tbuckley/cabot-search huggingface dataset:
Pilot study of pulse high-dose lapatinib in combination with temozolomide (TMZ) and radiotherapy (RT) for upfront treatment of glioblastoma (GBM).
Authors: Phioanh Leia Nghiemphu, Stacey Green, Emese Filka, Albert Lai, Ingo K. Mellinghoff, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2014)

2045 Background: The Epidermal Growth Factor Receptor (EGFR) is a potentially important therapeutic target for GBM since 45% of GBM tumors harbor either amplification, mutations, or both, of the EGFR gene (Cancer Genome Atlas Research Network, Nature, 2008).Lapatinibis a kinase inhibitor that potently targets the inactive conformation of EGFR. However, conventional, daily dosing of lapatinib is not sufficient to achieve a high intratumoral concentration for brain tumors and has proven ineffective in the treatment of recurrent GBM (Vivanco et al, Cancer Discov, 2012). High dosages of lapatinib given in pulses may be more effective at inhibiting brain tumor growth and enhancing the effect of chemotherapy and RT. We performed a pilot study of pulse high dose lapatinib to assess the safety of this novel dosage given in combination with TMZ and RT. Methods: After informed consent, adult patients with newly diagnosed GBM received lapatinib at 2500 mg twice a day, for 2 consecutive days per week, in combination with standard dosing of RT + TMZ. After RT, patients continued high dose lapatinib 2-day weekly pulses until progression and also received 12-24 cycles of adjuvant TMZ. Results: 10 patients were enrolled in this pilot study. At the time of this report, all patients had completed treatments in the Concurrent Period with RT + TMZ + pulse high dose lapatinib. Median follow-up was 16.6 weeks (range 8-59). The most common toxicities were lymphopenia (8 patients), diarrhea (7), fatigue (7), and skin rash (4), mostly at grade 1-2. The only grade 3 toxicity related to this combination was lymphopenia in 4 patients. There were no grade 4-5 toxicities. One patient withdrew from study after 10 weeks of treatment after a hospitalization for epigastric pain although no laboratory or imaging abnormalities were found, and patient improved on proton pump inhibitor. One patient had resection of an enhancing growth 6 months after completing RT and pathology was consistent with treatment-induced necrosis. Conclusions: High dose lapatinib given in 2-day weekly pulses with TMZ and RT was well tolerated, and this combination will be further evaluated in an expanded phase II trial for upfront treatment of GBM. Clinical trial information: NCT01591577.
Efficacy of S-1 compared to modified FOLFIRINOX as second-line chemotherapy regimens after gemcitabine plus nab-paclitaxel for patients with metastatic pancreatic cancer.
Authors: Gen Kimura, Hideaki Takahashi, Kumiko Umemoto, Kazuo Watanabe, Mitsuhito Sasaki, Yusuke Hashimoto, Hiroshi Imaoka, Izumi Ohno, Shuichi Mitsunaga, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2017)

449 Background: Recently, gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) has been frequently used as a first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer (mPC) in Japan. Nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (MM-398 plus 5FU/LV) has not yet been approved in Japan. Under these circumstances, a modified FOLFIRINOX (mFFX) regimen or S-1 is commonly used as a second-line chemotherapy regimen for patients with mPC after GEM plus nab-PTX has failed. Methods: Between December 2014 and March 2016, 45 patients with mPC received second-line chemotherapy after the failure of GEM plus nab-PTX (standard dose regimen) at the National Cancer Center Hospital East. Twenty-two patients received mFFX (irinotecan, 150 mg/m 2 ; bolus of 5FU was eliminated), 19 received S-1 (80 mg/m 2 /d; d1-28, q6w or d1-14, q3w), and 4 received other chemotherapy regimens. The clinical records of the patients were reviewed retrospectively. Results: At baseline, S-1 group had a more severe disease status than the mFFX group (performance status of 0: 21% vs. 68%, P = 0.003; median CA19-9 level: 1832 vs. 577 U/mL, P = 0.30). No significant difference in the response rate (S-1, 5.3% vs. mFFX, 9.1%, P = 0.56) or the disease control rate (S-1, 42% vs. mFFX, 36%, P = 0.71) was seen between the two groups. The progression free survival (PFS) (median: S-1 vs. mFFX: 2.7 vs. 2.4 months (m), P = 0.77), the overall survival (OS) from the second-line treatment (median: 6.1 vs. 6.4m, P = 0.87) and the OS from the first-line treatment (median: 10.9 vs. 12.4m, P = 0.77) were not significantly different between the two groups. These results were similar to those observed for MM-398 plus 5FU/LV (PFS, 3.1m; OS, 6.1m) in a pivotal Phase III study (NAPOLI-1). The incidences of peripheral neuropathy (5.3% vs. 32%, P = 0.04), fatigue (11% vs. 50%, P = 0.007), and neutropenia (11% vs. 64%, P = 0.001) were significantly lower in the S-1 group. Conclusions: S-1 was less toxic than mFFX and exerted a similar anti-tumor effect in the present study. S-1 could be a treatment option for patients with mPC refractory to GEM plus nab-PTX.
The Nationwide Cancer Genome Screening Projects for Gastrointestinal Cancer in Japan (SCRUM-Japan GI-SCREEN): Efficient identification of actionable cancer genome alterations in advanced colorectal and non-colorectal gastrointestinal cancer (GI Screen 2013-01-CRC and 2015-01-Non CRC).
Authors: Kohei Shitara, Izumi Miki, Tomohisa Sudo, Satoshi Fujii, Takeshi Kuwata, Wataru Okamoto, Tadamichi Denda, Takeshi Kajiwara, Satoshi Yuki, Takako Eguchi Nakajima, Atsuo Takashima, Kenta Kawasaki, Takao Tamura, Taito Esaki, Takeharu Yamanaka, Atsushi Ochiai, Toshihiko Doi, Atsushi Ohtsu, Tomomitsu Hotta, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2015)

TPS4134 Background: Several cancer genome alterations have been identified as important targets for treatment. Example of possible candidates in gastrointestinal (GI) cancer include BRAF mutations in colorectal cancer (CRC) or MET amplification in gastric cancer, for which corresponding targeting agents showed attractive activity in early phase clinical trials. Efficient screening systems for these relatively minor cancer genome alterations are necessary for the successful development of targeted therapies. We initiated a nationwide screening project in Japan (GI-SCREEN) in February 2014 to detect rare mutations from CRC (GI-SCREEN 2013-01-CRC). The patient’s population will be expanded to non-CRC GI cancer (SCRUM-Japan GI-SCREEN 2015-01-Non CRC). The objective of these consecutive projects is to evaluate the frequency of oncogenic genome alterations in advanced GI cancers and to facilitate the enrollment of patients in IND registration trials for targeted therapies as well as optimal individualized treatment. Methods: These prospective observational studies are designed to enroll patients with CRC or non-CRC GI cancer (gastric, esophageal, small-intestinal, appendiceal, anal carcinomas and neuroendocrine carcinoma) who are planned to receive systemic chemotherapy. Tumor samples from surgical or biopsy specimens have been examined by Luminex technology so far. Starting from February 2015, it will be redesigned to analyze more than 140 kinds of alterations in cancer genome, which included mutations, copy number variations, and gens fusions, using next generation sequencing of the Oncomine Cancer Research Panel (OCP) at a quality-controlled central laboratory. Patient characteristics and treatment outcome are also planned to be collected. The targeted sample size is 2000 patients with CRC and 1000 patients with non-CRC. As of January 26, 2015, a total of 844 CRC patients were enrolled and non-CRC study will be opened in April 2015 with planned participation of 18 major cancer centers in Japan. Clinical trial information: UMIN000016344.
Interim analysis of a phase I study of INCB040093, a PI3Kδ inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor, in patients (pts) with relapsed or refractory (r/r) B-cell malignancies.
Authors: Tycel Jovelle Phillips, Andres Forero-Torres, Taimur Sher, Catherine S. Magid Diefenbach, Moshe Talpaz, Peggy A Scherle, Richard Schaub, Li Zhou, Jennifer Pulini, Lance Leopold, Matthew A. Spear, Paul M. Barr
Journal: Journal of Clinical Oncology (2015)

8520 Background: Inhibiting the PI3K or JAK-STAT pathways may be therapeutic in B-cell malignancies due to their contribution to tumor growth and survival and effects on the tumor microenvironment. Blocking both pathways may be synergistic due to JAK-STAT augmentation of BCR activation of the NFκB pathway. Methods: This ongoing dose escalation study with expansion cohorts enrolled adult pts with r/r B-cell malignancies. INCB040093 was given at doses between 100–300 mg QD or BID alone or 150–300 mg QD or BID with INCB039110 at 400–600 mg QD. Safety, efficacy, and pharmacodynamics were evaluated. Results: A total of 83 pts have been enrolled: FL n = 19; cHL n = 17; DLBCL n = 15; CLL/SLL n = 13; others n = 19. Median age was 61 years and 70% were men. The median number of prior regimens was 4 and 24% underwent HSCT. Median exposure was 185 days (range: 5 – 491+ [ongoing]) for INCB040093 alone and 99 days (range: 6 – 337+ [ongoing]) for INCB040093 + INCB039110. The most common AEs were fatigue (28%), headache (19%), pyrexia (19%) and the most common grade ≥ 3 AE was pneumonia (6%). The most common laboratory abnormalities were liver enzyme elevations and cytopenias. One pt had a DLT on INCB040093 100 mg BID (GI bleed secondary to gastric DLBCL regression). Doses of INCB040093 100 mg BID and INCB040093 100 mg BID + INCB039110 400 mg QD were selected for expansion cohorts based on the incidence of liver enzyme elevations with INCB040093 and cytopenias with INCB040093 + INCB039110 at higher doses. At the selected doses, pAKT was decreased by ~90% at trough on INCB040093 and IL6-induced pSTAT3 was decreased an average of 65% on INCB039110. Of 75 pts thus far evaluated for a response, 28 responses have been reported. Notably, ORR was 60% (3 CRs) for r/r cHL and both pts with the non-GCB subtype of DLBCL had CRs. Conclusions: Treatment with INCB040093 ± INCB039110 was tolerable and produced responses, including CRs, in pts with heavily pretreated r/r B-cell malignancies. Given this activity, the study was expanded to enroll additional cohorts of pts with r/r B-cell malignancies such as DLBCL and cHL, and a phase II study in pts with r/r cHL was initiated. Clinical trial information: NCT01905813.
The changing role of the chief medical officer for England
Authors: Martin McKee
Journal: BMJ (2017)

CMOs today must undertake a careful balancing act

Every six months the chief medical officers (CMO) from each EU member state meet to discuss emerging public health issues. For more 40 years, the occupant of the British seat, the CMO for England, has been a valued contributor. If Theresa May has her way, and the United Kingdom actually manages to leave the EU, by 2019 that seat will be vacated. This will be a great loss to Europe, given the expertise that successive CMOs have brought, but even more so for the UK, which will be excluded from important discussions on policies that will, despite Brexit, inevitably have consequences for this country. Yet, this is only the latest change in a role that has continually been evolving since it was created in 1855.1 The world has changed enormously. Has the role of CMO managed to keep pace?

Before answering this question, a few points should be clarified. First, there is no internationally agreed definition of a CMO. Only a few of those attending the EU meetings actually have the …
Combined Interferon Alfa, Corticoid Withdrawal and AcyclovirTherapy in the Treatment of HBsAg Positive Active ChronicHepatitis
Authors: Pavel Ježek, Stanislav Plíšek, Pavel Chalupa, Petr Hůlek, Václav Dostál, Miroslava Volfová, Jiří Firbas, Petr Husa
Journal: Journal of Hepatology (1994)
Right versus left: Impact of primary location on survival and cure in patients undergoing hepatic resection for metastatic colon cancer.
Authors: John M. Creasy, Eran Sadot, Bas Groot Koerkamp, Joanne F. Chou, Mithat Gonen, Nancy E. Kemeny, Andrea Cercek, Leonard Saltz, Vinod P. Balachandran, T. Peter Kingham, Peter J. Allen, Ronald P. DeMatteo, William R. Jarnagin, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2017)

664 Background: Recent prospective studies in metastatic colorectal cancer (mCRC) have demonstrated an association between left-sided primaries and improved overall (OS) and progression-free survival (PFS). Primary location (right vs left colon) has not been well studied in patients undergoing potentially curative hepatic resection. Methods: A single-institution database was queried for all initial hepatic resections for mCRC 1992-2004. Postoperative deaths and patients with no followup after 90 days were excluded. Primary location determined by chart review (Right = cecum to transverse; Left = splenic flexure to sigmoid). Rectal cancer (distal 16cm), multiple primaries, and unknown location were excluded. Kaplan Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with no recurrence or resected recurrence with at least 3 years of disease-free followup. Results: 907 patients were included with a median followup of 11 years. 578 patients (64%) had left-sided and 329 (36%) had right-sided primary. Median OS for patients with a left-sided primary was 5.2 years (95% CI: 4.6-6.0) versus 3.6 years (95% CI: 3.2-4.2) for right-sided (p = 0.004). The hazard ratio (HR) for right-sided tumors was 1.22 (95% CI: 1.02-1.45, p = 0.028) after adjusting for age, CEA &gt; 200, DFI &lt; 12 months, hepatic tumor &gt; 5cm, &gt; 1 tumor, lymph node status, margin, and extrahepatic disease. Recurrence-free survival (RFS) was marginally different stratified by primary location (p = 0.065). Estimated cure rates were 22% for left and 20% for right-sided tumors. Conclusions: Among patients selected for hepatic resection of metastatic colon cancer, left-sided primary tumors were associated with an improved OS but not RFS. This difference in OS was independent of common prognostic variables. Estimated cure rates were not statistically different. Patients with left-sided primary tumors display a prolonged clinical course after recurrence suggestive of more indolent biology. [Table: see text]
Costimulatory molecule profiles and NK cell recovery after autologous hematopoietic cell transplantation (HCT) in multiple myeloma (MM) patients.
Authors: Myo Htut, Ghislaine Gallez-Hawkins, Joycelynne Palmer, Xueli Liu, Ricardo Tomas Spielberger, Pablo Miguel Parker, Len Farol, Anne Franck, Xiuli Li, Laëtitia Jeannet, Eunicia Reburiano, Valerie Jimenez, Lupe Duarte, Firoozeh Sahebi, Chatchada Karanes, Stephen J. Forman, Amrita Y. Krishnan, John Zaia
Journal: Journal of Clinical Oncology (2012)

8089 Background: Increased immune responses post autologous HCT may be of benefit in long term disease control. Responses may be mediated by NK cell function and possibly other alternate pathways, including costimulatory molecule pathways. This pilot study assesses the expression of inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and CD28) molecules on NK cells after auto-HCT in MM patients and evaluates the effect of lenalidomide treatment on these pathways. Methods: 17 patients with MM undergoing HCT, median age 56.7 years (36 – 67), were included in the study. Peripheral blood samples were taken 3 days prior to HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 patients were receiving lenalidomide with d91 as median start date. NK cells and their costimulatory molecules were evaluated by flowcytometry using 2 six color panels of antibodies. One way ANOVA test and Kruskal-Wallis test (non-parametric) were applied to analyze the data using the Graphpad Software. Results: See table below. NK cell number was highest (median: 26% of total lymphocytes) at d14 (p: &lt; 0.0001) compared to pre and post HCT levels. At d180, TNF-R OX40 expression was significantly increased in ≤PR group (n=5) (median: 9.5% of NK cells) compared to ≥VGPR (n=12) (0.8%; p=0.0084). In addition, NK cell number was higher in the lenalidomide group (n=13) (median: 15.15 % of total lymphocytes) compared to the no lenalidomide group (n=4) (6.74%; p=0.0108) at d180 post HCT. Significantly lower level of CTLA-4 expression was also found in the lenalidomide group (0.33% vs. 2.54%; p=0.0362). Conclusions: We observed NK cell recovery to baseline values at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was higher in ≤PR group than ≥VGPR group. Lenalidomide treatment was associated with higher NK cells number and decreased expression of CTLA-4. This observation could be a possible marker of enhanced host NK cell immune response against MM. Future clinical trials will explore therapies that increase NK cell responses. [Table: see text]
Feasibility and clinical utility of molecular profiling among metastatic cancer patients: A cancer center experience in Philippines.
Authors: Herdee Gloriane Cristal Luna, Amherstia Morelos, Mary Milisa Catedral, Ana Lea Lava, April Love Malasig, Jomer Dennis Pinzon, Jose Roberto Amparo, Conrado Lola, Gloria R. Cristal-Luna
Journal: Journal of Clinical Oncology (2014)

e22132 Background: Molecular tumor profiling can serve as a biomarker to facilitate directed personalized treatment guided by tumor biology, thus, maximizing treatment potential. However, feasibility and clinical utility in a hospital/clinic with low-resources is unclear. Conduction of molecular profiling is still a challenge due to (1) cost (2) availability (3) limited data on risk-benefit ratio and outcome among Filipinos (4) being not part of standard treatment approach (5) Filipino attitude and concept of resorting to palliative care or alternative medicine. Primary objective is todescribe feasibility and outcome (based on RECIST) of patients who underwent Molecular Profiling. Methods: Chart review of all metastatic cancer patients who underwent molecular profiling was done from 2009-2012. Age, gender, diagnosis, chemotherapeutic/ biologic treatment, number of lines of treatment and molecular profiling (using microarray and IHC) were documented. RECIST based outcome using CT scan after each regimen of at least 3 cycles. Results: 7,239 metastatic cancer patients were seen. Of these, 32 (0.4%) had molecular profiling ordered by 1 treating physician. Common cancers profiled were colorectal cancer and ovarian cancer, and common mutations discovered included TS overexpression, BCRP overexpression and ERCC1 overexpression. Median turn-around time from ordering the test to result was 21 days (range: 14-24 days). Of 9 patients profiled, none were enrolled in a matched genotype driven clinical trial. Among patients whose treatment agents were documented to be “benefit” by molecular profiling (N = 8), complete response, partial response, stable disease & progressive disease were recorded at 12.5%, 62.5%, 12.5% and 12.5% respectively. Clinical benefit ratio was 87.5%. Conclusions: Molecular tumor profiling is feasible even in hospital/clinic with low-resources & could have potential clinical utility. However, there are challenges and usage is very low. Additional research is needed to develop strategies to overcome challenges to increase usage & to gain insights into gene expressions and mutations found among Filipino cancer patients, so as to provide appropriate targeted treatment.
Midwall Fibrosis and 5-Year Outcome in Moderate and Severe Aortic Stenosis
Authors: Vassilios S. Vassiliou, Aris Perperoglou, Claire E. Raphael, Sanjiv Joshi, Tamir Malley, Russell Everett, Brian Halliday, Dudley J. Pennell, Marc R. Dweck, Sanjay K. Prasad
Journal: Journal of the American College of Cardiology (2017)
Multidisciplinary assessment and reporting of fitness to drive in brain tumor patients: A gray matter.
Authors: Alexander V. Louie, Esther Chan, Michelle Hanna, David Palma, Glenn Bauman, Barbara Fisher, George Rodrigues, Abhinay Sathya, David D'Souza
Journal: Journal of Clinical Oncology (2012)

6130 Background: In some jurisdictions, there is a legal requirement for physicians to report medically unfit drivers. Objectives of this study are to determine physician knowledge and attitudes on reporting legislation and driving assessment, and review our institution’s experience in evaluating fitness to drive in brain tumour patients. Methods: Physicians caring for brain tumour patients in South-western Ontario were identified by public databases and surveyed by mail. Survey questions elicited demographics, opinions, and factors influencing the decision to report. Patients receiving brain radiotherapy at our institution between January and June 2009 were identified and details of driving assessment were extracted. Fisher’s exact test and a logistic regression model were used to determine differences in responses between specialists and family physicians and factors influencing reporting. Results: Surveys (n=467) were distributed with 198 (43%) responses. Most (76%) felt that reporting guidelines were unclear. Neurologists (43%) and Family Physicians (22%) were felt to be the most responsible to report unfit drivers. Compared to specialists, Family Physicians were less likely: to be comfortable with reporting (p=0.02), to consider reporting (p&lt;0.001), or discuss the implications of driving (p&lt;0.001). Perceived barriers in assessing fitness to drive included: lack of tools to assess (57%) and the impact on the patient-physician relationship (34%). 158 patients were retrospectively reviewed. Forty-eight patients (30%) were reported to the provincial licensing authority and 64 (41%) were advised not to drive. 53 patients experienced seizures, of which 36 (68%) had a documented discussion on driving. Only 30 (56%) of these patients were reported to the licensing authority despite legal requirements. Age, primary disease, previous neurosurgery and seizures were predictive of reporting (p&lt;0.05). On logistic regression modeling, seizures (OR 12.4) and primary CNS disease (OR 15.5) remained predictive of reporting. Conclusions: Despite guidelines and laws, the assessment of fitness to drive in patients with brain tumours is not routinely conducted or documented in a multidisciplinary setting.