tbuckley/cabot-search huggingface dataset:
Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (pts) with high-intermediate/high-risk diffuse large B-cell lymphoma (DLBCL).
Authors: Nancy L. Bartlett, Charles M. Farber, Christopher A. Yasenchak, Stephen Maxted Ansell, Ranjana H. Advani, Mark H. Knapp, Luis Fayad, Kathryn S. Kolibaba, Dipti Patel-Donnelly, Mahesh Seetharam, Habte Aragaw Yimer, Thomas John Manley, John M. Burke, Beata Holkova, L. Elizabeth Budde, Ahmad Sami Halwani
Journal: Journal of Clinical Oncology (2015)

8506 Background: Pts with high-intermediate/high-risk DLBCL have relatively poor outcomes with R-CHOP. Single-agent brentuximab vedotin has shown activity in pts with relapsed or refractory DLBCL (CD30+ pts, 17% CR; CD30– pts, 10% CR). Methods: In this study, pts were randomized to 6 cycles of BV+R-CHOP: 1.2 or 1.8 mg/kg BV q3 wks intravenous with standard R-CHOP. Key inclusion criteria were standard International Prognostic Index (IPI) scores of 3–5 or age-adjusted IPI (aaIPI) scores of 2–3 (high-intermediate/high risk). Disease response was per Cheson 2007 with PET/CT. Results: At the planned interim analysis, 53 pts were enrolled and 51 were treated. At baseline, 62% were high-intermediate risk (IPI 3, aaIPI 2) and 38% were high risk (IPI 4-5, aaIPI 3). 70% had stage IV disease and 28% had an Eastern Cooperative Oncology Group score of 2. Due to an increased rate of G3 neuropathy seen early in the 1.8 mg/kg BV+RCHOP arm (30% vs 8%), an SMC recommended treatment continue at 1.2 mg/kg BV+R-CHOP. At EOT, the overall response rate was 97% with 80% PET-negative CR (1.2 mg/kg BV+RCHOP, 86% CR; 1.8 mg/kg BV+R-CHOP, 75% CR) for 30/51 pts with an assessment. CD30+ pts (n=13) had a higher CR rate than CD30– pts (n = 16) (92% vs 69%); 4 CD30– and no CD30+ pts have progressed after a median follow-up of 5 months. CR rates were similar between ABC and GCB subtypes. Treatment-emergent adverse events (AEs) occurred in 96% of treated pts; the most frequent ( ≥ 30%) were nausea, fatigue, peripheral sensory neuropathy, diarrhea, anemia, decreased appetite, febrile neutropenia, and vomiting. ≥ G3 events occurring in > 20% of pts were febrile neutropenia (27%), neutropenia (25%), and anemia (24%). AEs of neuropathy (mostly G1/2) occurred in 55% (38%, 1.2 mg/kg BV+R-CHOP; 77%, 1.8 mg/kg BV+RCHOP). AEs caused discontinuations in 10% of pts; 2 pts died due to AEs (sepsis, hypovolemic shock), and 3 pts died following progression. Conclusions: BV+R-CHOP has encouraging activity in frontline high-intermediate/high risk DLBCL; data suggest that the CR rate in CD30+ pts was higher than in CD30– pts. When combined with R-CHOP, BV is better tolerated at 1.2 mg/kg than 1.8 mg/kg due to reduced neuropathy. The protocol has been amended to assess the safety and activity of 1.8 mg/kg BV+R-CHOP in CD30+ high-intermediate/high risk DLBCL pts. Clinical trial information: NCT01925612.
A retrospective analysis of the effect of time from diagnosis to cystectomy on survival in patients with muscle-invasive bladder cancer receiving neoadjuvant chemotherapy.
Authors: Jong Chul Park, Nilay M Gandhi, Trinity Bivalacqua, Mark Schoenberg, Michael Anthony Carducci, Mario A. Eisenberger, Alexander S Baras, George J. Netto, Jen-Jane Liu, Charles G. Drake, Noah M. Hahn
Journal: Journal of Clinical Oncology (2015)

360 Background: Retrospective population-based studies have shown that an interval longer than 12 weeks between diagnosis and cystectomy is associated with worse outcomes in patients with muscle-invasive bladder cancer (MIBC). Neoadjuvant chemotherapy (NAC) is widely used however the impact of duration from diagnosis to cystectomy is unclear in MIBC patients treated with NAC. Methods: We performed a retrospective analysis of patients with MIBC who received NAC followed by cystectomy between 1996 and 2014 at a single institution. Total therapy duration was defined as the time interval between diagnosis of MIBC on biopsy and the date of cystectomy. Cox proportional hazards regression models were used to investigate the effect of total therapy duration and other factors on overall survival (OS). Results: 201 patients who met the study criteria were analyzed.Demographics included: median age 62, 79% male, 62% cT2N0, 10% cN+, 29% w/variant histology (VHx). Cisplatin-based therapy was given to 91% of patients for a median of 3 cycles. The median time from diagnosis to the cystectomy was 28 weeks. A total therapy duration &lt; 28 weeks did not impact OS (hazard ratio [HR], 0.68; p=0.39). Pretreatment clinical covariates associated with improved OS included age&lt; 62 (HR 0.56; p=0.034) and absence of VHx (HR, 0.40, p=0.001). Post-treatment factors of significance included less than 3 cycles of chemotherapy received (HR 1.75, p=0.037), pT3/T4 or N+ (HR 5.18, p&lt;0.001), and N- (HR 0.58, p=0.048). Conclusions: Total therapy duration does not significantly impact OS in patients with MIBC receiving NAC. This data adds to the evidence supporting the use of NAC in MIBC patients fit to receive cisplatin-based regimens.
Phase I trial of escalating doses of total marrow irradiation (TMI) with helical tomotherapy and peripheral blood progenitor cell rescue (PBPC) following high-dose melphalan and PBPC as part of tandem high-dose therapy (THDT) for patients with multiple myeloma (MM)
Authors: J. Y. Wong, G. Somlo, R. Spielberger, S. Forman, L. Poppelwell, T. Schultheiss, P. Frankel, A. Krishnan, F. Sahebi, P. Parker
Journal: Journal of Clinical Oncology (2007)

8121 Background: Attempts to combine total body irradiation (TBI) with high-dose melphalan (Mel) resulted in substantial organ toxicities and precluded optimal dosing of Mel. Helical tomotherapy may allow delivery of total marrow irradiation (TMI), while avoiding collateral toxicities. Methods: We designed a phase I/II study for patients (pts) with responding or stable stage I-III MM. Following PBPC mobilization, pts receive THDT first with Mel 200 mg/m 2 and PBPC, and, ≥ 6 weeks later, escalating doses of TMI (starting dose: 200 cGy daily × 5 [1,000 cGy], up to 200 cGy twice daily × 5 days [2,000 cGy]) and PBPC. Maintenance consists of dexamethasone 40 mg/day × 4 days every 28 days and thalidomide 50–200 mg/day. Results: The median number of prior chemotherapy regimens is 2 (1- 4). The median duration from diagnosis to the HDT is 8 mos (4–13). Median age of pts is 53 (35–66). Sixteen pts with stages II (6) and III (10) MM have received Mel; 15 of 16 pts (8F/8M) have received treatment at dose levels 1–5 of TMI (1,000 cGy through 1,800 cGy); 1 pt is about to start TMI at 1,800 cGy. The median time between the first and second THCT cycles is 74 days (47–125). Hematopoietic toxicities were independent of TMI dose levels: granulocyte recovery to &gt;1,000/microliter following Mel required 12 days (11–38) versus a median of 10 days after TMI (range; 9–12). Platelet (excluding 6 pts not needing plt transfusion) independence was seen by day 10 (8–13) versus 8 (6–11) following TMI. In the first 15 pts the estimated median radiation dose to normal organs was 15–60% of the targeted bone marrow dose. Reversible grade 3 non-hematologic toxicities by TMI dose levels included fatigue and febrile neutropenia (FN) (level 1: 1 pt each), FN (level 2: 1 pt); none (level 3); fatigue (level 4: 2 pts); anorexia and stomatitis (level 5: 1pt; anorexia: 1 pt). The median follow-up is 8 mos (3–21); 1 pt progressed at 8 mos. Final data on toxicities including patients already in screening for treatment at TMI 2,000 cGy, tolerability of maintenance, and response rate will be presented. Conclusion: TMI is feasible and could potentially be useful as part of THDT for patients with MM. No significant financial relationships to disclose.
L1CAM-dependent NFκB activation upregulates fascin expression and augments tumor cell invasion and motility
Authors: KW Lee, Rtp Poon, PW Yuen, P Altevogt, ST Fan
Journal: Cancer Research (2007)

1347   Cell migration and invasion are fundamental components of tumor cell metastasis, which contributed to the poor prognosis of hepatocellular carcinoma (HCC). Establishment of a pair of metastatic HCC cell lines (MHCC97L and MHCC97H) provide an indispensable tool to study the molecular mechanism of HCC metastasis. By comparing the genetic alterations between these two cell lines by cDNA microarray analysis, we identified the neuronal  cell adhesion molecule L1- mediated signalling as a key event HCC metastasis. L1CAM was significantly associated with HCC metastasis in HCC tissue microarray (p  significantly correlated with fascin expression in tissue microarray (p=0.007). L1CAM was found to activate fascin promoter through NFκB activation. The RGD sites in the Ig domain 6 of L1CAM was responsible for NFκB dependent fascin over-expression by interaction with αvβ5, augmenting HCC cell invasion and motility. In conclusion, our results demonstrated the significance of L1CAM in HCC. Fascin is an important for L1CAM mediated downstream effects, augmenting cell motility and invasiveness.
Incidence and management of bevacizumab associated hypertension in outpatient oncology clinic
Authors: C. Jee, B. Brockstein, W. Hui, J. Lawton, A. Harper, G. Carro
Journal: Journal of Clinical Oncology (2009)

e20677 Background: Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor is utilized to treat a wide range of cancers. However, clinical trials of bevacizumab reported the incidence of hypertension (HTN) up to 36%. A national guideline has not been established to manage bevacizumab-induced HTN. The incidence and management of bevacizumab associated HTN were evaluated in an outpatient oncology clinic. Methods: A randomized, retrospective chart review of 100 patients who received at least one dose of bevacizumab from 1/1/07 to 12/31/07 was conducted. The overall incidence and management of hypertension were evaluated. Other bevacizumab associated toxicities were compared in patients with or without hypertension. Results: The overall incidence of bevacizumab-induced HTN was 31% (95%CI: 22%-40%) with CTC (v 3.0) grade 3 HTN rate of 10%. The number of patients with a history of HTN or uncontrolled BP prior to bevacizumab therapy was significantly different across the four HTN grade groups (p= 0.0019). Out of 31 patients who had grade 1–3 HTN, 8 patients (26%) were managed by the oncologists, 8 patients (26%) by the primary care physicians, and 15 patients (48%) had no management. Bevacizumab was held in 3 patients due to high blood pressure (BP) resulting in one patient discontinuing bevacizumab therapy. The odds of other bevacizumab associated adverse events in patients with grades 1–3 HTN was 2.776 times than that of patients with grade 0 HTN (p=0.0201). Conclusions: Bevacizumab was associated with HTN in 31% of patients. Patients with history of HTN or uncontrolled BP prior to initiating bevacizumab were at an increased risk to develop a higher grade of HTN. Management of bevacizumab-induced HTN could be improved since BP of 63% of patients with grades 2 and 3 HTN was not adequately controlled. No significant financial relationships to disclose.
Tumor necrosis factor-α-induced protein 3 down-regulates nuclear factor-κB-mediated drug resistance in vitro and is a favorable clinical prognostic factor in human glioblastomas
Authors: M. Bredel, C. Bredel, D. Juric, G. E. Duran, R. X. Yu, G. R. Harsh, H. Vogel, L. D. Recht, A. C. Scheck, B. I. Sikic
Journal: Journal of Clinical Oncology (2006)

1508 Background: Resistance to chemotherapy is major impediment to the successful treatment of human glioblastomas. Methods: We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O 6 -alkylating agents in glioblastoma cells. Results: We identified a transcriptomic signature of 286 genes that predicts a common in vitro and in vivo resistance phenotype to these agents. This signature was significantly enriched for genes with functions in organismal survival (27.5%) and cell death (49.0%), both with P &lt; 0.00001. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-κB (NF-κB), which included the persistent alterations of various NF-κB pathway elements. Tumor necrosis factor-α-induced protein 3 (TNFAIP3) was identified as a new endogenous regulatory component of a putative cytoplasmic signaling cascade that mediates NF-κB activation in response to DNA damage caused by O 6 -alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-κB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037). TNFAIP3 expression was a favorable factor in patient prognosis (P = .028), and was part of an optimized four-gene predictor (TNFAIP3, CD44 antigen, syndecan 1, and F-box protein 32) significantly associated with patient survival (P = .022). Conclusions: Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-κB en route to O 6 -alkylating agent resistance in glioblastoma cells. This gene may be an attractive target for therapeutic modulation of glioblastomas. No significant financial relationships to disclose.
The relationship between adolescent suicidal behavior and life events in childhood and adolescence
Authors: E J de Wilde, I C Kienhorst, R F Diekstra, W H Wolters
Journal: American Journal of Psychiatry (1992)

Although the relationship between experience of problematic life events and adolescent suicidal behavior has frequently been recognized during the past decade, few studies of life events have been initiated that discriminated between adolescent suicide attempters and depressed adolescents. Therefore, the authors compared adolescent suicide attempters with both depressed and nondepressed adolescents who never attempted suicide with respect to life events that happened in two periods: childhood (defined as the period up to age 12 years) and adolescence (age 12 and older).Using a semistructured interview, the authors gathered life event data about childhood and adolescence from three groups of adolescents: 48 suicide attempters, 66 depressed adolescents who had never made a suicide attempt, and 43 nondepressed adolescents who had never made a suicide attempt.The group of adolescents who attempted suicide differed from both of the other groups in that they had experienced more turmoil in their families, starting in childhood and not stabilizing during adolescence. During adolescence, they were more often sexually abused. During the last year before the attempt, further social instability, such as changes in residence and having to repeat a class, occurred.For suicidal adolescents, the suicide attempt seems embedded not just in the problems every adolescent has to deal with but in greater turmoil in their families, rooted in childhood and not stabilizing during adolescence, in combination with traumatic events during adolescence and social instability in the year preceding the attempt.
Lack of efficacy with 3 oral dose levels of TMI-005 (Apratastat), in subjects with active rheumatoid arthritis on a background of methotrexate-A phase 2 double-blind, placebo-controlled, parallel, randomized study
Authors: R. Fleischman, Patrick Durez, M. Genovese, E. M. Keystone, L. Pavelka, S. Pavlik-Gaylord, T. M. Kirsch, S. Sridharan
Journal: Annals of the Rheumatic Diseases (2006)
Association of integrin beta-3 polymorphism and chronic oxaliplatin-induced peripheral neuropathy: Preliminary results
Authors: A. Antonacopoulou, A. Argyriou, A. E. Kottorou, C. D. Scopa, H. P. Kalofonos
Journal: Journal of Clinical Oncology (2009)

e15082 Background: Peripheral neuropathy (PN) is widely recognised among the major non-haematological dose- limiting toxicities of oxaliplatin (OXL) which is used to treat advanced or metastatic colorectal cancer (CRC). OXL induces two clinically distinct forms of PN. The acute transient syndrome and the chronic OXL-induced peripheral neuropathy (OXLIPN). The integrin beta-3 (ITGB3) polymorphism at residue 33 (L33P) has been previously associated with altered adhesion ability and ERK2 activation. Thus it may affect neuronal survival. The aim of the current study was to investigate the role of the ITGB3 polymorphism at residue 33 in the development of chronic OXLIPN. Methods: Thirty four patients with advanced CRC were genotyped. All patients, 22 males and 12 females had received adjuvant chemotherapy consisting of 12 courses of the formal FOLFOX-4 regimen. Following the discontinuation of treatment, 20 of the patients (58.8 %), developed OXLIPN, whereas the remaining 14 (41.2%) patients remained unaffected with normal peripheral nerve function. The grading of the OXLIPN severity was defined by Total Neuropathy scores, corresponding to the WHO grading scales 1–3 for chemotherapy-induced PN. Genotyping was performed using allele specific primers and sybr green in real time polymerase chain reactions. Statistics were performed using the SPSS for Windows (release 16.0). Results: Patients with normal peripheral nerve function OXLIPN were 14.3% homozygous for C, 28.6% heterozygous and 57.1% homozygous for T. The corresponding percentages for patients who developed OXLIPN did not differ significantly and were 5%, 25% and 70%, respectively. The majority of patients with mild OXLIPN were heterozygotes (50%, with 16.7% CC and 33.3% TT), whereas the majority of patients with moderate OXLIPN were homozygous for TT (85.7% with the remaining 14.3% being CT). Notably, the TT genotype was associated with increased OXLIPN compared to the genotypes containing the C allele (p= 0.046). Conclusions: The ITGB3 polymorphism at residue 33 appears to be unrelated to the development of OXLIPN but related to the grade of OXLIPN.Further study on this important clinical issue is warranted. No significant financial relationships to disclose.
Updated cardiac safety results of dose-dense (DD) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with trastuzumab (H) in HER2/neu overexpressed/amplified breast cancer (BCA)
Authors: C. DangK. Smith, M. Fornier, S. Sugarman, T. Troso-Sandoval, D. Lake, G. D’Andrea, A. Seidman, N. Sklarin, L. Norton, C. Hudis
Journal: Journal of Clinical Oncology (2006)

582 Background: DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival. Methods: Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m 2 × 4 → T at 175 mg/m 2 × 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is &gt; 4%, Rx is deemed not feasible. Results: From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT. Discussion: DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Amgen Genentech, Amgen Genentech, Amgen
Abstract 19912: Prognostic Value of Restrictive Left Ventricular Filling in Patients Undergoing Trans-catheter or Surgical Aortic Valve Replacement
Authors: Asim M Rafique, Hasan Jilaihawi, Tarun Chakravarty, Niraj Doctor, Mohammad Kashif, Mitch Gheorghiu, Wen Cheng, Raj Makkar
Journal: Circulation (2014)

Objectives: We evaluated prognostic value of restrictive left ventricular (LV) filling in patients with severe aortic stenosis (AS) undergoing trans-catheter (TAVR) or surgical aortic valve replacements (SAVR).

Methods: We included the patients with AS who had successful TAVR or SAVR at our institution. Restrictive filling was defined as: mitral E/A ≥ 2 and mitral deceleration time (DT) < 120ms.

Results: Of the 238 patients evaluated, 132 patients (55%) had a restrictive LV filling. Mean age (85±8 vs. 85±8, p =0.546) and STS score (11.2±3 vs. 11.0±2.5, p = 0.244) were similar but more male patients (62% vs. 47%, p = 0.021) in the group with vs. without restrictive filling. LV ejection fraction (LVEF) was significantly lower (54±15 vs. 63±12, p <0.001) and LV mass (LVM) was significantly higher (231±86 vs. 196±71, p = 0.003) in patients with restrictive vs. without restrictive filling. Patients with vs. without restrictive filling had: TF-TAVR in 49% vs. 57% patients, TA-TAVR in 18% vs. 14% patients, and SAVR in 33% vs. 29%. After procedure LVEF (54±15% to 57±14%, p = 0.005) and LVM (239±90 vs. 211±67, p < 0.001) improved significantly in patients with restrictive filling. 1-year mortality was 27% in patients with restrictive filling vs. 12% in patients with PASP < 50mmHg (p = 0.005) (Figure). Patients with vs. without persistent restrictive filling at 1 month of follow-up had worst 1-year mortality (31% vs. 12%, p = 0.004). In the Cox regression analysis, restrictive LV filling pattern was most significant predictor of 1-year mortality (HR 2.8, 95% CI 1.3-6.1, p value= 0.008) and PAP and LVM was independent predictor of restrictive LV filling.

Conclusions: Restrictive LV filling is associated with an increased mortality after TAVR and SAVR. After procedure there is significant reverse remodeling but persistent restrictive filling is associated with poor outcomes.

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