tbuckley/cabot-search huggingface dataset:
Relationship of rapid M protein reduction to outcomes in a trial of pegylated liposomal doxorubicin (PLD) plus bortezomib (B) versus B alone in previously treated multiple myeloma (MM)
Authors: J. J. Shah, A. Londhe, K. C. Lantz, C. Lowery, R. Z. Orlowski
Journal: Journal of Clinical Oncology (2009)

8591 Background: An early response in MM results in rapid improvement in symptoms and may benefit outcomes. To investigate the relationship between rapid response and outcomes, we retrospectively evaluated early reduction in M protein (MProt) in a trial of pegylated liposomal doxorubicin + bortezomib (PLD+B) vs B alone in relapsed/refractory multiple myeloma (MM). (Orlowski, JCO 2007) Methods: Patients (pts) were randomized to bolus IV B 1.3 mg/m 2 on days 1, 4, 8, &amp; 11 of each 3-week cycle (N=322) or to the same B regimen + IV PLD 30 mg/m2 on day 4 (N=324) of each cycle. % decrease from baseline of MProt was evaluated using a landmark analysis at the end of cycles 2 and 4. Pts were categorized into 4 groups by reduction in MProt at the landmark timepoints. 199 PLD+B and 205 B pts were included in the analysis at end of cycle 2. Time to progression (TTP) post-landmark was evaluated using a Cox proportional hazard model with treatment and the three ≥25% MProt reduction groups compared to the &lt;25% group as factors. Results: Regardless of treatment, a decrease in risk of TTP was observed for greater reduction in MProt. This was significant for the 50–75% and ≥75% MProt reduction groups. Hazard ratios (95% CI) were: [0.84 (0.55, 1.30), P=.438] for 25-&lt;50% vs 25%; [0.41 (0.26, 0.64), P=.001] for 50-&lt;75% vs &lt;25%; and [0.26 (0.15, 0.45), P=.001] for ≥75% vs &lt;25%. PLD+B had a significant benefit over B alone in extending TTP [1.68 (1.19, 2.37), P=.003]. TTP was longer as MProt decreased and improved for PLD+B vs B. Similar results were observed at the end of cycle 4 landmark. Safety profiles for the 2 regimens were consistent with known toxicities of the agents. Conclusions: PLD+B had significant benefit over B alone in extending TTP in landmark analyses similar to the overall study. A &gt;50% reduction in MProt resulted in a significant risk reduction for progression. These data suggest that early reductions in MProt may provide better outcomes. [Table: see text] [Table: see text]
Antibiotic cycling to decrease bacterial antibiotic resistance: A 7-year experience on a bone marrow transplant unit
Authors: C. A. Taboada, J. E. Patterson, D. S. Burgess, C. O. Freytes, J. Cadena
Journal: Journal of Clinical Oncology (2005)

8119 Background: The development of antibiotic resistance among bacterial pathogens is a major healthcare problem. Our objective is to determine if antibiotic cycling in a BMT unit, for the empiric treatment of febrile neutropenia, has decreased antimicrobial resistance among the most common gram positive (GPB) and gram negative bacteria (GNB). Methods: This is a retrospective case control study of all patients admitted to the BMT unit at a university hospital since January of 1997 to June of 2004. Since 1999, scheduled antibiotic rotations of 3-month duration with piperacillin/tazobactam (pip/tazo) and cefepime (CFP), have been used for treatment of febrile neutropenia. The total number of BMT inpatient bacterial isolates and susceptibility data from 1997 to 2004 were obtained from the Microbiology Lab on an annual basis and evaluated. Results: Susceptibility data were available for Enterobacter sp (N=44), E.coli (N=165), K. pneumoniae (N=166), P. aeruginosa. (N=97), Enteroccocus sp (N=276), VRE (115), coag-negative staphylococci (N=384), S. aureus (N=316), and MRSA (N=77). Susceptibility to pip/tazo, carbapenems and CFP remained stable or slightly increased among all GNB. K.pneumoniae susceptibility to pip/tazo increased from 70% to 100%. P. aeruginosa susceptibility to cefepime increased to 100%. Susceptibility to gentamicin increased from 80%–100% in K. pneumoniae, remained stable for P. aeruginosa, but decreased from 100% to 75% in E. coli. Overall susceptibility of GNB to fluoroquinolones decreased, except for Enterobacter sp. Susceptibility of vancomycin and ampicillin decreased significantly in Enterococcus sp from 100% to 52.38%, and 76.47% to 38.10% respectively. There was a significant decrease in S.aureus susceptibility to oxacillin and clindamycin from 89.66% to 33.33%, and 86.21d% to 20% respectively. Conclusions: During the study period, GNB susceptibility to beta-lactam antibiotics remained stable or slightly improved. Also, an increase in MRSA and VRE was noted, but mirrored the rise of MRSA and VRE elsewhere. Antibiotic cycling of extended-spectrum beta-lactam antibiotics in a BMT unit may help control emergence of GNB resistance in this setting. No significant financial relationships to disclose.
Role of IGSF10 mutations in self-limited delayed puberty
Authors: Sasha Howard, Leo Guasti, Gerard Ruiz-Babot, Alessandra Mancini, Alessia David, Helen Storr, Louise Metherell, Michael Sternberg, Claudia Cabrera, Helen Warren, Michael Barnes, Karoliina Wehkalampi, Valentina Andre, Yoav Gothilf, Anna Cariboni, Leo Dunkel
Journal: The Lancet (2016)
Activity of irofulven (IROF) combined with capecitabine (CAPE) in patients (pts) with advanced thyroid carcinoma: Phase II international multicenter study (preliminary results)
Authors: J. Droz, E. Baudin, V. Medvedev, J. Delord, M. Kane, R. Kloos, M. Ringel, C. Kahatt, G. Weems, M. Shah
Journal: Journal of Clinical Oncology (2006)

15511 Background: IROF, the first compound of the acylfulvene class to enter clinical trials, has demonstrated antitumor activity in a variety of chemoresistant tumors. Currently available chemotherapy offers limited benefit to pts with advanced thyroid cancer. A phase I trial of an IROF/CAPE combination showed confirmed partial responses in 2/4 pts (Alexandre, ASCO 2003). An international multicenter 2-stage, phase II trial was initiated to evaluate the objective response rate (RECIST) in pts with advanced thyroid cancer. Methods: Eligibility criteria included advanced Differentiated, Medullary or Anaplastic (D/M/A) thyroid cancer, ECOG PS 0–2, no benefit from prior I 131 and ≤1 prior chemotherapy regimen. Pts received IROF 0.4 mg/kg (30 min IV infusion), days 1 and 15 and CAPE orally 2000 mg/m 2 day 1 to 15 every 28 days. Results: As of Dec-05, 23 pts (D/M/A: 14/5/4) have been treated. Pt characteristics are (D/M/A); median age: 60/55/61 years (range 34–74), median PS: 1/1/1; prior chemotherapy in 4/1/2 pts; all had metastatic disease predominantly lung, bone and lymph nodes, with a median of 2/1/3 sites of metastasis. Median number of cycles given was 5/4/1. Efficacy: All pts are evaluable. No objective responses observed to date, SD was observed in 11 (79%)/ 3 (60%)/0 pts with median duration 4.8/5.2/0 months; 2/11 (D) pts with SD had 14% and 19% decreases in tumor size. Safety: Main adverse events were thrombocytopenia (grade [G] 1–2: 24% pts), neutropenia (G1–2: 17%; G3: 4%), nausea (G1–2: 41%), asthenia (G1–2: 41%); 1 pt had G3 asthenia. No pts discontinued due to toxicity. Conclusions: No objective responses were observed in pts with differentiated thyroid cancer treated with IROF/CAPE every 2 weeks, with 79% SD. Tolerance was acceptable and accrual is ongoing in the anaplastic cohort. [Table: see text]
Dosimetric predictors of toxicity and cosmesis in women treated with hypofractionated whole-breast irradiation.
Authors: Joshua T. Dilworth, Richard Val Hymas, Maha Saada Jawad, Victor S. Mangona, Leonid Zamdborg, Jessica Wobb, Arielle Pietron, Michelle Wallace, Peter Y. Chen, Inga S. Grills, Donald S. Brabbins
Journal: Journal of Clinical Oncology (2014)

77 Background: Large breast volume (BV) and distance of separation (DoS) have historically served as exclusionary criteria for hypofractionated whole breast irradiation (H-WBI). We investigate dosimetric parameters impacting toxicity and cosmesis. Methods: 299 consecutive patients with T0-2,N0-1,M0 breast cancer were treated with H-WBI at a single institution from 2007-2013. 4,256 cGy were delivered in 16 fractions via tangent photon beams utilizing inverse planning, with objectives to limit the V105 to 15%, the V110 to 2%, and the V115% to &lt;0.1%. 227 patients with available treatment planning information and at least 6 months of follow-up (FU) were analyzed. Dosimetric parameters were correlated with acute (≤6 months post-treatment) and chronic toxicity and overall cosmesis. Proportions of toxicity grade and cosmesis score were compared with chi-square or Fisher exact tests. Results: With a median FU of 2.7 years (range 0.4-6.6 years), there were no local or regional recurrences, 1 distant failure, and one in-field angiosarcoma. Rates of any acute and chronic grade 1/2/3 toxicity were 47%/32%/9% and 53%/22%/7%. Cosmesis (beyond 6 months) was reported as excellent, good, and fair in 45%, 55%, and &lt;1% of patients. The V105 was the best predictor for cosmesis and chronic toxicity, with a V105≤10% being associated with better cosmesis (excellent vs fair/poor) and lower toxicity (grade 0 vs grade 1 vs grade 2/3) compared to a V105&gt;10% (p=0.09 and 0.03, respectively). The mean DoS was 22 cm, with 22% and 3% of patients having a DoS greater than 25 cm and 28 cm. The mean BV was 1523 cc, with 19% and 5% having a BV greater than 2000 cc and 2500 cc. Neither a larger DoS nor a larger BV correlated with an inability to achieve a V105≤10% (p= 0.37 and p=0.13, respectively). Neither DoS nor BV predicted for worse acute toxicity, chronic toxicity, or cosmesis. Conclusions: Minimizing the V110 and V115 and limiting the V105 to ≤10% are useful dosimetric objectives to achieve excellent or good cosmesis following H-WBI. Acceptable toxicity and excellent cosmesis are achievable in women with large DoS or BV, provided techniques to maximize dose homogeneity are employed.
A cisplatin-gemcitabine-vinorelbine (PVG) first-line treatment in IIIB-IV non small cell lung cancer (NSCLC)
Authors: L. Portalone, A. Antilli, P. Brocchieri, A. Lombardi, F. Nunziati, A. Pezzuto, M. Signora
Journal: Journal of Clinical Oncology (2004)

7123 Background: The purpose of this monocenter phase II trial was to evaluate activity and toxicity profile of PGV schedule as first-line treatment in patients (pts) with NSCLC stage IIIB-IV. Methods: Elegible pts had: age ≥ 18 yrs; measurable or evaluable disease, ECOG PS ≤ 2, adequate bone marrow, liver and renal function; no previous chemo- or radiotherapy; life expectancy ≥12 weeks. Pts received G 1500 mg/m2 iv, V 25 mg/m2 iv d1 and P 80 mg/m2 iv d2 every 21 days for 6 cycles. Results: From Feb 2001 to Aug 2002, 94 pts were enrolled: male/female 77/17; median age 62 yrs (range 41–75); median ECOG PS 0 (range 0–1), weight loss> 10% in 4.2% pts, stage IIIB/IV 50%/50%; adenocarcinoma 51%, squamous 32%, anaplastic cells 3%, unspecified (no oat cells) 14%. In 35.1% stage IV pts we observed one site of metastases, in 10.6% two and 4.2% three metastatic sites. A total of 485 PVG cycles have been administered (median 6 pt, range 1–6). According to WHO criteria and Intention to treat, on 94 pts enrolled we observed: 1 CR (1%), 31 PR (33%), 57 SD (61%) and 2 PD (2%). All pts were evaluable for toxicity. In 66% toxicity was only hematological, in 22% hematological and non-hematological and in 12% non-hematological. On 485 cycles, there were 131 toxic events: only 2.3% grade 3 (neutropenia 4, nausea / vomiting 3, anemia 2 and thrombocytopenia 2) and 2.8% grade 4 (neutropenia 9, thrombocytopenia 3, anemia 1 and paresthesias 1). Hematological tox. G 3/4 was mild (4.3%). Neutropenia (without neutropenic fever) was transient and rapidly reversibile, no hemorrhage resulting from thrombocytopenia. No toxic deaths have occurred. Median TTP was 214 days (range 25–538) and MST 354 days (range 10–865). At this writing 15 pts (16%) are still alive. By stratifying stage IIIB and IV pts we didn't observe difference in reference to TTP or MST. The actuarial 1YS is 48%, 2YS is 18%. Conclusions: The results suggest that PGV shows promising activity in NSCLC pts. Tox. profile is favorable with myelotoxicity mild and reversible. The activity in terms of PR and SD is acceptable and the median overall survival and actuarial survival are promising considering high percentage of stage IV pts. No significant financial relationships to disclose.
Abstract 12801: Altering Myocardial Membrane Type-1 Following Myocardial Infarction Directly Affects LV Remodeling and Function Through a Novel Fibrotic Signaling Cascade
Authors: Francis G Spinale, Rupak Mukherjee, Juozas A Zavadzkas, Christine N Koval, Robert E Stroud, William T Rivers, Richard A McKinney
Journal: Circulation (2010)
A simulation study to define the number of patients necessary to meet primary pharmacokinetic (pk) aims of phase I oncology trials
Authors: P. C. Adamson, H. Zhao, A. Sievert, A. Troxel, R. Aplenc
Journal: Journal of Clinical Oncology (2007)

2579 Introduction: The primary pharmacokinetic parameters defined in oncology phase I trials include estimates of drug clearance and determining the relationship between dose and drug exposure as measured by AUC. The numbers of patients needed for reliable estimates of these parameters, however, has not been defined. We hypothesized that a threshold number of patients existed above which meaningful improvement in such estimates would not occur. Methods: We identified 28 English language adult phase 1 oncology publications (2004-2006) from which individual patient dose and AUC data could be extracted. Analyses of clearance precision were performed in PASS 2000. Simulations were performed by determining a distribution of r 2 coefficients for the regression of AUC on dose for each trial, for sample sizes of 2 to n-1, where n was the total patient number studied. Median values for the simulated r 2 and a 90% confidence interval (CI) were obtained for every simulation. A stability boundary of 0.1 around the simulated r 2 value was calculated. A 90% confidence interval around the observed r 2 value was also bootstrapped. An r 2 value was considered stable when the simulated r 2 CI fell within the stability boundary for all subsequent sample sizes. Results: Analyses of the precision of mean clearance estimates over a range of confidence intervals demonstrated that the incremental gain in clearance precision estimates was marginal beyond the study of 8 to 12 patients. Linearity simulations of AUC vs dose demonstrated the median (range) of patients needed to determine a stable r 2 estimate was 7 (4 - 16), with a mean (±SD) of 7.8 ± 3.2. Conclusions: These simulations show that, in general, only 8–12 patients are needed to meet the primary PK objectives of phase I oncology trials. While such modest sample sizes are not sufficient to define pharmacokinetic-dynamic-genetic relationships, such relationships rarely emerge from phase I trials. Our simulations indicate that the number of patients needed to meet PK objectives may be more modest than previously anticipated, and should be readily achievable with voluntary participation in the PK component of oncology phase 1 trials. No significant financial relationships to disclose.
Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT).
Authors: Chris Verslype, Allen Lee Cohn, Robin Katie Kelley, Tsai-Shen Yang, Wu-Chou Su, David A. Ramies, Yihua Lee, Xiaodong Shen, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2012)

4007 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabo may therefore be a promising treatment strategy. Methods: Eligible HCC patients (pts) were required to have measurable disease per RECIST, ≤ 1 prior systemic regimen and Child-Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in stage. Results: Enrollment has been completed (n = 41); all pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 38%. Extra-hepatic spread observed in 70%. Median number of prior systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 18 weeks. 28/36 pts (78%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: was 68% (Asian subgroup: 73%). AFP responses (defined as reduction from baseline of &gt;50% in pts with elevated AFP at baseline) in 26 pts with ≥1 post-baseline result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior sorafenib treatment. The safety profile was comparable to that of other VEGFR TKIs.
Retrospective analysis of outcomes among more than 1,000 patients with newly diagnosed anaplastic oligodendroglial tumors
Authors: A. B. Lassman
Journal: Journal of Clinical Oncology (2009)

2014 Background: Treatment of anaplastic oligodendroglial tumors is controversial. Early results of randomized trials suggest chemotherapy (CT) with procarbazine-lomustine-vincristine (PCV) before or after radiotherapy (RT) improves progression-free but not overall survival (OS) versus RT alone. It is unknown if CT alone affects outcome versus CT&amp;RT, or if temozolomide (TMZ) compares favorably with PCV. Methods: We retrospectively identified adults with newly diagnosed anaplastic oligodendroglioma (AO) or oligo-astrocytoma (AOA) seen at 17 medical centers from 1981–2007 exclusive of phase III or bone marrow transplant trials. Data were updated January 1, 2009. Survivals were estimated by Kaplan-Meier method and compared with log-rank. Results: There were 1054 patients: 594 men, 460 women; median age 42 (18–88); 661 with AO, 443 with AOA. Treatment was: observation (82, 8%), RT alone (n = 210, 20%), RT then chemotherapy (283, 27%), RT + CT concurrently (118, 11%), CT alone (205, 19%), CT then RT (137, 13%), or other (19, 2%). Median time to progression (TTP) and OS were 2.8 and 6.5 years, respectively, with median follow up of 4.1 years (0.03–20.8) on surviving patients (n = 560, 53%). 1p19q co-deletion was observed in 292 (48%) and no deletion in 232 (38%) of 606 tested tumors. Co-deletion predicted longer median TTP (4.2 vs. 1.8 years for no deletion, p = 0.0002) and OS (8.4 vs. 3.3 years, p &lt; 0.0001). Median TTP was longer following CT&amp;RT (sequential or concurrent) than CT alone (3.7 vs. 2.6 years, p = 0.0007), but median OS did not differ (6.6 vs. 7.1 years, p = 0.8); co-deletion was more common with CT alone than CT&amp;RT (p &lt; 0.0001, χ 2 ), although restricting analysis of CT&amp;RT versus CT to the co-deletion cohort yielded analogous results (median TTP 7.2 vs. 3.8 years, p = 0.011; OS 7.9 vs. 10.4 years, p = 0.26). Median TTP was longer following PCV alone (7.6 years, n = 17) than TMZ alone (3.3 years, n = 65) with co-deletion (p &lt; 0.02); median OS was also longer (not reached, vs. 7.1 years), but did not reach statistical significance (p = 0.07 log-rank). Conclusions: 1p19q co-deletion predicted improved outcome. Treatment strategies varied widely. CT alone did not appear to shorten OS versus CT&amp;RT. PCV may be superior in efficacy to TMZ. Multivariate analyses and additional 1p19q testing are in progress. [Table: see text]
Drugs and sperm [letter]
Authors: Hong Cy, Turner P
Journal: BMJ (1982)

Sperm motility another aspect of drug sperm interaction is discussed.  Since the development of a transmembrane migration method it has been possible to measure objectively the dose-response relation between drugs and human sperm motility.  Drugs which belong to the different therapeutic classes but possess a common local anesthetic property all inhibited human sperm motility with similar dose-response curves.  Their sperm-immobilizing potencies correlated with their local anesthetic potencies measured on nerve preparations.  It is proposed that these drugs immobilized human sperms by a mechanism similar to that by which local anesthetics act on the nerve cells.  A study of 5 different beta-adrenoceptor blocking drugs which had different anesthetic potencies as well as varied lipil solubilities also showed that the sperm-immobilizing effect was related to local anesthetic activity.  In addition from the data derived in this experiment a mathematic formula was constructed to predict the sperm-immobilizing potency of beta-blockers from their lipid solubility.  The concentrations of these drugs which were required to inhibit human sperm motility fell in the millimolar range.  The information concerning the presence and quantity of these drugs in the genital tract is unavailable but they are unlikely to reach such high concentrations in the genital tract after systemic administration.  For propranolol the concentration required to immobilize sperm is more than 1000 times higher than its therapeutic serum concentration.  This series of experiments may have significance for the future development of vaginal contraceptives because the sperm-immobilizing concentrations can be reached by local administration.  The search for more potent and reliable spermicides is 1 of the key factors in developing a better vaginal contraceptive because at this time the high pregnancy rate is the major problem hindering wide acceptance of this approach.  It is suggested that an influence on sperm motility should be included in any discussion of drugs and sperm.