding from the Systemic Treatment-Quality Based Program (ST-QBP) for treatment with evidence-informed regimens inclusive of inexpensive drug, preparation and delivery costs. Under the new CT policy, randomized CTs with a standard of care comparator arm receive funding for all arms of the trial from the ST-QBP for older inexpensive drugs and all treatment administration costs at the band level for the disease type and stage. Non-randomized CTs are funded at the level of best supportive care or other appropriate band level. CT costs over and above the standard of care must be negotiated with industry sponsors. New and expensive drugs in CTs may be funded through separate provincial drug reimbursement programs if used according to publicly approved funding indications. Weekly joint reviews of new CT submissions by staff of the ST-QBP and drug reimbursement programs ensures timely communication to investigators concerning policy alignment and public funding and addresses potential concerns with regard to downstream access to expensive drugs. Results: As of January 29, 2016, 121 CT applications have been assessed (Phase 0 = 1, Phase I = 26, Phase II = 31, Phase III = 39, Phase IV = 1 and Multi-Phase = 23). Almost all CTs are aligned with the new policy and were assessed in a timely fashion. Assessments are posted on Cancer Care Ontario’s website within 1 week of review to allow all Ontario investigators access to this information. Conclusions: A clear CT funding policy and timely reviews support patient and investigator access to new and innovative therapies within an evidence-informed public funding model in Ontario, Canada. [Table: see text]
History of autoimmunity to predict clinical response to DNA methyltransferase inhibitors (DNMTI) in myelodysplastic syndromes (MDS), and MDS-derived acute myeloid leukemias (AML).
Authors: Ashkan Emadi, Hossein Sadrzadeh, Payal Patal, Kathleen H. Burns, Amy Duffield, Karen K. Ballen, Philip C. Amrein, Eyal C. Attar, B. Douglas Smith, Amir Tahmasb Fathi
Journal: Journal of Clinical Oncology (2012)

6629 Background: MDS is comprised of a heterogeneous group of clonal myeloid disorders. Chronic immune stimulation has been reported as a trigger for the development of a subset of MDS, with increased autoreactive cytotoxic T cells present in the bone marrow. Autoimmunity has been associated with MDS and other marrow failures. DNMTIs, 5-azacytidine and decitabine, are approved for the treatment of MDS. In addition to epigenetic impacts, these agents may have immunomodulatory effects, including augmentation of MAGE-related anti-tumor response. These reports and clinical observations led us to hypothesize that MDS patients with a history of autoimmunity may be more responsive to DNMTIs. Methods: To identify patients with MDS, a retrospective database review (2007-2011) was performed at Johns Hopkins Hospital (JHH) and Massachusetts General Hospital (MGH). The MGH data also included those with AML whose disease had progressed from MDS. Past medical history of autoimmune disorders, diagnosis, blood counts, flow cytometry and cytogenetics were reviewed. Patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria or non-malignant etiologies of cytopenia were excluded. Patients with MDS were further studied if they were treated with DNMTI. Results: Of 137 patients with MDS or MDS/AML, 23 had a documented history of autoimmunity in the medical record. Of these, 15 (65.2%) experienced a response to therapy as defined by the International Working Group. Of 114 patients without a documented history of autoimmunity, 34 (29.8%) achieved a response during therapy, a significantly lower percentage as compared to those with autoimmune conditions (p-value 0.002, t-test). The majority of responding patients with a history of autoimmunity displayed a normal karyotype (9 of 15 patients). Conclusions: A history or co-presence of an autoimmune disorder may predict a high likelihood of achieving a clinical response to DNMTIs. Correlative studies in this unique population of patients with MDS and MDS/AML and prospective clinical studies are needed to improve our understanding of the possible mechanism of action of DNMTIs in these patients.
The effect of telotristat etiprate on clinical and biochemical responses in patients with symptomatic carcinoid syndrome: Preliminary results of an ongoing phase II, multicenter, open-label, serial-ascending dose study.
Authors: Bertram Wiedenmann, Marianne E. Pavel, Thomas Seufferlein, Joel Freiman, Linda Law, Phillip Lee Banks, Kenneth Frazier, Jessica Jackson, Brian Zambrowicz
Journal: Journal of Clinical Oncology (2012)

e14564 Background: Excess serotonin (5-HT) may contribute to gastrointestinal (GI) symptoms such as diarrhea in carcinoid syndrome (CS) patients. Telotristat etiprate, an oral serotonin synthesis inhibitor (SSI), is designed to reduce peripheral 5-HT levels and alleviate GI distress. Methods: This study evaluates the safety and tolerability of ascending doses (150 mg, 250 mg, 350 mg, and 500 mg tid) of telotristat etiprate in symptomatic CS patients, averaging ≥4 bowel movements (BMs)/day, either therapy-naïve or receiving somatostatin analogs. Secondary objectives include symptomatic response (change in: number of BMs/day, stool form/consistency, sensation of urgency to defecate, sensation/severity of nausea, global assessment of symptoms, assessment of abdominal pain/discomfort, reduction of cutaneous flushing episodes), and assessment of plasma drug concentrations, pharmacokinetics, and pharmacodynamics (urinary 5-hydroxyindolacetic acid [u5-HIAA] and blood 5-HT). All patients began dosing at 150 mg. Dose will be increased following 2 weeks of therapy with no dose-limiting toxicity. If dose-limiting toxicities occur, the dose will be reduced to prior level. Treatment will continue at the individual maximum-tolerated dose for 4 weeks; patients may elect to continue in an extension phase. Results: As of 1/2012, 13 patients, refractory to octreotide LAR have enrolled and been treated with telotristat etiprate. Eight (8) of 9 patients have completed the 12-week ascending dose study and 6 of 6 eligible patients have enrolled into the long-term extension, up to 72 weeks; 4 more patients are eligible for the long-term extension. Mean age: 63 years (range 51-81), mean BMs at baseline: 6.0 (range 4.7-8.5) for the 9 patients. Upon completion of 12 weeks of dosing, 7 of 9 patients (78%) had sustained reductions of ≥30% in BMs/day. All 7 of these patients had multiple assessments indicating ≥50% BM reductions) during the 6 weeks while on their highest dose. No major safety issues were detected. Conclusions: Telotristat etiprate produced biochemical and clinical responses/benefit in CS.
Obesity in early pregnancy may link to epilepsy in offspring, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Being overweight or obese in early pregnancy is associated with increased risk for childhood epilepsy in offspring, a nationwide study in Sweden has reported.1

Epilepsy is one of the most common neurological disorders of childhood, but its cause is poorly understood, and no definitive cause is identified in more than 60% of cases. Several studies have found increased risks of intellectual disability, attention deficit hyperactivity disorder, …
Anaphase-Promoting Complex Adaptor FZR1/CDH1 Blocks BRAF Signaling Both by Targeting BRAF for Proteolytic Degradation and by Disrupting BRAF Dimerization
Authors: Chao Zhang, Gideon Bollag
Journal: Cancer Discovery (2017)

Abstract Summary: Blocking dimerization and stimulating protein degradation are two mechanisms known to inhibit BRAF activity. The study reported by Wan and colleagues identifies BRAF as a substrate of the APC/CFZR1–ubiqutin–proteasome system. The interaction between FZR1 and BRAF also induces a conformational change that disrupts BRAF dimerization. These findings identify a dynamic interplay between FZR1 and BRAF with strong implications for cell-fate determination and the tumor suppressor role of FZR1. Cancer Discov; 7(4); 356–8. ©2017 AACR. See related article by Wan et al., p. 424.
Patients needing urgent GP care could be seen at neighbouring practices under CCG plans
Authors: Ingrid Torjesen, Gareth Iacobucci
Journal: BMJ (2017)

Patients requesting an urgent GP appointment at their registered practice could be sent to see a doctor or other health professional at a neighbouring practice, under proposals being considered in Oxfordshire.

In an effort to manage growing demand for same day urgent appointments and difficulties recruiting staff to general practice, Oxfordshire clinical commissioning group (CCG) has drafted a five year strategy for primary care which recommends that more care is provided across localities.

The Primary Care Framework document1 emphasises that patients will not have an automatic right to same day appointments or home visits. Anyone requesting one will be triaged …
Sensitivity and specificity of self-reported cancer history compared to cancer registry.
Authors: Craig Earle
Journal: Journal of Clinical Oncology (2017)

234 Background: The Ontario Health Study (OHS) is a large prospective epidemiologic cohort study in which any Ontario resident eighteen years of older may enroll regardless of prior medical history. Baseline data are collected using web-based tools. As part of the consent process, participants are asked for consent to link study data with administrative and health care claims databases, including the Ontario Cancer Registry (OCR). There is an option to enter their Health Insurance Number (HIN) for this purpose. The purpose of this study was to link these data and evaluate the accuracy of self-reported cancer history compared to the cancer registry. Methods: Consenting participants that provided HINs were deterministically linked to the administrative data. Those that did not were probabilistically linked using name, sex and date of birth. Cancer registry records indicating a cancer diagnosed before the date of completion of the OHS baseline survey were considered the gold standard. Concordance, sensitivity, and specificity were assessed. Results: OHS records were successfully linked to administrative claims data and the Ontario Cancer Registry (OCR) with an 85.13% match rate. The final cohort consisted of 139,798 participants. A personal history of cancer was reported by 13,171 of these subjects, out of which 10,066 were found with a record in the OCR. The sensitivity of self-report was 77% and the specificity 95%. Excluding cancers diagnosed after the completion of the baseline survey increased sensitivity of self-report to 93%. The main area of discrepancy causing low sensitivity was the self-reporting of non-melanomatous skin cancers in the OHS questionnaire. Conclusions: While some self-over-reporting of cancer history may occur, cancers with lower metastatic potential tend to be under-captured in our provincial cancer registry. These findings have implications for cohort creation for research and quality improvement.
Improving patient wait time by implementing visual management tools in an outpatient oncology infusion unit.
Authors: Kit Yu Lu, Candace Fuerst, Irina Veytsman
Journal: Journal of Clinical Oncology (2017)

200 Background: The number of cancer diagnosis and oncology visits have increased by 30% over the past decade nationwide. Similarly, our institution also experienced more than 30% growth this past year due to increased number of physicians and patients. However, the amount of resources including staffing, infusion chairs, and hour of operation remained the same. This has caused significant delays for patients and decreased patient/staff satisfaction. Methods: Visual Management tools can be used to communicate information by using visual diagrams instead of text. Various instruments were used to visually assess patient flow during their chemotherapy admission in the infusion unit. The workflow process was organized into a Value Stream Map. Root cause analysis was performed for high problematic areas. Results: Average patient wait time were as follows: patient registration to infusion chair (20min; range 5-45min), chair to nurse assessment (15min; range 0-30min), blood draw to “ok for treatment” (60min; range15-90min), “ok to treatment” to drug delivery (20min; range 15-30min). Through visual stream mapping, we identified the complexity of work flow and areas of highest impact for patient wait time (ex. blood draw/laboratory process, drug delivery). We used root-cause analysis to identify deficiencies and limitation in the process. Pick chart was created to assess and stratify useful ideas and current resources. We achieved several low effort/high impact interventions (i.e. designated parking space for drug delivery, supplying tools in nursing stations) and some high effort/high impact interventions (i.e. extending office hours and making changes to our computer order systems). These strategies has improved efficiency and decreased wait time by more than 50%, and also improved patient and staff satisfaction. Conclusions: Incorporation of Visualization Management tools helped engaged our high stake holders in the improvement processes. These tools helped facilitate a deeper understanding of department workflow, identify issues in the process, standardize the process and improve efficiency.