tbuckley/cabot-search huggingface dataset:
Final results of a phase I study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110δ (PI3Kδ), in patients with relapsed or refractory mantle cell lymphoma (MCL).
Authors: Stephen Edward Forbes Spurgeon, Nina D. Wagner-Johnston, Richard R. Furman, Ian Flinn, Steven E. Coutre, Jennifer R. Brown, Don M. Benson, John C. Byrd, John Leonard, Sissy Peterman, David Michael Johnson, Jessie Gu, Roger D. Dansey, Wayne R. Godfrey, Brad S. Kahl
Journal: Journal of Clinical Oncology (2013)

8519 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ. Initial response rate of 42% was previously reported in MCL (Kahl, ICML 2011). Long-term follow-up is now presented. Methods: This phase 1 study evaluated the activity of continuous (48 weeks) idelalisib monotherapy in pts with relapsed or refractory hematologic malignancies. Doses ranged from 50 mg BID to 350 mg BID in 8 cohorts. Response was based on investigator assessments using standard criteria (Cheson et al, 2007). Patients who continued to benefit were able to enroll in an extension study. Results: 40 patients with recurrent MCL enrolled. Patients were 88% male, median age [range] of 69 [52-83] years, 43% with refractory disease. The median [range] number of prior therapies was 4 [1E14]. The median [range] duration of idelalisib treatment was 3.5 [1-26+] months, with 6 (15%) patients continuing on treatment in the extension protocol. Overall response rate (ORR) was 16/40 (40%), with 2/40 CR (5%). The median duration of response (mDOR) was 2.7 months, and median PFS (mPFS) was 3.7 months. The 1-year PFS was 22%. For patients dosed with ≥100 mg BID, ORR was 12/23 (52%), for patients dosed with ≥150 mg BID, ORR was 11/16 (69%) including both CR (12.5%). Most common adverse events included (total%/≥G3%); diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (25/3), decreased appetite (20/15), URI (20/0), and pneumonia (13/13). Abnormal lab values included (total%/≥G3%) ALT/AST elevations (65/20). 6/40 (15%) patients discontinued therapy due to AEs, potentially treatment related. Conclusions: The oral PI3Kδ inhibitor idelalisib (GSE1101) is active and well tolerated in heavily pre-treated pts with MCL. A proportion of patients have long-term (&gt;1 year) clinical benefit. These data support further clinical evaluation of idelalisib in MCL. Clinical trials with idelalisib in combination with other agents are in progress. Clinical trial information: NCT00710528.
Phase I-II study of the combination of NED, ADM, and 5-FU for the treatment of previously untreated advanced esophageal cancer
Authors: M. Hirao, T. Tsujinaka, K. Fujitani
Journal: Journal of Clinical Oncology (2004)

4149 Background: Esophageal cancer has a poor prognosis. Several strategies including chemotherapy (CDDP+5-FU), either alone or with radiotherapy, depends on document reviewhave been used to improve prognosis. However, since CDDP itself has substantial toxicities, including renal and gastrointestinal toxicities, newer platinum analogues, such as nedaplatin (NED), have been developed, and it is of interest to test this new platinum analogue in a combination chemotherapy. Methods: We conducted a phase I-II study of the combination of NED (3 levels, 60–80 mg/m2 on day 1), ADM (30 mg/m2 on day 1), and 5-FU (700 mg/m2 on day 1–5) for treatment of previously untreated advanced esophageal squamous cell carcinoma. Cycles were repeated every 28 days. Objectives were to determine dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) for a phase II study, and to explore antitumor effect. Results: Phase I: 12 patients (pts) (male/female=11/1) were evaluable. Median age 65 (range 46–74), PS 0/1=7/5. At level 1, 1 pt developed DLT (grade 4, neutropenia). At level 2, 2 pts developed DLT (grade 4 neutropenia and grade 3 diarrhea). Level 2 (70 mg/m2) was determined as the MTD and the dose at level 1 (60 mg/m2) was recommended. Phase II: 13 pts (male/female= 10/3) were at RD of level 1 at the present time. Median age 65 (range 46–75), PS 0/1= 10/3. Median number of cycles on phase II study at RD was 2 (range 1–3). 10 PRs were obtained. Response rate was 69%. Median survival time (MST) is not reached at the present time. Conclusions: This combination therapy appears to be highly active and generally well tolerated for advanced esophageal cancer. No significant financial relationships to disclose.
Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis
Authors: Rachel E. Miller, Shingo Ishihara, Bula Bhattacharyya, Ada Delaney, Daniela M. Menichella, Richard J. Miller, Anne‐Marie Malfait
Journal: Arthritis & Rheumatology (2017)

To determine the ability of drugs that activate inhibitory G protein-coupled receptors (GPCRs) expressed in peripheral voltage-gated sodium channel 1.8 (NaV 1.8)-positive sensory neurons to control osteoarthritis (OA)-associated pain.We used designer receptors exclusively activated by a designer drug (DREADD) technology, which employs engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand clozapine N-oxide (CNO). NaV 1.8-Pdi C57BL/6 mice were generated to express the inhibitory DREADD receptor Pdi in NaV 1.8-expressing sensory neurons. Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male mice. Four, 8, 12, or 16 weeks after surgery, knee hyperalgesia or hind paw mechanical allodynia was tested. Subsequently, CNO or vehicle was administered, and the effect on pain-related behaviors was measured by a blinded observer. Morphine was used as a control.Immunohistochemistry and electrophysiology confirmed functional expression of the inhibitory DREADD receptor Pdi by NaV 1.8-positive sensory neurons. Acute inhibition of NaV 1.8-expressing neurons in mice treated with CNO reduced knee hyperalgesia 4 weeks after DMM surgery and reduced mechanical allodynia 8 weeks after DMM surgery. Inhibition had no effect on pain-related behaviors 12 and 16 weeks after DMM surgery. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage of experimental OA.Chemogenetic inhibition of NaV 1.8-expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental OA, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic OA pain.
Feasibility study of liposomal doxorubicin consolidation therapy after platinum/paclitaxel-based chemotherapy for suboptimally debulked stage IIIC/IV ovarian cancer patients
Authors: J. M. Straughn, R. P. Rocconi, C. A. Leath, L. C. Kilgore, W. K. Huh, R. D. Alvarez
Journal: Journal of Clinical Oncology (2004)

5044 Background: To assess the utility of liposomal doxorubicin (Doxil) as a consolidation strategy in patients with advanced ovarian cancer who have attained a clinically defined complete response (CR) to initial platinum/paclitaxel-based chemotherapy. Methods: Patients diagnosed with suboptimally debulked Stage IIIC/IV ovarian cancer who attained a clinically defined complete response (CA-125 < 35, normal CT scan, and normal pelvic exam) at the completion of platinum/paclitaxel-based chemotherapy were eligible for this protocol. Patients were treated with Doxil at a dose of 40 mg/m2 every 28 days for four cycles. Primary endpoints included toxicity, quality of life (QoL), and time to progression. Results: Of the 30 patients enrolled, 26 patients are evaluable, three patients are currently being treated, and one patient was ineligible due to inaccurate staging. 22 of the 26 evaluable patients (85%) completed all four cycles of consolidation therapy. Three patients were removed from the study after their 3rd course due to palmar-plantar erythrodysesthesia (PPE) and one for recurrent disease after her 3rd course. 13 patients required a 25% dose modification (11 patients for grade 2/3 PPE and 2 patients for grade 3 myelosuppression). A subset of patients completed a baseline and post-treatment QoL questionnaire and no difference was detected between the baseline and post-treatment QoL scores (p=0.179). Of the 26 patients who completed consolidation therapy, 10 remain clinically without evidence of disease with a median follow-up of 15 months from completion of primary chemotherapy (range, 7–20 months). Sixteen patients have recurred following treatment with a median time to recurrence of 10 months (range, 3–18 months). Conclusions: Consolidation therapy with Doxil chemotherapy administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial chemotherapy appears feasible. PPE is the most common toxicity leading to dose modification and study discontinuation. Impact on progression-free survival awaits additional follow-up. No significant financial relationships to disclose.
Increase in the patient wait-time and delays in the clinic workflow post-implementation of the electronic health record.
Authors: Meyyammai Narayanan, Xiao Zhou, Shawn J Janarthanan, Mary Daniel, Maria Olmedo, Colleen Jernigan, Shreyaskumar Patel, Saroj Vadhan-Raj
Journal: Journal of Clinical Oncology (2017)

194 Background: Growth in patient (pt) volume and limited clinic capacity can lead to long wait-times and pt/provider dissatisfaction. We have previously shown that the room pooling model, can reduce pt wait-time in the exam room, improve room utilization, and pt/providers satisfaction (ASCO 2016, Abstract 6595). One of the important goals of adopting electronic health records (EHR) is also to increase the clinical efficiencies, productivity and quality of care. The purpose of this study was to evaluate the impact of implementation of EHR on pt wait-time in the exam room and satisfaction in the Sarcoma Center. Methods: The time studies and pt and provider wait-time satisfaction surveys were carried out over 2 weeks prior to (baseline) and 6 months after the implementation of EHR. All times of when pts, mid-level providers, and doctors (MD) entered and exited the exam rooms were collected for a total sample size of 578 pts (300 before, 278 after) seen during the clinic hours and analyzed using JMP and SAS. Results: The proportion of pts seen within 30 minutes (Min) by MDs from the time pts roomed into exam room decreased by about 32% [from 53% (148/280) to 36% (94/259), p = 0.0001] post implementation of EHR. The median time for pts in the exam room waiting for MD increased (p = 0.0001) from 30 min (range: 0-126 min) to 40 min (range: 0-121 min). Although, the pt satisfaction did not significantly change [increase from 8% (23/278) to 12% (31/267) in the number of pts that were not satisfied to little-satisfied, and decrease from 92% (255/278) to 88% (236/267) in pts that were moderately to very-satisfied], the number of times MD had to wait for an open exam room increased from 8% (5/65) to 24% (14/59, p = 0.01). The delays to see MDs were associated with longer time spent with the nurse (from median 4 to 7 min), followed by delays in seeing Mid-level provider (from 11 to 18 min). Conclusions: These findings indicate that in the initial stages of implementation of EHR, the increase in pt wait-time and reduced clinical efficiencies can be related to the learning of and adapting to the new system. Attempts targeted to the areas of delays (such as training and redesigning workflow) may reduce the pt wait-time and improve the clinical efficiency.
Proliferation-, estrogen-, and T-cell-related metagenes to predict outcome after adjuvant/neoadjuvant chemotherapy for operable breast cancer in the ECTO trial.
Authors: Giampaolo Bianchini, Vera Cappelletti, Maurizio Callari, Maria Luisa Carcangiu, Wolfgang Eiermann, Vladimir Semiglazov, Vicente Guillem, Ana Lluch, Mauro Mansutti, Milvia Zambetti, Gabriella Mariani, Domenico Magazzu, Pinuccia Valagussa, Biagio Paolini, Valeria Musella, Eleonora Di Buduo, Patrizia Miodini, Manuela Scuro, Maria Grazia Daidone, Luca Gianni
Journal: Journal of Clinical Oncology (2013)

1014 Background: Predicting recurrence in operable breast cancer (BC) despite optimal chemotherapy would be relevant to new drug development and tailored treatments. Methods: A large series (n=3,154) of public Affymetrix gene-expression profiles (GEP) was used to define prognostic/predictive metagenes in different BC subtypes. In ER+/HER2- a proliferation and an ER-related metagene were combined to predict low, intermediate and high risk of recurrence. In TN and in HER2+ a T cell metagene was used to predict low, intermediate and high risk (higher expression associated with lower risk). The metagenes were validated in patients enrolled in the phase III ECTO trial (Gianni L. JCO 2009) and treated with the same taxane-anthracycline-CMF regimen as neoadjuvant or adjuvant therapy before endocrine therapy if indicated. The outcome was distant event free survival (DEFS). Results: 283 good quality GEPs were obtained (neoadjuvant n=121; adjuvant n=162) from 464 retrospectively collected samples. Median follow-up was 8.9 years. In ER+/HER2- tumors the 10-yrs DEFS was 92.3, 81.2 and 66.6% in low, intermediate and high risk groups, respectively [high vs low HR 4.38 (1.01-19.1) p=.048] according to proliferation and ER-related metagenes. In HER2+ and TN subgroup the 10-yrs DEFS was 97.2, 75.6 and 78.8% in low, intermediate and high risk groups, respectively [high vs low HR 8.73 (1.09-69.8) p=.041]. In TN tumors, the pCR rate was 20% in the high and 61.5% in the low risk group. By combining the predicted risk group in each molecular subtype the 10-yrs DEFS was 95.3, 79.2 and 71.5% in low (24.2%), intermediate (42.7%) and high (33.1%) risk group, respectively [logrank p=0.003; high vs low HR 6.22 (1.87-20.6) p=.002]. ER, PGR, Ki67 and lymphocyte infiltration (LI) by IHC underperformed compared to genomic predictors. Conclusions: BC patients at higher risk of relapse despite optimal standard treatment can be identified who should be spared ineffective and toxic therapy and considered for investigational new strategies. In TN and HER2+, high T cell metagene and to a lesser extent LI are prognostic/predictive and associated with an extremely low risk of DEFS after chemotherapy.
Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer
Authors: Shikhar Mehrotra, Carolyn D. Britten, Steve Chin, Elizabeth Garrett-Mayer, Colleen A. Cloud, Mingli Li, Gina Scurti, Mohamed L. Salem, Michelle H. Nelson, Melanie B. Thomas, Chrystal M. Paulos, Andres M. Salazar, Michael I. Nishimura, Mark P. Rubinstein, Zihai Li, David J. Cole
Journal: Journal of Hematology & Oncology (2017)

Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells. Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease. Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC. NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).
Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis
Authors: Joseph F. Merola, Boni Elewski, Svitlana Tatulych, Shuping Lan, Anna Tallman, Mandeep Kaur
Journal: Journal of the American Academy of Dermatology (2017)

Tofacitinib is an oral Janus kinase inhibitor. Efficacy and safety of tofacitinib in patients with moderate-to-severe plaque psoriasis have been demonstrated.We sought to assess the efficacy of tofacitinib for the treatment of nail psoriasis over a period of 52 weeks.In 2 identical phase 3 studies (OPT Pivotal 1 and 2), patients were randomized 2:2:1 to receive tofacitinib 5 mg, tofacitinib 10 mg, or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. This post hoc analysis of patients with existing nail psoriasis assessed the Nail Psoriasis Severity Index (NAPSI) score and proportions of patients achieving ≥50% reduction in NAPSI from baseline (NAPSI50), NAPSI75, or NAPSI100.Baseline mean NAPSI scores for patients treated with tofacitinib 5 mg (N = 487), tofacitinib 10 mg (N = 476), and placebo (N = 233) twice daily were 27.0, 27.3, and 26.9, respectively. At week 16, significantly (all P < .05) more patients receiving tofacitinib 5 mg and tofacitinib 10 mg versus placebo twice daily achieved NAPSI50 (32.8%, 44.2% vs 12.0%), NAPSI75 (16.9%, 28.1% vs 6.8%), and NAPSI100 (10.3%, 18.2% vs 5.1%), respectively. Improvements were sustained to week 52.Limitations include discontinuation of clinical nonresponders at week 28.Tofacitinib treatment resulted in improvements in nail psoriasis versus placebo at week 16; improvements were maintained over 52 weeks [NCT01276639; NCT01309737].
Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL
Authors: Paul M. Barr, Jennifer R. Brown, Peter Hillmen, Susan O'Brien, Jacqueline C. Barrientos, Nishitha M. Reddy, Steven Coutre, Stephen P. Mulligan, Ulrich Jaeger, Richard R. Furman, Florence Cymbalista, Marco Montillo, Claire Dearden, Tadeusz Robak, Carol Moreno, John M. Pagel, Jan A. Burger, Samuel Suzuki, Juthamas Sukbuntherng, George Cole, Danelle F. James, John C. Byrd
Journal: Blood (2017)
Support overseas doctors for first year, says leader of doctors’ mental health service
Authors: Abi Rimmer
Journal: BMJ (2017)

International medical graduates should be supported for a year when they start working in the NHS, one of the doctors providing a national doctors’ mental health service has said.

Clare Gerada, a partner at the group of GP practices that run the NHS GP Health Service and the Practitioner Health Programme, says that doctors from overseas need to be given “a year of care” to help integrate them into the NHS.

“If you think your doctors are suffering, try being a doctor coming from a war torn area, not just unable to speak the language fluently …
Peculiarities of clinical characteristics in different aged patients with vulvar cancer.
Authors: Victoria Aleksandrovna Ivanova, Galina Nerodo, Ekaterina Alekseevna Nerodo
Journal: Journal of Clinical Oncology (2013)

e16512 Background: Comparison of vulvar cancer clinical flow in patients of reproductive and old age. Methods: The studying of vulvar cancer clinical delopment included 64 patients of reproductive age and 775 patients of old age. Results: The patients were from 20 to 90 years old; 64 (7.6%) of them were from 20 to 50 years old; the other 92.4% were more than 50 years old. The patients of reproductive age at early stages made up 70.3%; the patients of old age at early stages made up 70.3%. Hypertensive disease (13.5%), obesity (13.5%), diseases of liver and stomach (11.8%) and the sole case of diabetes mellitus (1.6%) were among the concomitant diseases of the reproductive age patients. Among the seniors,: hypertensive disease (77.7%), atherosclerosis (42.9%), obesity (62.8%), osteochondrosis (18.3%), diabetes mellitus (9.1%), diseases of liver and gall bladder (29.95%). Only 16% of the patients from the younger group had leukokeratosis and kraurosis; among the seniors, 62% had those diseases. At the same time, the younger the group of patients with vulvar cancer, the more often they had papilloma, condyloma on vulva in their anamnesis, and infection of human papilloma virus. In the group under 50 such patients made up 87.5%, and in the group of seniors there was one case of infection of human papilloma virus – 0.48%. All the patients undergone different types of complex curing; more than half of the patients undergone chemotherapy. 17% of the patients of the reproductive age, and 23.3% of the seniors had the relapses of the disease. Conclusions: Our study proved the statement about existence of two pathogenetic variants of vulvar cancer appearance: the first variant is HPV– positive, diagnosed in young women; the second variant is HPV– negative, diagnosed in women of elderly age, associated with neurodystrophic processes and chronic infection.
Molecular biomarkers for lung adenocarcinoma
Authors: Olivier Calvayrac, Anne Pradines, Elvire Pons, Julien Mazières, Nicolas Guibert
Journal: European Respiratory Journal (2017)

The identification of oncogenic driver alterations that underlie sensitivity to small inhibitors has led to growing interest in identifying additional targetable oncogenes in nonsmall cell lung cancer. Although the therapeutic impact of the discovery of these alterations has now been widely demonstrated, the epidemiological data associated with each of these biomarkers remain insufficiently studied. In this review, we discuss the techniques used to discover each of these candidate oncogenes, their prevalence in nonsmall cell lung cancer, and briefly outline the epidemiological features of the major oncogenes and ways in which their identification can determine therapeutic strategies.