tbuckley/cabot-search huggingface dataset:
Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy
Authors: K. A. Blum, M. Smith, H. Fung, J. Zalevsky, D. Combs, D. A. Ramies, A. Younes
Journal: Journal of Clinical Oncology (2009)

8531 Background: XmAb2513 is a novel 2 nd -generation humanized monoclonal antibody (mAb) directed against CD30 (a cell surface antigen expressed on Reed-Sternberg cells of HL and ALCL), with an Fc region engineered to have increased binding affinity to Fcγ receptors (FcγRs) leading to improved FcγR-dependent effector cell functions. In vitro, XmAb2513 was more potent and more efficacious than 1 st -generation anti-CD30 mAbs (e.g., SGN-30 &amp; MDX-060). In cynomolgus monkeys (cynos), XmAb2513 exposure was dose-proportional with half-lives ranging from 12 - 17d in repeat dose studies, which suggested biweekly (QOW) dosing in man. A Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients (pts) with relapsed HL and ALCL. Methods: Phase 1 open-label study with QOW dosing of XmAb2513; dose-escalation study design with doses of 0.3, 1, 3, 6, 9, and 12 mg/kg via IV-infusion to establish the maximum tolerated dose (MTD). Pts receive up to 4 cycles (8 infusions) with sample collections at regular intervals for safety, PK, soluble CD30 (sCD30) and detection of immunogenicity [i.e., human Abs to humanized Abs (HAHA)]. Tumor response is assessed every 2 cycles. Results: 13 HL pts have been enrolled in the 1 st 4 dose levels (0.3 to 6 mg/kg). XmAb2513 has been well tolerated. The MTD has not been achieved. 1 pt with an extensive treatment history and chronic immunosuppression died due to fungal pneumonia after a single 3 mg/kg dose. The event was considered unrelated to XmAb2513. PK parameters were computed for the 1 st dose alone and for the entire course of XmAb2513 treatment. PK parameters appeared non-linear across the dose range from 0.3 - 3 mg/kg. Half-life appeared to increase after multiple infusions and ranged from 5.3 - 30.2 days in the 1 and 3 mg/kg cohorts. Immunogenicity (HAHA) results have been negative. Tumor reduction has been observed in 1 pt in the 1 mg/kg cohort and 2 in the 3 mg/kg cohort. Conclusions: The MTD of XmAb2513 has not yet been reached due to its tolerability and lack of immunogenicity. PK results are on track with simulations based on PK results from cynos. XmAb2513 has demonstrated encouraging biologic activity in patients with refractory HL. [Table: see text]
Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis
Authors: T Yamagami, H Sugiyama, K Inoue, H Ogawa, T Tatekawa, M Hirata, T Kudoh, T Akiyama, A Murakami, T Maekawa
Journal: Blood (1996)
A pilot study using carboplatin, vincristine, and temozolomide for children with progressive/symptomatic low-grade glioma: A Children's Oncology Group (COG) study.
Authors: M. M. Chintagumpala, A. Adesina, M. C. Morriss, T. Zhou, E. Holmes, C. C. Lau, A. J. Gajjar
Journal: Journal of Clinical Oncology (2010)

9539 Background: Midline progressive/symptomatic low-grade gliomas in young children cause significant morbidity and mortality. Chemotherapy is the initial treatment modality of choice in these patients. Current chemotherapy regimens, although effective, do not provide a consistently prolonged disease-free survival. COG initiated a pilot feasibility study to evaluate the timely delivery of a combination of several active agents: carboplatin, vincristine and temozolomide. Methods: Children 10 years old or younger with progressive and/or symptomatic low-grade glioma were eligible to receive cycles of weekly carboplatin, vincristine alternating with temozolomide. Children with neurofibromatosis-type 1 were excluded. Short-term feasibility endpoint was defined as the ability to complete induction and one maintenance cycle in 24 weeks without more than 25% reduction in either carboplatin or temozolomide in 80% or more of the patients. The long-term feasibility was defined as the ability to deliver induction and 4 maintenance cycles within 60 weeks in 70% or more of the patients. Results: 66 patients were enrolled on the study with 37 males. The median age was 4.6 years (range 0.4 to 9.8). 50 patients were evaluable for the primary and secondary end points of the study. Of the remaining 16 patients, 10 progressed early, 2 were lost to follow up, 1 had meningitis and 3 had incomplete data. There were 12 episodes of febrile neutropenia. 7 patients developed allergic reactions to carboplatin. No serious adverse events or deaths were attributed to the treatment. 44/50 (88%, 95% CI, 76%-95%) evaluable patients met the criteria for short term feasibility. 39/50 (78%, 95% CI, 65%-87%) met the criteria for long-term feasibility. The 2 year EFS was 80 ± 5.1% and the 2-year OS was 97 ± 2.2%. Conclusions: It is feasible to deliver cycles of vincristine and carboplatin alternating with temozolomide over a prolonged period of time with tolerable side effects. Preliminary data suggests that this combination is at least as effective as previous regimens in controlling disease progression. Further follow up is necessary to assess the efficacy of this regimen. No significant financial relationships to disclose.
Functional and psychological evaluation after exclusive chemoradiation therapy in oral and oropharyngeal cancer
Authors: C. Zanon, M. Airoldi, M. Garzaro, L. Raimondo
Journal: Journal of Clinical Oncology (2009)

e17012 Purpose: The treatment of head and neck tumours often negatively affects speech, swallowing, body image and quality of life (QoL). Aim of this study was the evaluation of the impact of exclusive chemoradiation therapy (CH-RT) on QoL and psychological functioning. Patients and Methods: Twenty-eight patients, affected by a carcinoma of the oral cavity and oropharynx received exclusive CH-RT. Late effects of CH-RT and psycho-oncological assessment included: Radiation Therapy Oncology Group (RTOG) - European Organisation for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring system, DISCHE morbidity recording scheme, Hospital Anxiety and Depression Scale (HADS), Montgomery Asberg Depression Rating Scale (MADRS), Mini Mental Adjustment to Cancer (MINI MAC), and EORTC QoL Head and Neck 35. Results: After a median follow-up of 42 months (range 12–60 months) moderate-severe late toxicity was as follows: taste impairment (89.20%), salivary function (82.12%), subcutaneous tissue (7.08%). Concerning dysphagia 39% of patients complained some discomfort, 28% had a more severe toxicity whereas 7% could not have an oral feeding; patients with severe dysphagia showed higher levels of anxiety (p &lt; 0.05): dysphagia influences the QoL, fatigue and physical-social functioning. Rates of depression and anxiety were generally low: 78.6% of our sample did not show clinical relevant anxious symptoms and 82.1% of patients did not reach the threshold of an overt depression. Just a fair concordance in rate of depression between self- and hetero-evaluated scale was observed, with higher rates relieved by MADRS compare to HADS depression subscale using 8 or 10 cut-off (Cohen's k test = 0.401) Conclusions: Our data suggest low rates of anxiety and depression, in patients treated with CH-RT, with a different evaluation between self-evaluative and hetero-evaluative scales. No significant financial relationships to disclose.
CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients
Authors: Matthew J. Bottomley, Paul N. Harden, Kathryn J. Wood
Journal: Journal of the American Society of Nephrology (2015)

Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8 + T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8 + T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8 + T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8 + T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.
A multi-center phase II study of arsenic trioxide (AT) in patients (Pts) with advanced pancreatic cancer (PC) refractory to gemcitabine
Authors: M. Aklilu, H. L. Kindler, S. Nattam, A. Brich, E. E. Vokes
Journal: Journal of Clinical Oncology (2004)

4114 Background: There is no effective chemotherapy for PC pts who progress after treatment with Gemcitabine. Novel agents with unique mechanisms of action are clearly needed for this chemo-refractory disease. Arsenicals have been used in Chinese folk remedies for 2000 years. In vitro, AT has a potent anti-proliferative effect against PC. AT is thought to induce apoptosis in PC cell lines by activating the caspase cascade via the mitochondrial pathway and by decreasing Bcl-2 expression. Thus, we postulated that AT might have activity in PC pts. Methods: Eligibility required advanced PC that had progressed on a gemcitabine-containing regimen, measurable disease, ECOG PS 0–1, normal organ function, QTc < 500ms, no evidence of NYHA functional class III or IV heart failure. AT 0.3 mg/kg was administered intravenously over 1 hour daily for 5 consecutive days every 28 days. CT scans were obtained every 2 cycles. Results: 13 pts enrolled 12/02–11/03 at 5 centers. 21 cycles were administered (median 2; range 1–2). There were no grade 3/4 hematologic toxicities; grade 1/2 anemia occurred in 50% pts and grade 1/2 leukopenia in 25%. Two pts developed Grade 4 small bowel obstruction attributed to their cancer. Grade 3 toxicities included fatigue 17%, thrombosis 17%, nausea/vomiting 8%, diarrhea 8%, constipation 8%, hypocalcemia 8%, and elevated liver transaminases 8%. Only 1 pt developed prolongation of the QTc interval (Grade 1). There were no objective responses. Median progression-free survival was 7 weeks (95% CI, 5.4–8.1). Median survival was 16.6 weeks (95% CI, 6.9–29.7). Conclusions: Despite in vitro activity in PC cell lines, AT has no clinical activity in PC pts who develop progressive disease after gemcitabine. Multi-center phase II trials are feasible in this patient population, though they are challenging due to the rapid clinical deterioration that occurs following front-line chemotherapy in PC. Trials of novel agents are urgently needed. Supported by NCI grant N01-CM-17102. No significant financial relationships to disclose.
Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)
Authors: S. Modi, A. Stopeck, M. S. Gordon, D. Solit, W. Ma, J. Wheler, G. Cropp, R. G. Johnson, A. L. Hannah, C. Hudis
Journal: Journal of Clinical Oncology (2006)

501 Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m 2 ; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range &lt;1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3 rd and 4 th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea &amp; anorexia at 375 mg/m 2 ; delayed recovery of platelets at 450 mg/m 2 . Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m 2 ; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going. [Table: see text]
Role of IL-6 in cachexia progression in advanced pancreatic cancer.
Authors: S. Mitsunaga, M. Ikeda, K. Nakachi, E. Suzuki, J. Furuse, M. Inagaki, Y. Uchitomi, S. Higashi, K. Terao, A. Ochiai
Journal: Journal of Clinical Oncology (2010)

4101 Background: Cachexia is major cause of death associated with advanced pancreatic cancer (PC). Patients with cachexia show decreased body weight, mainly due to the loss of fat and skeletal muscle, progressive fatigue and anorexia, and biochemical abnormalities such as anemia, hypoalbuminemia, and increased CRP. IL-6, one of the pro-inflammatory cytokines, is recognized as a potential mediator of the cachectic process. In this study, circulating IL-6 in advanced PC is characterized to reveal the pathophysiology of cachexia. Methods: Patients with unresectable PC who had not received any anti-cancer therapy for PC were eligible for inclusion in this study. Patients with obvious infectious conditions were excluded. Serum levels of pro-inflammatory cytokines, including IL-6, were measured by electrochemiluminescence assay. The detection limit of IL-6 was 0.23 pg/mL. Fat, muscle, and fat-free mass were evaluated using bioelectrical impedance analysis. Fatigue and anorexia were rated numerically from 0 to 10 using the Japanese version of the M. D. Anderson Symptom Inventory. The usual biochemical parameters, including hemoglobin, albumin, and CRP level, were examined. The Mann-Whitney test was used to be compared between non- categorical data. Results: From June 2008 to November 2009, 102 patients (male/female: 54/48, performance status: 0/1/2/3: 70/29/2/1, median age: 66 years) were enrolled. Serum IL-6 was detected in 93.8% of patients with a median value of 1.45 pg/mL. High cytokine level was defined as being more than the median value, and the high IL-6 group (n = 54, median 3.72 pg/mL) showed losses of body weight (p = 0.025), skeletal muscle (p = 0.012), and fat-free mass (p = 0.024), compared to the low IL-6 group (n = 48, median 0.78 pg/mL). In symptom analysis, fatigue score was significantly higher in the high IL-6 group (p = 0.020), but anorexia was not associated with IL-6 level (p = 0.104). The high IL-6 group had low albumin (p < 0.001) and hemoglobin (p < 0.001), and elevated CRP (p < 0.001). Conclusions: High IL-6 was associated withall aspects of the wasting condition, symptom progression, and biochemical abnormalities in cachexia. The physiological effects of IL-6 may play a crucial role in the progression of cachexia in patients with advanced PC. No significant financial relationships to disclose.
Phase II trial of ABT-869 in advanced renal cell cancer (RCC) after sunitinib failure: Efficacy and safety results
Authors: N. Tannir, Y. Wong, C. Kollmannsberger, M. S. Ernstoff, D. J. Perry, L. J. Appleman, E. Posadas, J. Qian, J. L. Ricker, D. M. Michaelson
Journal: Journal of Clinical Oncology (2009)

5036 Background: ABT-869 is a novel, orally active and potent inhibitor of all VEGF and PDGF receptor tyrosine kinases. Results from a phase I study suggested antitumor activity in advanced solid tumors including RCC. The recommended dose for phase II investigation was 0.25 mg/kg (maximum 25 mg) daily. Methods: We conducted an open-label, multicenter phase II trial of oral ABT-869 in advanced RCC. Eligibility criteria included progressive disease (PD) within 100 days of enrollment after at least 2 cycles of sunitinib, prior nephrectomy, and adequate organ function. The primary endpoint was objective response rate (ORR) per RECIST by central imaging. Secondary endpoints were best response, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Safety was assessed by NCI-CTCAE, v3.0. Results: 53 patients (pts, median age, 61 y [range, 40–80]; clear-cell histology [41 pts]; median number of prior therapies, 2 [range, 1–4]) were enrolled from 8/07 to 10/08. All pts were previously treated with sunitinib, and additional prior treatments included cytokine (19%), sorafenib (15%), temsirolimus (4%), and bevacizumab (4%). Preliminary efficacy data are shown in the Table below. Median TTP was 4.9 mos [95% CI: 3.5–6.8] per central imaging. Median OS is not estimable. The most common adverse events (AEs) were diarrhea (78%), fatigue (67%), hypertension (53%), nausea (51%) and vomiting (39%). AEs ≥ grade 3 included hypertension (24%), fatigue (18%), diarrhea (14%) and hand-foot syndrome (14%). 39 pts required dose reductions. Of the 20 pts who have discontinued therapy at the time of this analysis, 16 were due to PD, 3 due to AEs (1 hemoptysis, 1 fatigue, 1 fatigue/hypertension) and 1 withdrew consent. The remaining 33 pts continue protocol treatment, and updated results will be presented. Conclusions: ABT-869 has activity in RCC after sunitinib failure. The dose will be optimized for future studies. [Table: see text] [Table: see text]
A front-line window of opportunity phase II study of sorafenib in patients with advanced non-small cell lung cancer: A North Central Cancer Treatment Group study
Authors: A. A. Adjei, J. R. Molina, S. L. Hillman, R. F. Luyun, N. F. Reuter, K. M. Rowland, J. R. Jett, S. J. Mandrekar, S. E. Schild
Journal: Journal of Clinical Oncology (2007)

7547 Background: Sorafenib is a multikinase inhibitor with single-agent activity in previously treated NSCLC. In an effort to evaluate its single agent activity in previously untreated NSCLC, the NCCTG undertook a front-line “window of opportunity” study. Materials and Methods: Patients with stage IIIB (pleural effusion) or stage IV NSCLC received sorafenib dosed at 400 mg BID continuously, with a cycle defined as 4 weeks. Patients were evaluated weekly during the first 2 cycles with those who progressed rapidly going on to receive standard chemotherapy. Based on a two-stage Fleming design, if only at most 1 confirmed response was observed in the first 20 patients enrolled to stage I, the regimen would be considered ineffective. If 2 or more responses were observed, the study would proceed to stage 2 and accrue an additional 22 patients. If 5 or more confirmed responses were observed, the regimen would be recommended for further testing. Results: The study did not meet the stage I efficacy criteria (only 1 confirmed partial response in the first 20 patients) and was permanently closed after enrolling 25 evaluable patients [15 females, 10 males; 4 stage IIIB, 21 stage IV; median age 67 (45–85)]. 2 patients are still receiving treatment (14 and 15 months). No grade 3 or higher hematologic adverse events were observed. Thirteen (52%) patients had a grade 3 non-hematologic adverse event with fatigue (20%), diarrhea (8%), and dyspnea (8%) being the most common. There was one grade 4 pulmonary hemorrhage. A total of 3 (12%) PRs; and 7 (28%) SD were observed in the 25 patients 7 (28%) patients were progression- free at 24 weeks. Median survival and median time to progression were 8.8 and 2.9 months respectively. Conclusion: While the pre- specified efficacy endpoints were not met, the objective response rate of 12% and median survival of 8.8 months suggest that single agent sorafenib has activity similar to two-drug combinations. The feasibility and utility of the “window of opportunity” design in estimating the activity of novel compounds was demonstrated. Finally, the single-agent activity of sorafenib argues for combination studies with standard chemotherapy agents. No significant financial relationships to disclose.
The incidence of psychosurgery in the United States, 1971--1973
Authors: J Donnelly
Journal: American Journal of Psychiatry (1978)

As part of the work of the APA Task Force on Psychosurgery, the author surveyed 1,901 neurosurgeons on how many psychosurgical procedures they performed in 1971, 1972 and 1973. A total of 1.481 questionnaires were returned: 195 neurosurgeons indicated they had performed a total of 476 procedures for intractable pain and 1.039 procedures for psychiatric conditions. Excluding the procedures reported by 4 neurosurgeons who performed more than 20 psychosurgical operations in any one of the three years, the number of psychosurgical operations in 575 for the three years, which the author suggests should allay fears about the abuse of psychosurgery.