tbuckley/cabot-search huggingface dataset:
Epidemio-clinic and evolutionary profile of laryngeal cancer at oncology department of Mohamed VI University Hospital
Authors: M. Benhamidoune, A. Tahri, M. Aiterraisse, N. Derhem, N. Bouras, F. Tahiri
Journal: Journal of Clinical Oncology (2007)

16536 Background: Larynx cancer is one of the most frequent cancers of the superior airways. Narrowly linked to the chronic tobacco use, often associated with other addictive behaviours notably chronic alcoholism. It touches males in more than 90% of cases, with preponderance between 40 and 59 years old. It is often epidermoïd carcinoma of which the overall prognosis is one of the better within the cancers of the superior airways. Methods: Our study concerned 58 cases of larynx cancer treated at the oncology department of Mohamed VI university hospital in Marrakech between October 2002 and December 2005. Results: The mean age was of 55 years. 90% patients were males and 62% of urban origin. The tobacco use was discovered in 91% of the cases and the alcoholism in 40%. Symptoms at diagnosis were essentially dysphonia in 95% and dyspnea in 88% of case the lather having necessitated a tracheotomy in urgency in 55% of cases. The pathology showed that it was exclusively an epidermoïd carcinoma, well differentiated in 80% of the cases, 80% of the patients were initially locally advanced (T3 - T4), while 5% only had a localized stage . 27% of patients received a radiation therapy after surgery (total laryngectomy + lymphadenectomy in all cases) and 61% an exclusive radio-chemotherapy. 5% were lost from view before the beginning of the radiotherapy. On the assessable patients, 73% were in complete remission. Conclusions: The delay to the diagnosis in our country strongly darkened the prognosis of this cancer. The adoption of an information and sensibilisation strategy (anti-tobacco campaign) is necessary. No significant financial relationships to disclose.
In Vitro Generation of Highly Purified Functional Invariant NKT Cells in Multiple Myeloma: A Strategy for Immunotherapy.
Authors: Weihua Song, Hans J.J. van der Vliet, Yu-Tzu Tai, Ruojie Wang, Rao Prabhala, Klaus Podar, Laurence Catley, Masood Shammas, Steven P. Balk, Kenneth C. Anderson, Mark A. Exley, Nikhil C. Munshi
Journal: Blood (2006)
Oxycodone/acetaminophen addition to constant opioids in metastatic bone pain: A randomized, double-blinded, controlled, multicenter trial.
Authors: L. Sima, X. Wu, W. Fang, F. Li
Journal: Journal of Clinical Oncology (2010)

e19691 Background: Pain relief is often unsatisfied in metastatic bone pain despite the availability of strong opioids, and some pts can not bear severe opioids side effects. Our trial is to determine whether adding oxycodone 5 mg/acetaminophen 325 mg combination tablet on time could improve pain in pts already receiving strong opioids. Methods: Inclusion criteria were: Bone cancer pain with definite iconography diagnosis; NRS (0 no pain, 10 worst pain) of pain intensity ≥4; stable dose of opioids for at least 72 hours; KPF score≥50. Exclusion criteria were: Hepatic function abnormal; taking aspirin or NSIADs; chemotherapy, endocrine or radiotherapy from 15 days before or during the trial. Adjuvant therapy (diphosphate, corticosteroid, tricyclic antidepressants and anticonvulsants) could be started more than 1 week earlier, but the dose could not be changed afterwards. Participants took Oxy/APAP 1 tablet, q6h, d1-d10, ten days continuously. Pts in controlled group took placebo. Long-acting opioids could be increased step by step from d3 according to the pain in two groups. NRS and breakthrough pain at d2, d6 and d10 were the primary outcome. Short-Form Health State Classification (SF-6D) score from 6 (no influence to daily life) to 31(influence severely), nausea, vomiting, drowsiness, constipation and diaphoresis at d10 were secondary outcomes. Results: 86 patients completed the trial. Characteristics were no different between two groups (43 pts respectively) at the beginning. NRS were better in Oxy/APAP group than controlled: d2 (3.8±1.6 vs. 5.7±1.8, p<0.001), d6 (2.5±1.7 vs. 4.9±1.8, p<0.001), d10 (2.7±1.4 vs. 4.7±1.9, p<0.001). Pts in Oxy/APAP group suffered less breakthrough pain: d2 (1.1±0.4 times/d vs. 3.0±1.2, p<0.001), d6 (1.3±0.5 v. 2.6±1.1, p<0.001), d10 (0.9±0.5 vs. 2.5±0.9, p<0.001). SF-6D score at d10 were 14.5±4.4 vs. 17.9±4.6, p = 0.023. There were no differences in the other outcomes. Conclusions: Oxy/APAP addition on time improved pain and quality of life without major side effects. It should be considered to add Oxy/APAP first in bone pain pts with opioids inadequate response. Hepatic function in long term treatment is on observation. No significant financial relationships to disclose.
Phase I evaluation of telatinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors.
Authors: M. H. Langenberg, P. Witteveen, J. M. Roodhart, M. P. Lolkema, H. Verheul, M. Mergui-Roelvink, E. Brendel, J. Krätzschmar, J. H. Schellens, E. E. Voest
Journal: Journal of Clinical Oncology (2010)

3045 Background: Telatinib (BAY 57-9352) is an oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR-2). Bevacizumab is a monoclonal anti-VEGF-A antibody. We hypothesized that blocking both receptor and ligand of the VEGF/VEGFR pathway was feasible and would increase antitumor activity. Methods: In a phase I study 26 patients ≥ 18 years with histological or cytological proven advanced solid tumors refractory to standard treatment would be treated in successive cohorts with increasing doses of telatinib (twice daily, starting dose 450 mg) or bevacizumab (once every two weeks, starting dose 5 mg/kg). In case of exceeding toxicity, the dose of both agents could be stepwise decreased. Pharmacokinetics, endothelial (progenitor) cell (E(P)C) analysis by flowcytometry and VEGF(R2) and SDF-1α measurements were performed. Results: Most frequent adverse events were pain (head, bone, abdominal), nausea, voice changes, and fatigue. Five dose limiting toxicities (DLTs) occurred: grade 3 hypertension (cohort I and II), bowel perforation, grade 3 lipase increase and atrial flutter (cohort III). In 3 patients cardiac toxicity was observed. Due to cumulative toxicity, in cohort 3 bevacizumab dose was reduced to 1mg/kg. This cohort exhibited acceptable toxicity but due to 3 DLTs (n=14) it also represented the maximum tolerated dose. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. EPC and SDF-1α levels increased during monotherapy telatinib. Twelve patients had stable disease (clinical benefit of 46%). Conclusions: The recommended phase II dose with an acceptable toxicity profile is telatinib 450 mg bid and bevacizumab 1mg/kg biweekly although determined in a small population. Further studies with a larger patient number should investigate the tolerability more precisely and the relationship of observed EKG changes with the study treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Healthcare AG Netherlands Cancer Institute
Postpsychotic depression and the need for personal significance
Authors: B L Mackinnon
Journal: American Journal of Psychiatry (1977)

The author, who considers postpsychotic depression as a reaction to psychosis, illustrates some of the dynamics involved in the development and persistence of the state with letters from a patient. Among other dynamic and psychotherapeutic considerations, the need for self-realization and meaning in everyday life merits special emphasis in the treatment of those for whom escape from psychosis has meant not only deliverance from terror, but also a loss of grandeur and significance.
Drugging Membrane Protein Interactions
Authors: Hang Yin, Aaron D. Flynn
Journal: Annual Review of Biomedical Engineering (2016)

The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind cells to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally “undruggable” regions of membrane proteins, enabling modulation of protein–protein, protein–lipid, and protein–nucleic acid interactions. In this review, we survey the state of the art of high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets.
Incidence and clinical significance of sunitinib-induced cardiotoxicity in metastatic renal cancer.
Authors: M. Teo, M. Yusra, D. Moore, R. S. McDermott
Journal: Journal of Clinical Oncology (2010)

e15102 Background: Sunitinib, a small-molecule tyrosine-kinase inhibitor is the first line treatment of choice in metastatic renal cancer (mRCC). However, reported rates of cardiotoxicity are as high as 33.8% (Schmidinger, JCO 26:5204-5212). We prospectively sought to assess the rate of echocardiographically and/or clinically apparent cardiotoxicity in patients with mRCC receiving sunitinib as first line therapy. Methods: Patients with a diagnosis of mRCC commencing sunitinib had a baseline echocardiogram and repeat imaging every two cycles while on therapy. Patients were seen after each cycle and specifically questioned regarding potential cardiac symptomatology. This analysis is based on recorded symptoms and serial cardiac scanning in patients who had a minimum of two echocardiograms. Results: 27 patients were suitable for analysis with a median age of 61 years (range 35-78). 8 had pre-existing cardiac risk factors, A total of 103 echocardiograms were performed, a median of 3 scans per patient, with per patient breakdown shown in the Table. Median time interval between each scan was 3.2 months; no patient experienced cardiac symptomatology (angina or dyspnoea). 20 patients had pre-treatment left ventricular ejection fraction (LVEF) >55%, 6 had LVEF 50-55%, and 1 with <50%. 4 patients experienced a reduction in EF of >10%. In the absence of symptoms, treatment was continued and in 2 cases EF had returned to baseline on subsequent echocardiogram. In a 3rd case EF remains stable with a greater than 10% reduction in EF and patient is asymptomatic on treatment. The fourth patient was taken off drug due to disease progression. 3 patients experienced a reduction in EF of >5% but < 10%. Treatment was not changed and in all cases EF returned to normal on the subsequent scan. Overall, while 7 patients experienced a reduction in LVEF, in 5 of these it was transient. No patient developed cardiac symptoms and no treatment cessation was required due to cardiotoxicity. Conclusions: In mRCC, sunitinib may cause transient reductions in EF; however most are not clinically significant and treatment may safely be continued. No. of echos Pt No. 2 12 3 3 4 4 5 1 6 2 7 3 8 2 No significant financial relationships to disclose.
Cyclooxygenase-2 (COX-2) mediated anti-apoptosis may occur via Bcl-2 in the progression of Barrett's esophagus to adenocarcinoma
Authors: D. Shimizu, J. H. Peters, D. Vallboehmer, H. Kuramochi, K. Uchida, S. Schneider, P. T. Chandrasoma, K. D. Danenberg, T. R. Demeester, P. V. Danenberg
Journal: Journal of Clinical Oncology (2004)

9529 Background: Upregulation of COX-2 is considered to be important in the pathogenesis of esophageal adenocarcinoma. The mechanism by which this occurs is unknown. In vitro studies suggest that COX-2 may regulate expression of the anti-apoptotic protein Bcl-2, possibly accounting for reduced apoptosis in carcinogenesis. The aim of this study was to investigate the relationship of these 2 genes in the development of Barrett's-associated adenocarcinoma. Methods: Histologic sections from endoscopic biopsies or esophagectomy specimens were classified as: reflux-esophagitis (n=8), non-dysplastic Barrett's (n=37), dysplastic Barrett's (n=16) and adenocarcinoma (n=38). The desired tissue was isolated by laser capture microdissection. Cellular RNA was extracted and reverse transcribed to cDNA. Expression levels of COX-2 and Bcl-2 were measured by quantitative real-time PCR (Taqman®). Gene expression levels were compared to proximal esophageal squamous epithelium of patients (n=40) without Barrett's or cancer. Results: Expression of both Bcl-2 and COX-2 were increased in non-dysplastic Barrett's (p=0.045, p=0.006) and adenocarcinoma (p<0.001, p<0.001) compared to squamous mucosa. Expression of these two genes rose parallel in normal squamous epithelium, non-dysplastic Barrett's, dysplastic Barrett's and adenocarcinoma (see table below). Conclusions: COX-2 and Bcl-2 expression levels are highly associated in both normal and pathologic foregut tissues. This has not been previously demonstrated in patients. These data suggest that COX-2 mediated anti-apoptosis may occur via Bcl-2 in the development of esophageal adenocarcinoma. No significant financial relationships to disclose.
Phase I study of s-trans, trans-farnesylthiosalicylic acid (FTS), a novel oral Ras inhibitor, in patients with refractory hematologic malignancies
Authors: G. Borthakur, F. Ravandi, S. O'Brien, B. Williams, F. Giles
Journal: Journal of Clinical Oncology (2007)

7071 Background: Ras activation (mutational or non-mutational) is a key pathway for survival and proliferative advantage of leukemic cells. Farnesyl transferase inhibitors (FTI) that are thought to alter lipid modification of Ras and thereby alter its membrane targeting, are in clinical trial in hematologic malignancies but their target may not be specific for Ras. Toxicities of FTIs include diarrhea, skin rash and hepatic toxicity. FTS is an oral Ras inhibitor that causes dislocation of Ras from its membrane location by competing directly with farnesylated Ras to bind to its putative membrane binding proteins. FTS does not inhibit farnesyl transferase enzyme. Methods: We report on an ongoing phase I study of FTS in patients with relapsed/refractory hematologic malignancies in which FTS is administered orally twice daily on days 1–21 of a 28 day cycle in a “3+3” dose escalation design. Results: To date, 12 patients (pts) have been enrolled, with 11 pts treated (1 cycle=3, 2 cycles=5, 4cycles=1, 2= too early). Four pts were enrolled at dose level (DL) of 100 mg , 3 pts at each DL of 200 and 400 mg and 2 pts at DL of 600 mg. One pt enrolled at 100 mg DL was never treated. Median age was 74 years (range, 57 to 85 years), median ECOG status 1 (range, 0–2) and median no. of prior therapies 2 (range, 0–7). Diagnoses included: Acute myelogenous leukemia (AML) = 6 pts, myelodysplastic syndrome (MDS) = 4 pts, chronic myelomonocytic leukemia (CMML) = 1 pt and chronic myelogenous leukemia (CML) = 1 pt. Of 9 pts evaluable for response, 6 pts (3 MDS, 1 CMML, 2 AML) had hematological improvement (HI) (3 in two lineages, 3 in one lineage). Grade 1 diarrhea has been the only non-hematologic toxicity seen, observed in 8 of 10 (80%) pts evaluable for toxicity and is completely correctable with oral antidiarrheals. Conclusions: FTS shows promising activity in refractory hematologic malignancies and to date has minimal toxicity. No significant financial relationships to disclose.
Evaluation of chemoradiotherapy for elderly esophageal cancer patients
Authors: T. Yoshii, K. Nishimura, N. Nakayama, S. Takagi, O. Motohashi
Journal: Journal of Clinical Oncology (2008)

15613 Background: Radiotherapy based treatments are less invasive than radical surgery and are attractive for elderly patients. Concurrent chemoradiotherapy(CRT) outperforms radiotherapy alone(RT) in clinical outcomes, but tends to have higher toxicity. Therefore, the safety and efficacy of CRT for elderly patients needs clarification. Methods: Clinical features were studied retrospectively in 29 patients, median age 79.0 years (range 76–89), who underwent RT or Chemoradiotherapy (sequential or concurrent) for esophageal cancer between January 2000 and December 2007 at our hospital. Statistical analysis was performed by log-rank and Kaplan-Meier methods; χ2 test, and multivariate analyses were conducted. Results: Patient clinical stages were I;6, II;15, III;7, IV;1. Performance status was 0;3, 1;15, 2;9, 3;2, 4;0. Those who underwent RT (n=14) and sequential chemoradiotherapy (n=5) were categorized to the “non-CRT” group, and those who had concurrent chemoradiotherapy (n=10) the CRT group. RT consisted of 55–70Gy- 2 or 2.5Gy/fx/day. Concurrent chemotherapy (CHT) was basically adapted cisplatin (70mg/m2/d day1) and civ 5FU (700mg/m2/d day 1–4) weeks 1 and 5, or cisplatin (4mg/m2/d) and civ 5FU (200mg/m2/d) ×5d/weekly ×6w. Sequential and adjuvant CHT were 5FU based regimens. MST was 551.0 days (62–2373). Overall response rate (RR) was 79.3% (23/29). Twenty cases were deceased; 16 were cause specific, but no deaths related to treatment. There was no statistical significance in MST or RR between the CRT and non-CRT groups (MST:886 vs.551, p=0.927,RR:80.0% vs.78.8%, p=1.000). However, there tended to be more AEs in the CRT than the non-CRT group (60.0% vs. 21.1%, p=0.092). Five CRT group cases could not complete the treatment schedule; 4 because of adverse events (AEs) of more then grade 3. In advanced cases (>stage2), multivariate analysis revealed that response to 1st treatment was a significant, independent factor influencing survival (p=0.002, HR 0.151 (95%CI 0.30–0.762)) and adjuvant CHT for responders (n=5) tended to influence survival (MST: (+);634 vs. (-);255 days, p=0.061). Cause specific deaths in both group were equivalent (50% vs. 57.9%, p=0.989). Conclusions: CRT cannot overcome non-CRT remarkably for elderly esophageal cancer patients. Adjuvant CHT may be important. No significant financial relationships to disclose.
Effects of chemotherapy and zoledronic acid on bone metabolism measured by the osteoclast specific TRAP level in patient with bone metastases due to lung cancer
Authors: G. Rabinowits, A. Janckila, L. Yam, G. H. Kloecker
Journal: Journal of Clinical Oncology (2008)

19069 Background: Imaging and clinical assessment are often inadequate to fully predict the effect of biphosphonates. Tartrate Resistant Acid Phosphatase - 5b (TRAP) has been found to be a very specific maker of osteoclast activity. This study examines the effect of zoledronic acid and chemotherapy on TRAP levels and N-telopeptides of type I collagen (NTx). Methods: Lung cancer patients with bone metastases received monthly zoledronic acid. Serum TRAP levels and NTx levels were tested at baseline and every 2 weeks for the first two months, then monthly. The levels were tested while patients were on and off chemotherapy for lung cancer. Results: Seventeen patients were enrolled. Forty-five blood samples were tested. The mean of TRAP levels while on chemotherapy and zoledronic acid increased from 2.1 U/L to 2.41 U/L over time. In contrast the mean of TRAP levels while on zoledronic acid alone decreased from 1.98 U/L to 1.18 U/L. The difference was statistically significant (p<0.05). The NTx values ranged from 27–101 nMBCE (normal:8–23 nMBCE), and correlated with TRAP levels at 0.59 (p=0.06) Conclusions: The present study was undertaken to evaluate TRAP levels in lung cancer patients with bone metastases treated with zoledronic acid. The unexpected increase in TRAP levels in patients receiving chemotherapy and zoledronic acid, suggests that chemotherapy increases the osteoclast activity and decreases bone mass. After completion of chemotherapy, TRAP levels decreased with continuation of zoledronic acid. The drop in TRAP levels confirms that zoledronic acid has a significant inhibitory effect on osteoclast activity in patients with bone metastases, which would explain the beneficial effect of zoledronic acid on skeletal related events in previous studies. The rise in the TRAP levels in a few patients, despite zoledronic acid, off chemotherapy, could be a marker of poor response to therapy and disease progression. Further studies are needed to evaluate the correlation between skeletal related events and TRAP levels and the effect of chemotherapy on bone metabolism. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Effect of the combination of retinoic acid and rapamycin on cerebellar granule cell and medulloblastoma proliferation
Authors: T. R. Gershon, A. Shirazi, A. M. Kenney
Journal: Journal of Clinical Oncology (2009)

2077 Background: Cerebellar granule cell precursors (CGCPs) are neuroblasts that proliferate in early postnatal life and may become transformed, giving rise to medulloblastoma. The proliferation of CGCPs is driven by mitogenic signals including Sonic Hedgehog (SHH), and growth factors that activate the protein mTOR. Dysregulation of these intercellular signals can promote medulloblastoma formation. We propose that microenvironmental signals that down-regulate the response of CGCPs to mitogens may inhibit medulloblastoma growth. Retinoic acid (RA) is an endogenous signaling molecule with potent anti-neoplastic effects. We investigated whether SHH, mTOR, and RA signaling pathways interact to regulate CGCP and medulloblastoma proliferation. Methods: We measured proliferation in cultured CGCP explants and the CGCP-derived murine medulloblastoma cell line PZp53 using quantitative phosphohistone-H3 immunocytochemistry. We examined the effects of adding to culture medium SHH, the mTOR inhibitor rapamycin, and all trans-RA (ATRA) in specific combinations. We compared CGCPs from wild type animals to CGCPs from mice with constitutive mTOR activation due to TSC2 mutation. Results: A minimum concentration of 1uM ATRA inhibited SHH-driven CGCP proliferation measurably but incompletely, while 10uM ATRA caused widespread necrosis. CGCPs from TSC2 mutant animals, in which mTOR was constitutively active, were 50% less effected by 1uM ATRA than wild type CGCPs. PZp53 medulloblastoma cells were relatively resistant to ATRA, tolerating 10uM ATRA with reduced but persistent proliferation. 10nM rapamycin decreased but did not eliminate PZp53 proliferation. The combination of rapamycin and ATRA, however, acted synergistically, suppressing proliferation &gt;90%. This suppression persisted at 10-fold lower drug concentrations. Conclusions: CGCPs and CGCP-derived medulloblastoma cells integrate signals transduced by SHH, mTOR, and RA pathways. These signaling pathways can be manipulated by pharmacologic agents in combinations that confer dramatically enhanced antineoplastic effect. We are investigating the molecular basis of the synergy of rapamycin and ATRA. We plan to test the combination in xenografts and ultimately in patients with medulloblastoma. No significant financial relationships to disclose.