tbuckley/cabot-search huggingface dataset:
Phase I trial of imatinib and temozolomide in patients with metastatic melanoma
Authors: L. Schuchter, K. Flaherty, R. Davidson, L. Cavallaro, M. Hendricks, P. Deming, A. Recio, D. Tuveson
Journal: Journal of Clinical Oncology (2004)

7572 Background: Imatinib mesylate (Gleevec) is a selective tyrosine kinase inhibitor with multiple targets including the KIT and PDGR receptors. Preclinical studies suggest that the combination of Gleevec (G) may have activity against melanoma, based in part on the effects of G on c-kit, as well as its antivascular effects via alterations in the PDGF receptor. Novel strategies are needed to improve upon the results of single agent chemotherapy in patients with melanoma. Methods: This phase I study was initiated to define the safety profile and the maximum tolerated dose of Gleevec combined with Temozolomide (T) in patients with locally advanced melanoma or metastatic disease. No prior treatment with T was allowed. Results: Sixty-three percent of patients had received prior therapy. Gleevec was given daily starting on Day 1 and T was given daily × 5 on Days 1–5, administered every 28 days. To date 8 patients have been entered onto the study. Overall therapy has been well tolerated. Predictable side effects of T include mild nausea, myelosuppression, and fatigue. Toxicities related to Gleevec are primarily fluid retention. No unexpected toxicities have been seen to date. MTD has not been reached. There have been no grade 4 toxicities. There was only one grade 3 toxicity related to treatment, which was edema. Conclusions: Preliminary analysis of the data shows a favorable toxicity profile. As the MTD is established, a phase II trial will begin to further define the overall activity of this combination therapy. Accrual to the clinical trial continues and updated results will be presented. No significant financial relationships to disclose.
Granulocyte Colony-Stimulating Factor as an Adjunct to Induction Chemotherapy for Adult Acute Lymphoblastic Leukemia — A Randomized Phase-III Study
Authors: Klaus Geissler, Elisabeth Koller, Eva Hubmann, Dietger Niederwieser, Wolfgang Hinterberger, Dietmar Geissler, Paul Kyrle, Paul Knöbl, Ingrid Pabinger, Renate Thalhammer, Ilse Schwarzinger, Christine Mannhalter, Ulrich Jaeger, Renate Heinz, Werner Linkesch, Klaus Lechner
Journal: Blood (1997)
Diabetes has protective effect against metastasis in patients with non-small cell lung cancer
Authors: A. Hanbali
Journal: Journal of Clinical Oncology (2004)

7234 Background: Cancer can spread by both lymphatic and hematogenous routes, and metastases are found most commonly in organs fed by the downstream lymphatic and blood flow. In patients with long-standing diabetes mellitus, diabetic microangiopathy render the vascular basal membrane less digestible by tumor cells, which may play a role in impeding neoplastic cell spread and metastasis. Objective: To determine whether cancer patients with diabetes mellitus have less risk of metastasis and subsequently decreased mortality compared to patients without diabetes. Study Population: 566 non-small cell lung cancer patients diagnosed during the period 1996 to 2000 were identified using the Henry Ford Hospital tumor registry. Medical records were reviewed to confirm study eligibility and to obtain data on diabetic status and progression to metastatic disease. Methods: Patient characteristics at the time of diagnosis were compared by chi square and t-test. Associations between diabetic status and progression to metastasis and death were assessed using log rank tests and proportional hazards regression models. Kaplan-Meier survival estimates were used to summarize time to metastasis and time to death. Results: Stage and diabetes are significant predictors of metastasis. As expected a higher stage is associated with a greater risk of metastatic progression (risk ratio = 1.70, p<0.001). However, diabetes is associated with a lower risk (RR = 0.51, p=0.010). Stage and age are the only significant predictors for death, with risk ratios of 1.56 and 1.03, respectively. Diabetes does not have a significant association with death(RR=0.89, p 0.410). Conclusions: Diabetes is associated with lower risk of metastasis in patients with non-small cell lung cancer, but is not associated with lower mortality rate. No significant financial relationships to disclose.
Assessing the value of progression-free survival (AVALPROFS).
Authors: Lesley Fallowfield, Lucy Matthews, Susan L. Catt, Mairead MacKenzie, Jacqui Gath, Valerie A. Jenkins
Journal: Journal of Clinical Oncology (2014)

187 Background: Controversy exists about progression free survival (PFS) as an endpoint in novel cancer therapy trials. PFS is attractive for practical and methodological reasons but is not always a surrogate for overall survival. It is debatable whether or not PFS has discernable clinical benefit for patients (pts), the main treatment (tmt) goal. Also overlooked are pt perceptions. Few trials directly address if disease stabilisation is worth tmt side effects (SEs) or include relevant patient reported outcome (PRO) measures. AVALPROFS examines longitudinally pts’ understanding of therapeutic intent, PFS and the value placed on drugs that control cancer but have SEs. We report the pilot study here. Methods: The primary pilot aim was to obtain feedback from pts having drugs offering only PFS or modest OS gains, about the acceptability and comprehensibility of PROs for use in a longitudinal study. These included validated quality of life and anxiety measures and 4 study specific interview schedules. In close collaboration with Independent Cancer Patients’ Voices (ICPV) and using an iterative process, draft interviews (pre-tmt, on-tmt, at withdrawal due to toxicity or progression) were developed. Pilot study pts’ clinic consultations were taped prior to home interviews by researchers. Results: 11/19 eligible pts with metastatic breast, lung and head and neck cancers at different treatment phases participated. No pt recalled the phrase PFS being used in consultations. Few knew their latest scan results. Some were confused about the therapeutic aims of further tmt, 4/10 thought it would extend survival. All had experienced or anticipated considerable toxicity. None found the interview schedules too upsetting; all provided comprehensive feedback about these and the trade-off questions. Conclusions: PFS is confusing and questions remain about its true value. Involvement of ICPV in potentially distressing research about study design and PROs at the outset was invaluable. Inclusion of feedback from pilot study pts permitted further refinements to the AVALPROFS study which is currently open and recruiting. Clinical trial information: 16342. [Table: see text]
Abstract 15595: Protein Tyrosine Phosphatase 1B Knockout Attenuates Obesity-Induced Cardiomyopathy
Authors: Machender R Kandadi, Evgeniy E Panzhinskiy, Nathan D Roe, Sreejayan Nair, Jun Ren
Journal: Circulation (2012)

Obesity, type 2 diabetes and other features of metabolic syndrome are major risk factors for cardiovascular diseases. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin action. However, the role of PTP1B in obesity-related cardiomyopathy is unknown. This study was designed to evaluate the effect of genetic disruption of PTP1B on cardiac function in diet-induced obesity. Cardiac function was evaluated in Wild-type (WT) and PTP1B-/- mice fed a low fat (10% calorie) or high fat diet (45% calorie) for 5 months. High fat diet intake resulted in larger body weight (41.5±4 vs. 28.2±1g), heart weight (HW) (146±6 vs. 123±6 mg) and glucose intolerance in WT mice, the effect of which was attenuated by PTP1B knockout (n=8-10, p<0.05). Echocardiography showed an increase in wall thickness, end diastolic diameter (2.92±0.16 vs. 2.69±0.08 mm), end systolic diameter (1.73±0.12 vs. 1.33 ±0.06 mm) and a decrease in fractional shortening (39.7±1.4 vs. 51.4 ±2.1) following HFD which were significantly reconciled by PTP1B knockout (n=8-10, p<0.05). In addition, assessment of cardiomyocyte contractile function revealed decreased peak shortening, maximal velocity of shortening and relengthening following HFD feeding, the effect of which was rescued by PTP1B knockout (n=110-120 cells from 3 mice, p<0.05). High fat diet feeding resulted in increased cardiomyocytes cross-sectional area (330±0.05 vs. 233±0.04µm2) and hypertrophic proteins ANP and GATA4, which were significantly attenuated in PTP1B knockout mice (n=3-4 mice, p<0.05). Furthermore, Western blot analysis revealed high fat feeding upregulated Akt and mTOR phosphorylation and decreased AMPK and ACC phosphorylation in WT mice. Interestingly, PTP1B knockout caused a significant increase in phosphorylation of AMPK and ACC without affecting Akt and mTOR phosphorylation. In vitro silencing of PTP1B using siRNA dampened the expression of hypertrophic genes while it promoted AMPK phosphorylation. In conclusion, our data revealed that PTP1B knockout prevented obesity-induced cardiomyopathy by preserving AMPK signaling, suggesting the therapeutic promise of this enzyme in the treatment of obesity-induced cardiac anomalies.
Hematologic outcomes and drug cost considerations of erythropoiesis stimulating agents (ESTs) in cancer patients (pts) with fixed dosing regimens: Results from practice patterns in a prospective observational study
Authors: K. Larholt, E. Chen, C. Peake, B. Bookhart, C. Tak Piech, R. McKenzie
Journal: Journal of Clinical Oncology (2007)

17063 Background: The erythropoietic agents available today have FDA-approval for weight-based as well as fixed dosing in cancer pts with chemotherapy-induced anemia [epoetin alfa (EPO) 40,000 Units QW, darbepoetin alfa (DARB) 500 mcg Q3W]. To understand hematologic outcomes and EST cost considerations based on actual patterns of use, not protocol-driven use, data were analyzed from the Dosing and Outcomes Study of Erythropoiesis-Stimulating Therapies (D.O.S.E.) Registry, an ongoing registry of real-world practice. Methods: Data from 18 U.S. practice settings from 1/06–12/06 were assessed. Chemotherapy-treated adult cancer pts initiated at either EPO 40,000 Units or DARB 500 mcg were evaluated. Outcomes assessed included mean treatment duration, hematologic outcomes, mean administered dose, mean cumulative administered dose, and total EST cost (based on 9/2006 wholesale acquisition cost). Results: 168 pts (145 EPO, 23 DARB) were eligible. Patient groups were similar with regard to baseline age, gender distribution, tumor type, Karnofsky score and Hb. Treatment duration was similar for both agents, approximately 7 weeks. The proportion of pts transfused from Week 5 to end of study and number of units/ pt was not significantly different between groups (% transfused: EPO 10%, DARB 13%; Units/pt: EPO 0.2, DARB 0.3). Mean administered dose was 42,879 Units in the EPO group and 497 mcg in the DARB group. Mean cumulative administered dose for the treatment episode was 305,241 Units for EPO and 1,665 mcg for DARB, corresponding to an EST cost of $3,715 for EPO and $7,404 for DARB (p &lt;.0001). Conclusions: Real-world practice pattern data from this observational study found similar treatment duration and transfusion patterns in the EPO-treated group versus the DARB-treated group in pts initiated with FDA-approved fixed dosing regimens. Cumulative EST cost was $3689 lower in the EPO group, a 50% reduction versus the DARB group. No significant financial relationships to disclose.
The effect of induction therapy with carboplatin-paclitaxel and low dose radiotherapy followed by hyperfractionated radiotherapy and intraarterial chemotherapy on advanced cancers of the head and neck
Authors: G. W. Warren, S. M. Arnold, G. Curtis, J. Valentino, Y. Brill, W. F. Regine, P. M. Spring, M. Mohiuddin, W. H. St. Clair, M. R. Kudrimoti
Journal: Journal of Clinical Oncology (2006)

15517 Background: The purpose of this study is to evaluate the potential benefits of induction therapy followed by intraarterial cisplatin and hyperfractionated radiation (HYPERRADPLAT) on patients with advanced head and neck tumors. Methods: 20 patients with Stage III-IV squamous cell carcinoma of the head and neck were treated with induction therapy consisting of 2 cycles of carboplatin (AUC 6) and paclitaxel (225 mg/m 2 ) and 0.8 Gy BID on the day of and the day following chemotherapy. Induction therapy was given over 2 cycles separated by 3 weeks (previously described in ASCO 2002 abstract # 921 and 2004 abstract # 5593). Patients were then treated with the HYPERRADPLAT regimen consisting of external beam radiotherapy (74.4–81.6 Gy) delivered in 1.2 Gy BID fractions with intraarterial cisplatin (150 mg/m 2 ) administered when patients had reached 60 Gy. Tumor response, disease free survival, overall survival, and toxicity were assessed for all patients according to NCI CTCAE criteria. Results: Of 20 patients, 9 had tumors of the oropharynx, 9-supralaryngeal, and 2-hypopharyngeal. Fifty percent of patients had T4 tumors and 35% had T3 tumors. Complete tumor response was observed in 80% of patients and 20% had a partial response. Three-year disease free survival was 75% and overall survival was 75%. Locoregional recurrence was noted in 25% of patients and 15% had distant failure. Overall recurrence was noted in 40% of patients with a median time to recurrence of 12 months (range 6–55 months). Median weight loss during treatment was 10% of initial body weight and 13 patients required a feeding tube within 6 months of starting treatment. Grade 3 mucositis was noted in 65% of patients and no patients developed Grade 4 toxicity. Conclusions: Two cycles of carboplatin-paclitaxel induction therapy followed by intraarterial cisplatin and hyperfractionated radiotherapy produces excellent tumor response and reduces distant failure. These results compare favorably with historical controls and produce tolerable toxicity profiles. [Table: see text]
Vinorelbine (NVB) oral (NVBo) in combination with carboplatin (CBDCA) followed by maintenance therapy with single agent vinorelbine oral in stage III/IV non-small cell lung cancer (NSCLC): Final results of a multicenter international phase II trial
Authors: R. P. Abratt, H. Macha, S. Del Barco, D. Aubert, M. Mitrovic, Y. Parlier, U. Gatzemeier
Journal: Journal of Clinical Oncology (2006)

7126 Background: NVB i.v. day 1 (25 mg/ m 2 ) &amp; NVBo day 8 (60 mg/ m 2 ) and CBDCA AUC 5 have been previously studied in chemonaive NSCLC patients (pts) (O’Brien et al, Ann Oncol 2004; 15: 921). We investigated the efficacy and safety of NVBo weekly with CBDCA AUC 5 q3w for 4 cycles(Cy) followed by maintenance therapy with single agent NVBo in non progressive pts. Methods: Inoperable NSCLC stage IIIB, stage IV or delayed relapse of any stage becoming unresectable, KPS ≥ 80%, treated with combination therapy every 3 weeks for 4 Cy: NVBo 60 mg/m 2 on days 1, 8 and 15 (Cy1), 80 mg/m 2 (Cy2–4) in absence of neutropenia NCI CTC V2 G3/4; CBDCA AUC 5 day 1, administered over 1 hour. Maintenance therapy if pts did not have a PD: NVBo 60 mg/m 2 for the first three weekly administrations, followed by NVBo at 80 mg/m 2 /week until PD. Results: from December 2003 to January 2005 57/56 pts have been registered/treated: median age 61 yrs (37–71); median KPS 90%; male 71.4%; Squamous cell 30%, Adenocarcinoma 50%; Stage III/IV 32.1/62.5% ; median dose intensity NVBo (% RDI) : combination, 50.1 mg/m 2 /w (67.3%), maintenance 56.2 mg/m 2 /w (70.2%); pts with NVBo dose escalation from 60 to 80 mg/m 2 during combination : 36/52 (69.2%). Tolerance (% of pts with G3/4 NCI CTC V2) : Neutropenia 23.2/44.6; Platelets 16.1/1.8; Hb 19.6/3.6; Nausea 7.1/0; Vomiting 7.1/0; Diarrhea 5.4/0. No G3/4 toxicity was reported for Infection, Bilirubin, Creatinine, Stomatitis, and motor/sensory Neuropathy. Febrile Neutropenia was reported in 5 patients (8.9%). Efficacy: (RECIST) Percent Overall Response rates (n =56 pts) PR 17.9, SD 53.6, PD 23.2, NE 5.4; Progression-Free Survival 4.3 (95% CI [3.1–5.1]) months; Overall Survival 9.7 (95% CI [7.7–11.9]) months. Conclusions: NVBo on a weekly schedule and CBDCA AUC5 in combination therapy for 4 Cy followed by NVBo in maintenance therapy is an effective and safe treatment regimen for advanced NSCLC. The avoidance of further CBDCA administrations after 4 Cy and the use of NVBo as a maintenance therapy until PD has promise as an alternative to the 6 Cy option and calls for further comparative studies. [Table: see text]
Clinical features of joint symptoms observed in the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial
Authors: A. U. Buzdar
Journal: Journal of Clinical Oncology (2006)

551 Background: Aromatase inhibitors have been associated with higher rates of adverse events associated with the joints, or ‘joint symptoms’ (JS) than tamoxifen. Details of these were reviewed in the ATAC study. JS were reported spontaneously at a higher frequency with anastrozole (A) than with tamoxifen (T), and here we present a detailed assessment of these events. Methods: Adverse events related to the joints were coded into four COSTART terms: arthralgia, arthritis, arthrosis and joint disorder. Time of onset, duration of symptoms and their effect on treatment adherence were reviewed. Results: At 68 months’ median follow-up 1100/3092 (35.6%) patients in the A arm and 911/3094 (29.4%) patients in the T arm experienced JS. Almost half (46%) of patients with JS reported these as an exacerbation of a pre-existing condition in the joints and in most cases the location was generalized. The majority of first events developed within 24 months of initiation of treatment (A 68%, T 59%) with a peak occurrence at 6 months (A 29%, T 20%). Review of all available data showed that half of the patients who recovered from JS were symptom-free within 6 months of onset and in 75%, symptoms resolved within 18 months. Median time to resolution for these events was 5.5 months for the A arm and 5.9 months for the T arm. Sixty percent of patients experiencing JS received treatment, with &gt;90% of these patients managed with an NSAID alone or in combination with mild analgesics. Although the difference in overall prevalence between treatment arms was statistically significant (p&lt;0.0001), a similar occurrence of serious adverse events of JS was reported (A 10.6%, T 10.4%), and only a small number of patients experiencing JS required treatment withdrawal (A 2.1%, T 0.9%). Conclusion: 68-month data from the ATAC trial showed that treatment with A was associated with a modest increase in the incidence of JS compared with T. In most patients the events were mild-to-moderate in intensity and did not lead to withdrawal of treatment. [Table: see text]
Prognostic significance of S100A4 expression in biliary tract cancers.
Authors: J. Jo, E. Nam, K. Lee, Y. Mun, C. Seong, S. Lee, S. Min, H. Lee, M. Cho
Journal: Journal of Clinical Oncology (2010)

e14620 Background: S100A4, the S100 family of calcium-binding protein, has been shown to be related with cell proliferation and invasiveness of cancer cells. We investigated the clinical significance of S100A4 expression in biliary tract cancers. Methods: Archival tissues from 82 patients with primary biliary tract cancers who underwent surgery were obtained. The expression of S100A4 was evaluated by immunohistochemistry and analyzed with several clinicopathologic variables including survival time. Results: Thirty-three of 82 cases (40.2%) demonstrated positive staining for S100A4. The positivity of S100A4 was higher in patients with stage III, IV than in patients with lower stages (32.8% in stage I, II vs. 58.3% in stage III, IV, p = 0.032). Other clinicopathologic factors were not correlated with the expression of S100A4. On survival analysis, the median survival time of S100A4 positive group was significantly shorter than that of S100A4 negative group (18.8 months vs. 65.1 months, p = 0.025). On multivariate analysis, positive staining of S100A4 (HR 2.170, 95% confidence interval [95% CI] 1.185-3.575) and incomplete surgical resection (HR 2.931, 95% CI 1.473-5.830) were detected as significant poor prognostic factors. Conclusions: The expression of S100A4 is useful in assessing the prognosis of patients with biliary tract cancers and more aggressive therapy including complete resection should be considered for such patients. No significant financial relationships to disclose.
Bortezomib + gemcitabine (Gem)/carboplatin (Carbo) results in encouraging survival in advanced non-small cell lung cancer (NSCLC): Results of a phase II Southwest Oncology Group (SWOG) trial (S0339)
Authors: A. M. Davies, J. McCoy, P. N. Lara, P. H. Gumerlock, J. Crowley, D. R. Gandara
Journal: Journal of Clinical Oncology (2006)

7017 Background: Bortezomib (PS-341), a small molecule proteasome inhibitor, has single agent activity in NSCLC and potentiates Gem/Carbo in pre-clinical models in a sequence-specific manner (Mortensen, Cancer Chem Pharm, 2004). A phase I trial of Gem/Carbo + PS-341 in patients (pts) with advanced NSCLC yielded an encouraging response rate of 48%. Here we describe the results of a SWOG phase II study of this regimen in advanced NSCLC. Methods: 114 eligible chemonaive stage IV and selected stage IIIB (pleural effusion) NSCLC pts received Gem 1000 mg/m2 on days 1, 8 and Carbo AUC 5 on day 1, followed 1 hour later by PS-341 1.0 mg/m2 on days 1, 4, 8, 11, with cycles repeated every 3 weeks. Non-progressing pts could continue PS-341 alone after 4 cycles. Results: Pt characteristics: Median age: 64 years; Sex M/F = 68/46; Performance status 0/1 = 50/64; stage IIIB/IV = 13/101. Response rate: 20% (95% CI 13–29%); 66% (95% CI 56–75%) had stable disease. At a median follow-up of 13 months, progression free and median survival times were 5 months (95% CI 3.5–5.3) and 11 months (95% CI 8.2–12.5). One-year survival was 46% (95% C.I. 37–55%). Most common grade 3/4 toxicities: neutropenia (52%), thrombocytopenia (63%), and fatigue (13%). Ongoing correlative studies are examining markers of proteasome inhibition (Bcl2 family, NFKB, IKB) and hypoxia (PAI-1, VEGF, OPN, HIF-1) in tumor tissue and surrogate specimens. Conclusions: The 11 month median survival achieved with the addition of PS-341 to Gem/Carbo in this phase II study is unprecedented in prior SWOG trials in advanced NSCLC, and does not appear to be explained by altered patient characteristics. The toxicity profile of this regimen is favorable. A phase III trial of Gem/Carbo ± Bortezomib in advanced stage NSCLC is under development. Supported by CA38926, CA32102. No significant financial relationships to disclose.
Authors' response
Authors: M. Facco, A. Cabrelle, C. Agostini
Journal: Thorax (2011)

We thank Dr Brodlie and coworkers for their letter1 and fully agree on the necessity to evaluate whether cells other than lymphocytes and macrophages are involved in IL-17 release in sarcoid lungs. The main manifestation of sarcoidosis is an accumulation of mononuclear inflammatory cells, mostly CD4+ T cells and monocytes/macrophages in involved organs, including the lungs.2 As specified in our ‘Materials and methods’ section, we evaluated cells obtained by filtering bronchoalveolar lavage (BAL) fluid through gauze. A standard morphological and immunological analysis of BAL cellular components was performed. The …