tbuckley/cabot-search huggingface dataset:
Responses and molecular markers in patients with peripheral T-cell lymphoma treated on a phase II trial of depsipeptide, FK228
Authors: R. L. Piekarz, R. Frye, M. Turner, J. Wright, J. Leonard, S. Allen, S. Smith, M. Kischbaum, J. Zain, S. E. Bates
Journal: Journal of Clinical Oncology (2005)

3061 Background: The histone deacetylase inhibitors (HDIs) are a class of differentiating agents undergoing clinical testing. Depsipeptide, FK228 (Gloucester and Fujisawa Pharmaceuticals), is an HDI with potent cytotoxic activity in vitro and in vivo and clinical activity in patients with T-cell lymphoma. Based on these observations, we are conducting a multi-institutional phase II trial for patients with cutaneous and peripheral T-cell lymphoma. Methods: Forty-nine patients have been enrolled into 4 cohorts distinguished by tumor histology and prior therapy. Depsipeptide is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14mg/m2. Responses in PTCL are measured using the Cheson criteria. Results: Responses have been observed in 5 of 19 patients enrolled with relapsed or refractory PTCL at the NCI. Complete responses were observed in 2 patients; one in a patient with PTCL, unspecified, and anther with ALK-/CD30+ anaplastic large cell lymphoma. Partial responses in 3 patients were observed; 2 with PTCL, unspecified, and another with enteropathy-associated T-cell lymphoma. One patient recently enrolled with PTCL, unspecified, has completed 3 cycles with reduction of lesions on follow-up CT scan, that have not reached criteria for PR. Durations of response range from 8–14 months, with one patient continuing in CR at 14 months. Of these 19 patients, 5 had previously undergone autologous stem cell transplant, 2 of whom achieved a response with depsipeptide. Tumor cells were detected in the circulation of 7 patients and 2 had bone marrow involvement. Increased histone H3 acetylation has been observed by immuno-dot blot assay using GAPDH as a control in peripheral mononuclear cells obtained 4 or 24 hrs after initiation of treatment. Inductions ranging from 2 to 14-fold were observed in samples obtained from 10 of 14 patients. Conclusions: Depsipeptide as a single agent appears to have significant activity in patients with PTCL and combination therapy with depsipeptide should be pursued for this disease. All 4 cohorts remain open to accrual at the NCI and extramural sites. No significant financial relationships to disclose.
Time profile of adverse events (AEs) from regorafenib (REG) treatment for metastatic colorectal cancer (mCRC) in the phase III CORRECT study.
Authors: Axel Grothey, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Guillem Argiles, Takayuki Yoshino, Heinz-Josef Lenz, Richard M. Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Lisa Cupit, Dirk Laurent, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

3637 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]
Yttrium-90 microsphere selective internal radiation treatment (SIRT) with concomitant chemotherapy (Chemo-SIRT) as first/second-line therapy in patients with colorectal cancer liver metastases
Authors: K. L. Pennington, D. Bruetman, G. Mesoloras, R. Hostetter, S. A. Gulec
Journal: Journal of Clinical Oncology (2007)

14589 Background: Yttrium-90 (Y-90) microsphere selective internal radiation treatment (SIRT) has been studied in patients (pts) with colorectal cancer liver metastases (CRCLM) in combination with FUDR and 5FU-LV with promising results. This is a phase II trial of SIRT and concurrent contemporary chemotherapy in the frontline management of CRCLM. Methods: Pts with metastatic disease limited predominantly to the liver were eligible for the study. Other entry criteria included KPS 70 or &gt;, 3 month life expectancy and adequate marrow and renal reserve. Pre-treatment evaluations included the assessment of liver function, CEA level, 18 F-FDG-PET/CT imaging, an angiogram and a 99m Tc-MAA (macroagregate albumin) scan. SIRT with Y-90 resin microspheres (Sirtex Medical, Lake Forest, IL) was administered on day 2 of the first chemotherapy (Fol-Fox or Fol-Firi) course in either lobar or whole-liver fashion. Chemotherapy was repeated on a biweekly schedule. CEA levels and 18 F-FDG-PET/CT based anatomic and functional volume (V f ) changes were used to determine tumor response at 4, 8, and 12 weeks after therapy. CTC v3 toxicity grades were used to classify adverse events. Results: 6 pts were treated as first-line and 2 pts as second-line. 5 pts received single lobe and 3 pts received whole liver treatment. Administered activity of Y-90 microspheres ranged from 0.9 to 3.1 GBq (mean 2.3 GBq). Mean tumor radiation absorbed dose was 203.6 Gy (Range 91.0–351.4 Gy). Mean liver absorbed dose was 47.8 Gy (Range 7.9–85.9 Gy). 6/8 pts had complete/near-complete metabolic response with a mean tumor V f decrease in target lobe(s) of 98%). The remaining 2 pts demonstrated &gt; 50% reduction in V f in target lobe(s). A parallel decrease in CEA level was observed in responding pts. Surgical downstaging was attained in 3/8 pts. 2 pts developed grade III toxicity (one gastric ulcer and one alkaline phosphatase elevation). Conclusion: Chemo-SIRT as first-line therapy has a high level of response in CRCLM as measured by reductions in functional tumor volume and CEA level. Further follow-up of these pts is needed to confirm that this response is of clinical significance in terms of improved surgical downstaging and survival. [Table: see text]
The expression of uPAR is affected by NO, HIF-1<i>a</i> and ERK in MDA-MB-231 breast carcinoma cell line under hypoxic condition
Authors: S. Y. Yoon, Y. J. Lee, I. K. Choi, S. C. Oh, C. W. Choi, B. S. Kim, S. W. Shin, Y. H. Kim, J. S. Kim, J. H. Seo
Journal: Journal of Clinical Oncology (2004)

9664 Background uPAR has been known to play a major role in cancer invasion and metastasis. uPAR expression in various cancer type suggested poor prognosis. In hypoxic status, the expression of uPAR was increased. But, the exact mechanism was not elucidated yet. We tried to evaluate uPAR regulation mechanism under hypoxic condition. Material and mdethods MDA-MB-231 human breast cancer cell line, which is known to have highly invasive and metastatic potential, was used to evaluate uPA, uPAR, phosphorylated-ERK (p-ERK), HIF-1α expression. To compare hypoxic condition with normoxic condition, cells were incubated in the hypoxic incubator. uPA activity was evaluated by gel zymography. uPAR, p-ERK, HIF-1α expression was show by western blotting. Results uPAR and p-ERK expression was increased under hypoxic condition compared to normoxic condition. However uPA activity did not change according to oxygen tension. When we treat ERK inhibitor, uPAR expression was decreased. iNOS inhibitor (aminoguanidine) markedly increased p-ERK expression by dose dependent manner. However iNOS inhibitor did not change uPAR expression. HIF-1α expression was decreased by iNOS inhibitor and it was increased by exogenous NO donor. Conclusion In hypoxic MDA-MB-231 breast cancer cell lines, uPAR and p-ERK and HIF-1α expression was increased. uPAR expression under hypoxic condition was dependent on p-ERK expression directly. Nitric oxide (NO) and HIF-1α just have indirect effect on uPAR under hypoxic condition. No significant financial relationships to disclose.
Health and Safety Executive’s response to article on the demise of occupational medicine
Authors: Andrew Curran, David Fishwick
Journal: BMJ (2015)

We disagree with the view of former Health and Safety Executive senior medical inspector Anne Raynal.1

The UK health and safety system has led to the UK being one of the safest places to work in Europe.2

Raynal summarises the situation in terms of the likely numbers of work related ill health problems. …
The association of epithelial expression of hENT1 and survival from adjuvant gemcitabine in pancreatic ductal adenocarcinoma (PDAC).
Authors: Daniel John Renouf, Joanna Karasinska, Steve Kalloger, Renata D'Alpino Peixoto, Kate O'Connor, David Schaeffer
Journal: Journal of Clinical Oncology (2015)

296 Background: Human equilibrative nucleoside transporter 1 (hENT1) mediates the cellular uptake of gemcitabine. Low tumour hENT1 expression has been associated with reduced survival from gemcitabine in some studies. We analyzed the prognostic effect of hENT1 expression in a cohort of PDAC patients (pts) who underwent surgical resection. Methods: A tissue microarray (TMA) composed of duplicate 0.6 mm cores from 261 resected PDACs was constructed from all available cases derived from the archives of Vancouver General Hospital between 1988 - 2013. TMA sections (4 µm) were stained with an antibody for hENT1 (SP120- Spring Biosciences) and scored using a four-tiered scoring system (negative, weak, moderate and strong staining). The expression of hENT1 in the epithelial component of PDAC was quantified and patient samples were divided into low (negative and weak staining) and high (moderate and strong staining) hENT1-expressing groups. Treatment and survival data were collected. Survival differences were quantified with Kaplan-Meier method and log-rank statistic. Results: Our cohort included pts who received no adjuvant chemotherapy (CT) (n=182) or gemcitabine (n=59). Cases treated with other regimens (n=20) were excluded. There was no significant difference in the median overall survival (OS) between pts with low (14.0 months, n=167) and high hENT1 expression (15.2 months, n=15) in the absence of adjuvant CT. Gemcitabine treated patients with low hENT1 expression (n=51) had a median OS of 20.9 months. Median OS was not reached in the group of pts with high hENT1 expression (n=8) who received gemcitabine, with only 2 deaths at the 24 month time point and 6 censorings (p = 0.045). Pts who received gemcitabine had an increased median OS (24.8 months) compared to pts who did not receive adjuvant CT (14.0 months) regardless of hENT1 expression (p&lt;0.0001). Conclusions: Consistent with the ESPAC-3 data, in our analysis adjuvant gemcitabine was associated with increased OS in PDAC pts with high epithelial hENT1 expression (determined using the SP120 antibody) compared to pts with low hENT1 expression. Prospective evaluation of the predictive value of hENT1 expression in this setting is needed.
Stages I-II non-small cell lung cancer treated using either lobectomy by video-assisted thoracoscopic surgery (VATS) or stereotactic ablative radiotherapy (SABR): Outcomes of a propensity score-matched analysis.
Authors: Suresh Senan, Naomi E Verstegen, David Palma, George Rodrigues, Frank J Lagerwaard, A van der Elst, R Mollema, W F van Tets, Andrew Warner, J J.A. Joosten, M I Amir, Cornelis J Haasbeek, Egbert F Smit, Ben J. Slotman, J W Oosterhuis
Journal: Journal of Clinical Oncology (2012)

7009 Background: VATS procedures are increasingly used in early-stage NSCLC. As high local control rates are also seen with stereotactic ablative radiotherapy (SABR), we performed a propensity score-matched analysistocompare loco-regional control (LRC) after both treatments. Methods: Patients with stage I-II NSCLC treated at 6 hospitals (1 university and 5 regional hospitals) with VATS lobectomy were eligible. Details of SABR patients were obtained from a single-institutional database. All VATS-lobectomies were performed in accordance with ESTS guidelines. Patients were matched using propensity scores based on cTNM, age, gender, Charlson comorbidity score, lung function and performance score. Matching was performed blinded to all outcomes. Excluded were: synchronous lung tumors, COPD GOLD class 4 or history of prior lung cancer. A total of 86 VATS- and 527 SABR patients were eligible for matching (1:1 ratio, caliper distance of 0.025 without replacement). Loco-regional failure was defined as recurrence in/adjacent to the radiation planning target volume or surgical margins, the ipsilateral hilum or mediastinum. Recurrences were either biopsy-confirmed or PET-positive and reviewed by a tumor board. Patients upstaged during VATS and those developing recurrence were treated in accordance with national guidelines. Results: The matched cohort consisted of 128 patients with cT1-3N0 NSCLC following SABR (n=64) or VATS-lobectomy (n=64). Median follow-up was 30 and 16 months, respectively. The groups were well matched on baseline variables. SABR patients had better LRC rates at 1- and 3-years (96.8% and 93.3% vs. 86.9% and 82.6%, respectively, p= .03). Three-year progression-free survival (PFS) did not significantly differ after SABR (79.3% versus 63.2%, p = .09). Distant recurrence rates and overall survival (OS) did not significantly differ. Conclusions: Although loco-regional control was superior after SABR compared to VATS-lobectomy, PFS and OS did not differ at this time-point. Our findings support the current randomized controlled trial evaluating both treatments (ACOSOG Z4099).
Acute myeloid leukemia (AML): A study of 516 patients
Authors: L. Kumar, H. Menon, A. Sharma, J. Wadhwa, R. Kumar, V. Kochupillai
Journal: Journal of Clinical Oncology (2004)

6711 Background: To review the clinical presentation and treatment outcome. Methods: This is a retrospective audit of 516 AML patients seen in the ‘Leukemia Clinic’ between Jan.1991 and Dec. 2000. Results: Patient's median age was 30 years (range, to 83), M : F : 2:1. Patients presented with fever (82%), bleeding (47.5%), sepsis (17.8%), reduced appetite (12.6%) and weight loss (11%). Physical findings were - anemia (96%), icterus (2.4%), skin petechie (24%), gum hypertrophy (24%), lymphnode enlargement (33.7%), splenomegaly (24%), hepatomegaly (42%) and chloroma (2.4%). Investigations: Blood - mean Hb - 6.8 G%, Mean WBC- 47300/cmm, WBC counts were low in 15.8%, normal (16.4%) or high in 67.8%. 94.5% of patients had low platelets. PB blast (%) were [tmsnew]63[/tmsnew]10 % in 21%, 11- 49% in 26%, 50–80% in 27% and >80% in 25% . FAB subtype revealed- M0 (0.4%), M1(10.7%)., M2 (26.4%), M3 (6%), M4 (15.3%), M5 (14.7%), M6 (4%), M7(0.8%). Subtype was not known in 20% and 2.7% of patients had secondary AML. 266 (51.6%) patients received induction chemotherapy (CT) using 3:7 (80.5%) or 2:5 (7%) or 3:7 + ATRA (3%), low dose Ara-C (6.7%) or others. CR rate was 60.5% . Patients received consolidation (HD Ara-C (15–18g/m2), 1 to 3 cycles, 52%) or maintenance or BMT. 82 (50%) of CR patients relapsed at a median interval of 15.7 months; relapse sites were BM -79, BM +CNS -2, CNS alone- 1. The median overall (OS) & leukemia-free survival (LFS) for treated patients is 13.2 and 10.4 months, respectively. Kaplan Meier probability of OS at 3 and 5 years is 25% and 19.8% and of LFS is 20% and 19%, respectively. Comparison between two time periods (1991–1995) and 1996–2000) revealed improvement in both OS (8.8% vs 17%) and LFS (15% vs 25%,p<.05). Conclusions: Our patients were young and had higher leukemia burden (WBC count >30,000/cmm in >50%). Use of more effective induction CT (e.g.Daunomycin 60 mg/m2) to achieve higher CR rates & aggressive consolidation CT are possible areas of improvement in future studies. No significant financial relationships to disclose.
Morphofunctional Changes of Rat Pancreas Under Conditions оf Nitric Oxyde Excess
Authors: B.F. Schevchenko, A.M. Babiy, V.A. Makarchuk, N.Yu. OshmYanska, A.A. Galinsky, A.I. Rudenko
Journal: GASTROENTEROLOGY (2013)

The study was carried out on 40 male Wistar rats after daily intraperitoneal injection of donator of nitric oxide (NO) molecules sodium nitroprusside in a dose of 1.5 mg/kg in 1 day 1 (n = 6); 2 days (n = 6); 6 days (n = 6); 12 days (n = 6); 30 days (n = 6). It is established that an excessive NO intake leads to morphological changes in the pancreas: vasodilation with stasis of blood cells after 1 and 2 days, focal necrosis, destruction of acinar tissue, ductal dilatation with worsening outflow of pancreatic secretion after 6 days; fatty degeneration, segmental apoptosis in 12 days; compensated microcirculatory changes in the body, the formation of fibrous tissue in periductal and perivasal areas with penetration in the interlobular space in 30 days. In the blood serum we detected impaired exocrine pancreatic function: increased activity of pancreatic enzymes — α-amylase and trypsin up to 6 days, and in 30 days — they significantly reduced; increasing the levels of biochemical markers of fibrosis (protein-bound hydroxyproline and hexosamine); failure of endocrine function — increase of glucose level, that is, changes typical for chronic experimental pancreatitis.
Inhibition of progression of chronic puromycin aminonucleoside nephrosis by probucol, an antioxidant.
Authors: A Magil
Journal: Journal of the American Society of Nephrology (1996)

Oxidants have been shown to be involved in the initiation of chronic puromycin aminonucleoside nephrosis in rats, but it is uncertain whether they have a role in the progression of this disease. Rats given a single internal jugular venous bolus of puromycin aminonucleoside (PA) develop early nephrotic syndrome that subsides after about 28 days followed by a 4-wk period of minimal proteinuria and then the development of focal glomerulosclerosis and increasing proteinuria. Fifty-two rats on a high-cholesterol diet were divided into four groups. Two groups of 16 animals each received a single internal jugular venous bolus of PA. One of these groups was started on the dietary antioxidant, probucol (1% wt/wt), 4 days after the PA injection and continued on it until termination. The remaining rats were given an internal jugular venous injection of an equivolume of normal saline. Five of these animals were also started on dietary probucol 4 days after the saline injection. At 11 days postinjection all animals given PA, whether on probucol or not, developed marked proteinuria with histologically minimal glomerular change and significant increases in intraglomerular monocyte and proliferating cell nuclear antigen counts. Forty-two days after PA injection all PA-injected rats had minimal urinary protein injection and no glomerular changes. At 98 days postinjection rats given PA without probucol developed focal glomerulosclerosis and significant proteinuria compared with PA-injected rats on probucol and those injected with saline (P < 0.05). The probucol-fed PA-injected rats showed no glomerular disease and their urinary protein excretion rates were very similar to those of the saline controls. The results indicate that probucol inhibits the progression of chronic puromycin aminonucleoside nephrosis and are consistent with the suggestion that oxidants are involved in the progression of this entity.
Abstract 12695: B-type Natriuretic Peptide Promoter-mediated Suppression of Protein Phosphatase 1{beta} Mitigates Pressure Overload-induced Heart Failure in Mice
Authors: Kozo Shiraishi, Yasuhiro Ikeda, Yosuke Miyazaki, Toshiro Miura, Masunori Matsuzaki
Journal: Circulation (2012)

Aberrant increase in protein phosphatase 1(PP1) activity has been shown to be associated with inefficient sarcoplasmic reticulum Ca2+ cycling in failing hearts, leading to poor prognosis in chronic...
Prognostic factors for patients with advanced gastric cancer receiving irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) as salvage therapy after fluoropyrimidine/platinum-based chemotherapy: A retrospective analysis
Authors: Catalano, D Santini, D Spada, R Bisonni, E Vasile, P Giordani, P Alessandroni, S D'Emidio, B Vincenzi, A M Baldelli, D Rossi, E Testa, L Giustini, A Falcone, G Tonini, F Graziano
Journal: Annals of Oncology (2011)
A phase 1 dynamic accelerated titration dose escalation study of the vascular disrupting agent NPI-2358
Authors: M. A. Spear, P. LoRusso, A. W. Tolcher, C. Lin, D. Wang, E. Heath, G. K. Lloyd, G. Cropp, K. P. Papadopoulos
Journal: Journal of Clinical Oncology (2007)

14097 Background: NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models and also potentiates the effects of chemotherapeutic agents. Preclinical data indicate NPI-2358 may have advantages in terms of safety profile and activity (tumor blood flow remains markedly reduced after 24 hours). Methods: A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion for 3 weeks in 4-week cycles. Eight subjects have been enrolled. The dose of NPI-2358 was escalated in cohorts of 1–3 patients dependent on observed adverse events (any cohort may consist of 1 patient provided no =Grade 2 AE is reported in the prior cohort). A cohort is expanded to 6 patients if a DLT is reported. Escalation was conducted in 100% intervals, and decreased to 50% intervals once a Grade 2 adverse event was reported. In addition to weekly safety monitoring (including ECGs, Troponin I, and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 &amp; D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. Results: The dose has been escalated from 2 mg/m 2 to 9 mg/m 2 (predicted minimum efficacious dose = 7.5 mg/m 2 ) without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. Intrapatient values for Ktrans from DCE-MRIs appear highly reproducible. No responses have been reported, however, one patient with pancreatic adenocarcinoma has had stable disease (SD) for 3 cycles and continues to receive NPI-2358. Average Cmax and AUC last have increased from 16.2 ng/ml to 147 ng/ml, and from 101 to 360 ng/ml*hr respectively. No drug accumulation was observed; T1/2 was 4.2 ±1.9 h, clearance was 45 ±12 L/h and distributive volume was 251±57 L. Conclusions: NPI-2358 is well tolerated at doses above the minimum predicted efficacious dose. PK data show increasing Cmax and AUC with dose escalation and no drug accumulation on a weekly schedule. No significant financial relationships to disclose.