tbuckley/cabot-search huggingface dataset:
Treatment with Next-Generation ALK Inhibitors Fuels Plasma <i>ALK</i> Mutation Diversity
Authors: Ibiayi Dagogo-Jack, Marguerite Rooney, Jessica J. Lin, Rebecca J. Nagy, Beow Y. Yeap, Harper Hubbeling, Emily Chin, Jennifer Ackil, Anna F. Farago, Aaron N. Hata, Jochen K. Lennerz, Justin F. Gainor, Richard B. Lanman, Alice T. Shaw
Journal: Clinical Cancer Research (2019)

Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with ≥2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new ALK mutations on lorlatinib.ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.
Immunohistochemical Expression of CD123 Is Associated with an Inferior Clinical Outcome in Acute Myeloid Leukemia
Authors: Nana Arai, Bungo Saito, Maasa Abe, Megumi Watanuki, So Murai, Yuta Baba, Yukiko Kawaguchi, Shun Fujiwara, Hiroyuki Tsukamoto, Yui Uto, Nobuyuki Kabasawa, Kouji Yanagisawa, Norimichi Hattori, Mayumi Homma, Eisuke Shiozawa, Toshiko Yamochi, Masafumi Takimoto, Hiroshi Harada, Tsuyoshi Nakamaki
Journal: Blood (2016)
Superbug spreads in European hospitals as resistance to last resort antibiotics grows
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Drug resistant strains of Klebsiella pneumoniae —bacteria that live harmlessly in the human intestine but can cause serious infections if they spread elsewhere in the body—are rapidly spreading between patients in hospitals throughout Europe, research has found.1

Strains of the bacteria, which can cause pneumonia and meningitis, are quickly becoming resistant to the “last hope” group of antibiotics, the carbapenems.

Deaths from carbapenem resistant K pneumoniae in Europe have been rising in …
Dawn Elizabeth Hazlehurst
Authors: Nigel Thorley
Journal: BMJ (2019)

Dawn Elizabeth Hazlehurst was a very experienced, committed, and dedicated general practitioner. She grew up in Manchester, attended Manchester University Medical School, and carried out her training in hospitals throughout north west England. During her early career she was a senior house officer (SHO) for paediatrics, psychiatry, obstetrics and gynaecology, and accident and emergency medicine in various hospitals around north west England.

Following on from her SHO positions, Dawn entered primary care and …
Epidermal growth factor receptor (<i>EGFR</i>) mutation testing in non-small cell lung cancer (NSCLC) patients (pts)
Authors: L. V. Sequist, V. A. Joshi, P. A. Jänne, P. Fidias, A. Muzikansky, M. Meyerson, D. A. Haber, R. Kucherlapati, B. E. Johnson, T. J. Lynch
Journal: Journal of Clinical Oncology (2006)

7177 Background: Somatic mutations in EGFR are associated with response to therapy and prolonged overall survival (OS) of NSCLC pts treated with tyrosine kinase inhibitors (TKI). We began EGFR mutation screening in 2004 with a CLIA certified test. We determined the characteristics of pts tested, EGFR mutations identified, and analyzed response to therapy and OS. Methods: We performed a retrospective cohort study of all NSCLC pts referred for EGFR testing over 1 year. Samples underwent direct sequence analysis of EGFR exons 18–24. We used multivariable logistic regression models to examine associations between mutation and pt characteristics. We used chi-square tests to assess differences in response to therapy by EGFR status and analyzed OS with Cox proportional hazard models, adjusting for age, gender and stage. Results: We screened 269 NSCLC pts for EGFR mutations, including 188 (71%) with unresectable disease and 245 (91%) with adenocarcinoma. Mutations were identified in 62 (23%) pts. 15 samples (6%) yielded insufficient DNA for testing. Mutation was more likely in the 59 never-smokers compared to the 185 ever-smokers [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.5–9.2]. Each added pack-year of smoking history lowered the odds of mutation by 5% (OR 0.95, 95% CI 0.94–0.97). Mutation was more likely in the 12 Asians than in the 212 of all other races (OR 3.7, 95% CI 1.1–12.0). In multivariable analyses, pack-years of smoking remained predictive of mutation (OR 0.96, 95% CI 0.94–0.99). Among 44 pts with unresectable disease undergoing subsequent TKI therapy, the 20 EGFR positive pts had an increased response rate (RR) compared to the 24 EGFR negative pts (60% v. 4%, p &lt; 0.0001). In 27 pts given subsequent chemotherapy, RR was 33% and did not differ by EGFR status. Median follow-up was 9.8 months (mo) (range 0.2–135.8 mo). Among pts with unresectable disease, median OS is estimated to be 22.7 mo in EGFR negative pts and is not reached in EGFR positive pts (HR 0.22, 95% CI 0.80–0.63). Conclusions: Sequencing EGFR for somatic mutations is feasible in routine care of NSCLC pts. 23% of screened pts tested positive, and never smoking was the strongest predictor of mutation. Among patients with unresectable disease, EGFR mutation was associated with an increased RR to TKI therapy and OS. [Table: see text]
Observational Study of CML Italian Patients Who Discontinued TKIs
Authors: Carmen Fava, Giovanna Rege-Carmbrin, Irene Dogliotti, Marco Cerrano, Paola Berchialla, Gianantonio Rosti, Fausto Castagnetti, Gabriele Gugliotta, Bruno Martino, Carlo Gambacorti-Passerini, Elisabetta Abruzzese, Ester Maria Orlandi, Chiara Elena, Patrizia Pregno, Antonella Gozzini, Paolo Avanzini, Micaela Bergamaschi, Monica Crugnola, Monica Bocchia, Sara Galimberti, Davide Rapezzi, Alessandra Iurlo, Daniele Cattaneo, Roberto Latagliata, Massimo Breccia, Michele Cedrone, Marco Santoro, Mario Annunziata, Luciano Levato, Fabio Stagno, Francesco Cavazzini, Nicola Sgherza, Valentina Giai, Luigiana Luciano, Sabina Russo, Pellegrino Musto, Giovanni Caocci, Federica Sora, Francesco Iuliano, Francesca Lunghi, Giorgina Specchia, Fabrizio Pane, Michele Baccarani, Dario Ferrero, Giuseppe Saglio
Journal: Blood (2017)
High-dose chemotherapy and autologous stem cell transplantation in refractory/metastatic nonseminomatous germ cell-tumors: A retrospective study of the Turkish Oncology Association.
Authors: Mustafa Ozturk, Fikret Arpaci, Sukru Ozaydin, Nuri Karadurmus, Evren Ozdemir, Selmin Ataergin, Gokhan Erdem, Halit Karaca, Mustafa Cakar, Turker Turker, Ahmet Ozet, Okan Kuzhan, Selim Kilic, Seref Komurcu, Gulsum Ozet, Simten Dagdas, Bekir Ozturk, Serdar Sivgin
Journal: Journal of Clinical Oncology (2013)

e15623 Background: Testicular cancer is a chemosensitive tumor that may be curable even in relapsed disease. Those patients who do not respond to standard combination chemotherapy or relaps may be treated with high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) as salvage therapy. Methods: Eighty five patients that received HDC and ASCT between Feb 1993 - Dec 2012 in different university clinics of Turkey were retrospectively reviewed and evaluated. Results: Median age of the patients was 24 (range: 11-54 years) and 63 patients (74,1%) had stage III, 21 (24,7%) had stage II disease at initial diagnosis. The primary tumor location was testis in 71 patients (83,5%), and 14 patients (16,5%) had extragonadal region origin. Evaluation of metastatic focuses before HDC and ASCT was as follows: Liver metastasis (n = 23, 27.05%), lung involvement (n = 23, 27.05%) and multiorgan involvement (n =14, 16.47%) and other metastatic involvements (n=4, 4.7%). ICE (ifosfamide, carboplatin, etoposide) regimen was performed as HDC in all patients. Median follow-up was 59 (range: 8-218) months. Pre-ASCT patients’ condition was complete remission (n=28, 32.9%), partial remission (n=36, 42.4%) and never in CR (n=21, 24.7%) respectively. 32 patients (37.6%) relapsed or progressed within 1 year after HDC and ASCT median relaps was time 3 months (range: 0.3 - 36.13). Transplant related mortality was %3.5 and 3 patients died within the engraftment period after HDC. Five-year overall survival rate was 59.7%. Conclusions: HDC and ASCT is an effective and safe approach for patients with metastatic and refractory germ cell testicular cancer patients that do not respond to standard combination chemotherapy.
Long-term adverse events after sleeve gastrectomy or gastric bypass: a 7-year nationwide, observational, population-based, cohort study
Authors: Jérémie Thereaux, Thomas Lesuffleur, Sébastien Czernichow, Arnaud Basdevant, Simon Msika, David Nocca, Bertrand Millat, Anne Fagot-Campagna
Journal: The Lancet Diabetes & Endocrinology (2019)
Cognitive function (CF) and prognostic information understanding in advanced cancer patients (ACP)
Authors: F. J. Hlubocky, E. Larson, M. J. Ratain, G. Sachs, C. K. Daugherty
Journal: Journal of Clinical Oncology (2009)

9516 Background: The role of advanced cancer patients' (ACP) cognitive function (CF) and its relationship to understanding of a terminal prognosis has never been formally evaluated. Methods: ACP CF was evaluated among a population of terminally-ill patients enrolling in phase I trials at our institution using a neuropsychological battery designed to assess several domains of decisional capacity: Memory (Hopkins Verbal Learning HVLT); Executive Functioning (Verbal Fluency and Trail-making A/B); Language (Boston Naming-short); Attention (Digit Span); Comprehension (Auditory Comprehension &amp; WAIS comprehension). Semi-structured interviews of ACPs also evaluated md-pt communication regarding prognosis, and included the Hospital Anxiety and Depression Scale (HADS), BDI-II, and the FACT-COG. Results: To date, 110 ACP enrolling in phase I trials have been interviewed: median age 60 (23–83); 66% male; 88% Ca; 62% married; 71% &gt;high school education; 52% GI dx. 59% of ACPs reported having a discussion regarding life expectancy, and 55% stated that the physician gave them a prognostic timeframe regarding the amount of time left to live. ACP who stated the physician did not provide them a timeframe had measurable deficits in CF as indicated by Z scores for HVLT immediate recall (-1.3 ± .84 v -.74 ± 1.1, p=.03); total recall (-1.9 ± 1.2 v -1.2 ±1.5, p=.02); delayed recall (-1.7 ± 1.6 v -1.1 ±1.6, p=.04); language (.26 ± 1.3 v .78 ± .68, p=.03); Trails B (-1.6 ± 2.5 v -.61 ± 2.2, p=.04) and WAIS comprehension ss scores (14 ± 2.9 v 16 ± 3.0, p=.06). These ACP tended to exhibit more depressive symptoms (12 ± 10 v 6 ± 3, p=.04) and had lower scores for perceived cognitive impairment (96 ± 25 v 105 ±16, p=.04); impact on quality of life (26 ± 7 v 28 ± 5, p=.03); and FACT-COG total (152 ± 31 v 164 ± 22, p=.05). Conclusions: ACP enrolling in phase I trials who could not recall specific prognostic information had measurable cognitive impairment as compared to those ACP who could recall such information. Our data indicate that CF may play a role in ACP communication and/or understanding of prognostic information. [Table: see text]
Thomas Gruffydd Davies
Authors: Donald Williams
Journal: BMJ (2019)

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18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial
Authors: Jeremie Calais, Francesco Ceci, Matthias Eiber, Thomas A Hope, Michael S Hofman, Christoph Rischpler, Tore Bach-Gansmo, Cristina Nanni, Bital Savir-Baruch, David Elashoff, Tristan Grogan, Magnus Dahlbom, Roger Slavik, Jeannine Gartmann, Kathleen Nguyen, Vincent Lok, Hossein Jadvar, Amar U Kishan, Matthew B Rettig, Robert E Reiter, Wolfgang P Fendler, Johannes Czernin
Journal: The Lancet Oncology (2019)
Phase I clinical trial of temsirolimus (T) and vinorelbine (V) in advanced solid tumors.
Authors: Grace Lauren Lee, Lingyun Ji, Barbara Jennifer Gitlitz, Tanya B. Dorff, Syma Iqbal, Anthony B. El-Khoueiry, Lynda Roman, Susan Edwards, Xiomara Menendez, Phillip Cheng, David I. Quinn, Sarah Cole, Agustin Garcia
Journal: Journal of Clinical Oncology (2012)

e13084 Background: T, an mTOR inhibitor that regulates a signaling cascade which controls growth factor-induced cell proliferation was combined with V, an anti-mitotic drug in a phase I study. Synergistic effects have been reported with this combination. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to evaluate safety and tolerability. Methods: Eligible pts had advanced solid tumors, performance status 0-2, adequate organ function, and signed consent. Pts were treated with escalating doses of T and V. A 3+3 design was used. 4 dose levels were planned: Level I (T 20mg + V 20 mg/m2), Level II (T 25 + V 20), Level III (T 25 + V 25) and Level IV (T 25 + V 30). T was administered IV on days 1, 8, 15, and 22 while V was administered IV on days 1 and 15. Cycles were repeated every 28 days. MTD was defined as the highest dose tested in which fewer than 33% of pts experienced dose-limiting toxicity (DLT). DLTs included grade 3-4 non-hematologic toxicity (excluding inadequately treated nausea, vomiting, diarrhea, alopecia, myalgia, fatigue), hyperglycemia, hypertriglyceridemia, and grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Results: Nineteen pts were enrolled (10 female, 9 male, median age 62 (35-79)), tumor types: lung (5), bladder (2), endometrial (7), prostate (2), neuroendocrine (1), vagina (2) and received a total of 50 cycles. All pts had received prior chemotherapy. Six pts were inevaluable and replaced (1 disease progression, 4 missed doses, 1 withdrew consent). Four pts were enrolled at dose level I, 9 to dose level II and 6 to dose level III. There was 1 DLT at level II (1 pt with grade 3 anorexia and dehydration) and 2 at level III (1 pt grade 3 hypokalemia; 1 pt grade 4 neutropenia). Two pts died on dose level III (1 not study related, disease progression; 1 study related, grade 4 neutropenia). Grade 3/4 toxicities were anemia (2), edema (1), hyperglycemia (1), anorexia (1), dehydration (1), hypertriglyceridemia (1), hypokalemia (2), and neutropenia (1). Dose level II was the MTD. One pt had a partial response (prostate), 6 stable disease. Conclusions: The recommended phase II dose of T + V is T 25mg and V 20mg/m2. At this dose, treatment was well tolerated.
Perineal morbidity and functional results of pseudocontinent perineal colostomy for low rectal cancer surgery: Retrospective study of 149 cases.
Authors: Amine Souadka, Abdelilah Souadka
Journal: Journal of Clinical Oncology (2012)

e14133 Background: This retrospective study was designed to evaluate morbidity and functional results of pseudocontinent perineal colostomy (PCPC) using Schmidt’s technique in North African patients undergoing APR for managing low rectal adenocarcinoma. Methods: During 15 years, 380 Abdominoperineal resections for low rectal cancer were performed. One hundred forty nine cases among them had PCPC. There were 76 women, with an average age of 47 years old. All patients received néoadjuvante radiotherapy with or without chemotherapy. Functional results were evaluated prospectively at regular intervals. Results: There was no postoperative mortality. Operative Morbidity rate was only 18.3%, essentially dominated by perineal suppuration (40%). According to Kirwan score on a Functional level, 95 patients had gaz incontinence and 46 patients an occasional minimal soiling. At one year surveillance, the graft was clinically well detected in 72% of cases and anorectal manometric study on 15 cases showed a hypotonic pseudosphincter. Colic irrigation rhythm was, in 74% of cases, every 24 to 48h, and 15% of patients didn’t need irrigations any more 6 months after surgery. Except for major postoperative complications, no other conversion from perineal colostomy to an iliac colostomy was performed for dissatisfactory functional results since 77% of the patients were satisfied and 23% half-way satisfied of this technique. Conclusions: Pseudocontinent perineal colostomy is a simple, safe and reliable technique that represents an interesting alternative to permanent iliac colostomy after APR for low rectal adenocarcinoma. It improves perineal healing and provides good functional results and high degree of patient satisfaction in addition to body image preservation. it is well adapted to north-african cultural economical and religious coditions.
Serum levels of administered gefitinib correlate with the time to treatment failure in non small cell lung cancer patients
Authors: M. Nishio, F. Ohyanagi, A. Horikike, Y. Ishikawa, Y. Satoh, S. Okumura, K. Nakagawa, K. Nishio, T. Horai
Journal: Journal of Clinical Oncology (2006)

17027 Background: Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to have clinical activity against non-small cell lung cancer (NSCLC). The aim of the present study was to clarify the relationship between serum gefitinib levels and clinical efficacy in patients with advanced NSCLCs. Methods and Results: Sera from 89 cases (51 men and 38 women) were obtained after 2 weeks gefitinib (250 mg/day) monotherapy. The average gefitinib level was 429.4 ± 214.8 ng/ml (mean ± SD) with 17-fold variability observed. No significant variation was observed with reference to gender, smoking history or performance status. There was no direct link between gefitinib level and tumor response, but a significant positive correlation was evident with time to treatment failure in 44 patients receiving gefitinib for more than 3 months (R = 0.365, P = 0.0144). Conclusions: These results suggested that a dose response may exist for time treatment failure in the patients who benefit from gefitinib. Dose modification in accordance with the serum gefitinib level may thus improve the efficacy of gefitinib for NSCLCs. [Table: see text]
A phase I/II study (NCT01541332) of pomalidomide (POM), dexamethasone (DEX), and pegylated liposomal doxorubicin (PLD) for patients with relapsed/refractory (R/R) multiple myeloma (MM).
Authors: James D. Hilger, James R. Berenson, Leonard M. Klein, Alberto Bessudo, Peter J. Rosen, Shahrooz Eshaghian, Hilda Chamras, Youram Nassir, Regina A. Swift, Robert A. Vescio
Journal: Journal of Clinical Oncology (2013)

8598 Background: POM is a newer IMiD immunomodulatory compound with high in vitro potency that has shown promise in combination with DEX as an effective treatment option for R/R MM patients (pts), even those refractory to bortezomib and lenalidomide (LEN). We conducted a phase I/II trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using a modified dose and longer 28-day schedule in R/R MM pts. Methods: Phase I pts had progressive MM at the time of enrollment that was R/R to at least one anti-MM regimen. Phase II pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving LEN or relapse within 8 weeks of its last dose. During phase I, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX was administered IV at 40 mg over 30 min and PLD was administered at 5 mg/m 2 as an IV infusion over 30-90 min on days 1, 4, 8, and 11 of each cycle. POM doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent pts were enrolled at that dose. Results: To date, 27 pts have been enrolled, with 18 evaluable for efficacy and 19 for safety. Pts received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimens (range, 0-2). Pts have completed a median of 1 cycle (range: 0-8) with a median of 1.4 months of follow up (range: 0-7.1). No DLTs were seen during phase I, which established the MTD at 4 mg. Phase II has enrolled 16 pts at 4 mg so far. Clinical benefit was seen in 7 (39%) of evaluable pts (partial response = 22%; minor response = 17%) with another 44% showing stable disease. Common ≥ G3 adverse events included leukopenia (32% of pts), neutropenia (32%), lymphopenia (26%), and hyponatremia (16%). Neutropenia at ≥ G3 occurred in more than half of patients on the phase II trial (4 mg POM). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle shows efficacy for R/R MM pts. However, because of excessive ≥ G3 neutropenia, POM is being reduced to 3 mg for newly enrolled patients. Clinical trial information: NCT01541332.
‘S’-shaped curve: modelling trends in smoking prevalence, uptake and cessation in Great Britain from 1973 to 2016
Authors: Emma Victoria Beard, Robert West, Martin Jarvis, Susan Michie, Jamie Brown
Journal: Thorax (2019)

Background It is believed that declines in smoking prevalence naturally slow over time as the smoking population ‘hardens’ and that progress has come primarily from reducing uptake rather than increasing cessation. To address these issues, we undertook the first formal attempt to model the trajectory of smoking prevalence and indices of uptake and cessation in Great Britain from 1973 to 2016. Methods Using data from the General Lifestyle Survey between 1973 and 2008, the Integrated Household Survey between 2009 and 2014 and the Annual Population Survey between 2015 and 2016, this study modelled year-on-year changes in smoking prevalence, ever-smoking in 18–24-year-olds as an index of uptake, and quit ratios as an index of cessation. Results For all three outcomes, changes over time were best fitted by what may be broadly characterised as ‘S’-shaped curves: segmented functions characterised by initial rapid progress, a slowing or reversal, then renewed progress. Smoking prevalence in Great Britain showed a decelerating decline over time between 1973 and 2000, but then, after the introduction of the National ‘Smoking Kills’ tobacco control plan, the decline accelerated again and has remained nearly linear at −0.67 percentage points per year. Ever-smoking showed a decelerating decline which eventually ceased and began increasing around 1994 but then declined again after 2000. Quit ratios rose rapidly then slowed and then accelerated around 2000 and again more recently in 2013. Conclusion Long-term trends in smoking prevalence, uptake and cessation have followed a broadly ‘S’-shaped trend suggesting that they are responsive to major tobacco control initiatives. The decline in prevalence has resulted both from reductions in uptake and increases in cessation.