tbuckley/cabot-search huggingface dataset:
Phase I clinical study of heptaplatin (H) and paclitaxel (P) in previously treated patients with advanced solid tumor
Authors: K. H. Jung, D. H. Lee, H. K. Kim, J. Y. Han, I. J. Jang, Y. S. Park, S. Y. Joo, J. Ro, J. S. Lee
Journal: Journal of Clinical Oncology (2004)

2122 Background: Heptaplatin is a recently developed platinum analogue which has been reported to be less toxic than cisplatin. In a phase I clinical trial, the maximum tolerated dose (MTD) was 480 mg/m2 once every 4 weeks with dose limiting toxicity (DLT) of myelosuppression and hepatotoxicity (Proc ASCO; 14:A1556 1995). But, randomized study showed H 400 mg/m2 was more nephrotoxic than cisplatin 60 mg/m2 in terms of azotemia and proteinuria when combined with 5-FU (Ahn JH et al. Cancer Chemother Pharmacol. 2002). We initiated a phase I study of H plus P to determine MTD, DLT and toxicities, especially nephrotoxicity. Methods: Eligible pts were those with advanced solid tumor, age 20–65, ECOG 0–1, adequate organ function, 1 or more prior chemotherapy except platinum or taxane and informed consent. P was given first over 60 minutes with fixed dose of 60 mg/m2 followed by H over 60 minutes on days 1, 8 and 15, every 4 weeks. The dose escalation of H was designed to treat cohorts of 3 pts at doses of 120, 150, 200, 250, 300 mg/m2. DLT and MTD pertained to cycle 1 only. Serial blood samples were collected for determination of H and P pharmacokinetics (PK). Results: Between 2002/10 and 2003/12, 15 pts were entered into the study and all pts were evaluated for toxicity and response; median age: 45 (33–65)years, M/F: 9/6; Tumor types: 7 non-small cell lung cancers, 6 colorectals, 1 breast, and 1 gastric cancer. Neither DLT nor nephrotoxicity has occurred. The highest toxicity grade was 3 and no grade 4 toxicity; 4 neutropenia, 1 anorexia, 1 dyspnea, and 1 constipation. Antitumor acitivty has been observed with 3 PR (2 NSCLC, 1 Breast). Conclusions: This weekly combination regimen showed interesting response rate with good tolerability. MTD has not been defined and dose escalation continues. The PK data will be presented. No significant financial relationships to disclose.
Phase II study of POLY-ICLC in recurrent anaplastic glioma–A North American Brain Tumor Consortium study
Authors: S. M. Chang, K. Lamborn, P. Wen, L. Deangelis, K. Fink, F. Lieberman, A. Yung, I. Robins, T. Cloughesy, L. Junck, M. Prados
Journal: Journal of Clinical Oncology (2006)

1550 Background: The goals of this study were to determine the 6-month progression free survival (PFS) for patients with recurrent anaplastic glioma (AG) treated with the immune-modulatory agent POLY-ICLC, and to evaluate toxicity. Low dose Poly-ICLC has a direct immune enhancing action which includes an increased antibody response to antigen and activation of NK-cells, T-cells, macrophages and cytokines. Previously documented side effects include transient flu-like symptoms, which responds to acetaminophen and pain related to the intramuscular administration. Methods: Eligibility included age &gt;18 years, recurrent AG, no more than 2 prior relapses, normal laboratory parameters and informed consent. Poly-ICLC was administered at 20mcg/kg 3x/week by intramuscular injection in 4 week cycles continuously. Dose reductions were allowed for toxicities. Patients were assessed for tumor response every 2 months. Treatment continued until tumor progression, unacceptable toxicity or patient withdrawal. The study had a 2 stage design with the initial assessment of 6 month PFS for the first 22 patients with possible expansion to a total of 46 patients, if more than 7 patients of the 22 had a 6 month PFS. Results: As of 12/05, 46 patients were treated (49% males). Median age was 42 years (range 21–70 years) and median KPS was 90. The agent was well tolerated and the toxicity profile was as previously reported. The response rate and 6 month PFS of the 22 patients in the first stage of the study was 9% and 23% respectively. Based on these findings the cohort was expanded to 46 patients. Of the 15 patients in the second cohort with at least 1 post treatment response assessment available, there is 1PR and 7 SD (47%). Conclusions: 6 month PFS for the entire cohort continues to be assessed but preliminary results suggest antitumor activity of this agent in recurrent anaplastic glioma. No significant financial relationships to disclose.
Alterations of natural killer cells in metastatic prostate cancer
Authors: C. Veuillen, G. Gravis, M. Marcy, J. Walz, F. Bladou, N. Salem, S. Brunelle, D. Olive
Journal: Journal of Clinical Oncology (2009)

e16131 Background: Recently, prostate cancer (PCa) has been considered as a potential target for antitumoral immunotherapy and cells such as Natural Killer (NK) cells, with antitumoral activity are a promising candidate. NK cells activity is regulated by opposite signals delivered by inhibitory (NKRi) and activating receptors (NKRa). Primary human PCa express ligands for NKRa but the HLA class I (ligands for NKRi) expression is downregulated. Recently, our group have reported that patients with acute myeloid leukaemia have defective interactions receptor -ligand in NK cells due to a decreasing expression of Natural Cytotoxicity Receptors and it could be used as a evasion mechanism by leukaemia cells. The aim of this work was to evaluate the activating receptors expression to know if it could be used as evasion mechanism of the immune response in PCa. Methods: Activating and inhibitory receptors were analysed by flow cytometry in peripheral NK cells from 8 patients with metastatic androgen dependent prostate cancer (ADPC), 10 with metastatic androgen independent prostate cancer (AIPC), 7 patients with localized prostate cancer (LPC ) and 15 healthy donors. Results: The expression of NKp30, NKp46, and NKG2D (as determined by MFI) was significantly lower on NK cells from patients with ADPC and AIPC than in healthy donors. In ADPC patients, the ratio MFI (MFI receptor/MFI control isotype) of NKP30 (4.73 ± 1.07, p = 0.0003), of NKp46 (16.62 ± 3.42, p = 0.036) and of NKG2D (19.61 ± 6.44, p = 0.026) significantly differed from healthy donors (NKp30 26.65 ± 6.12; NKp46 39.73 ± 9.66 and NKG2D 37.97 ± 6.77). It was similar for AIPC NK cells(NKp30 6.28 ± 1.27, p = 0.0002; NKp46 16.24 ± 2.34, p = 0.014; NKG2D 13.61 ± 2.29, p = 0.0003). In ADPC and AIPC NK cells, the expression of NKRi and other NKRa did not differ from healthy donors. In LPC NK cells, the expression of NKRi and NKRa did not differ from healthy donors. Conclusions: We observed a decreased expression of principal activating receptors only in metastatic form of PCa. This could affect the interactions receptor-ligand in NK cells. Is it hormonal therapy or extension of the disease that is responsible of NK cells alterations? Moreover, this could constitute a potential mechanism for cancer cells immune escape and a possible target for therapies improving NK functions. No significant financial relationships to disclose.
The effect of age on adjuvant chemotherapy with uracil-tegafur for completely resected stage I lung adenocarcinoma
Authors: M. Tsuboi, H. Kato, Y. Ichinose, H. Tada, C. Hamada
Journal: Journal of Clinical Oncology (2008)

7538 Background: Adjuvant chemotherapy (CT) with uracil-tegafur (UFT) has been shown to increase survival in stage I lung adenocarcinomas, although adjuvant platinum-based CT is being still investigated among this population. However, uncertainty concerning its efficacy and toxicity exists in elderly patients (70 years old or more). Methods: We analyzed individual patient data of 979 patients in the Japan Lung Cancer Research Group trial, which was a prospective randomized study of CT with UFT for stage I lung adenocarcinoma. Patient characteristics, UFT toxicity and compliance, overall survival and disease-free survival (DFS) were compared among 3 age groups: 549 (56%) young (<65), 242 (25%) middle (65–69) and 188 (19%) elderly (≥70). The analysis was performed on an intent-to-treat basis. Survival was estimated using the Kaplan-Meier method, and difference in survival between the two groups was compared with the log-rank test. Cox models were used to test the trend of UFT efficacy on survival according to age. Results: Baseline characteristics were not statistically different among the age groups, although women were more frequent in elderly patients. The drug compliance of the elderly group was significantly lower than that of other ones (Chi-square test: p<0.05). Statistical differences in several kinds of toxicity, such as AST and anorexia, were observed between elderly population and other groups. The hazard ratio (HR) of death was 0.78 (95% C.I., 0.46–1.28) for the young patients, 0.76 (95% C.I., 0.40–1.39) for the middle category and 0.63 (0.35–1.10) for the elderly patients (test to trend: p=0.58). The HR for DFS was 0.79 (95% C.I., 0.53–1.16) for the young, 0.90 (0.54–1.50) for the mid category and 0.86 (0.52–1.40) for the elderly patients (test for trend: p=0.80). No difference in non-cancer related death was observed among the age groups. Conclusions: Although the drug compliance of UFT was significantly lower in the elderly patients, age did not have a statistical impact on the survival benefit from adjuvant treatment with UFT for patients with p-stage I lung adenocarcinoma. This may be due to lack of statistical power. Further molecular epidemiologic and molecular profiling studies investigating age as a prognostic factor for survival are required. No significant financial relationships to disclose.
Phase I and Pharmacokinetic Study of NSC 655649, a Rebeccamycin Analog With Topoisomerase Inhibitory Properties
Authors: Anthony W. Tolcher, S. Gail Eckhardt, John Kuhn, Lisa Hammond, Geoffrey Weiss, Jinee Rizzo, Cheryl Aylesworth, Manuel Hidalgo, Amita Patnaik, Garry Schwartz, Sally Felton, Elizabeth Campbell, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649. RESULTS: Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m 2 to 744 mg/m 2 . Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m 2 and 744 mg/m 2 , respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m 2 and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin. CONCLUSION: Recommended phase II doses are 500 mg/m 2 and 572 mg/m 2 IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.
Tumor heterogeneity and drug resistance.
Authors: D L Dexter, J T Leith
Journal: Journal of Clinical Oncology (1986)

Drug resistance has long been identified as a major reason for therapy failure in cancer patients. Concurrently, work from many laboratories in the past 10 years has established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms. The two most sinister aspects of intraneoplastic diversity in human solid tumors are the genesis of clones with metastatic potential, and the existence of drug-resistant variants in primary cancers and their metastases. Thus, recent investigations on drug resistance and on tumor heterogeneity have converged to focus attention on the clonal organization of primary tumors and their metastases as the underlying basis for anticancer drug resistance. This review examines the degree of heterogeneity observed within tumors and the relationship of this diversity to resistance that might be anticipated for any given agent. A question critical to our discussion is "How many subpopulations are there?" The impact of multiple tumor clones on therapy is next discussed in relationship to normal tissue tolerance, the barrier clinicians face regardless of the specific agent used in treatment. Finally, laboratory and clinical approaches are presented for addressing a drug resistance problem that is seemingly overwhelming because of its complex biological roots.
Effect of prophylactic cranial irradiation dose on CNS relapse, late cognitive decline and learning disabilities in children treated for acute lymphoblastic leukemia
Authors: M. M. Meshref, N. Elshazly, M. Nasr, R. Abdelhai
Journal: Journal of Clinical Oncology (2006)

9032 Background: Prophylactic cranial irradiation is still standard in treatment of high risk childhood acute lymphoblastic leukemia. In this study we assessed the effect of cranial irradiation dose of 1,800 cGy and 1200 cGy on CNS relapse as well as the late cognitive decline and learning disabilities in both groups versus a control group using neurophysiologic and psychometric studies. Methods: 42 patients treated from acute lymphoblastic leukemia and categorized to be at high risk of relapse were assessed in this study. 28 patients received prophylactic cranial irradiation at a dose of 1,800 cGy and 14 received a dose of 1,200 cGy. A control group of 42 age and sex matched normal children was also assessed. Visual and auditory P300 studies were carried out to assess high visual and auditory processing functions. Several selected subscales of Wechsler Intelligence scale for children were applied to both subgroups as well as the control group. Results: Mean age at receiving irradiation was 5.7 years. Mean testing age was 10 years. Mean follow up period was 4.6 years.There was one CNS relapse in the group who received 1,800 cGy (3.5%) and one in the group who received 1,200 cGy (7%). As compared to the control group the group of patient who received 1,800 cGy showed a high statistically significant delay in the latency and significant reduction in the amplitude of the Visual P300 (p &lt;0.001, =0.01 respectively). The Auditory P300 showed a significant delay in latency (p=0.01). In the group receiving 1,200 cGy only the latency of the visual P300 was significantly affected(p=0.01). The other parameters in the 1,200 cGy subgroup were not significantly affected. As for the psychometric studies there were significant differences in several subscales between controls and 1,800 cGy subgroup namely in similarities, total performance and picture compilation which were not found between controls and 1,200 cGy subgroup. Conclusions: These findings reflects that there is impairment in the intellectual abilities as well as visual and auditory processing functions in the subgroup receiving 1,800 cGy compared to the controls which was much less in the subgroup receiving 1,200 cGy at no significant increased protection from CNS relapse. No significant financial relationships to disclose.
Termination of intraperitoneal chemotherapy is driven by treatment toxicity rather than catheter dysfunction
Authors: R. P. Edwards, S. D. Richard, T. C. Krivak, K. K. Zorn, P. Sukumvanich, J. L. Kelley
Journal: Journal of Clinical Oncology (2007)

16054 Background: Three separate studies have shown increased survival for women with epithelial ovarian carcinoma treated with intraperitoneal (IP) chemotherapy. Barriers to its use have included toxicity concerns. We compared the morbidity associated with IP cisplatin- based chemotherapy and IP immunologic therapies. Methods: A retrospective cohort analysis of patients diagnosed with epithelial ovarian carcinoma treated with IP chemotherapy at a single institution from 1996–2006 was performed. Patients were separated into those who received IP Interleukin-2 or Interleukin-12 and those who received cisplatin-based IP chemotherapy. Primary endpoint was completion of the intended treatments. Complications arising from the placement or use of the catheter were deemed catheter-related and included obstruction of flow or catheter site infection. Those felt to be caused by treatment toxicity (e.g. nausea, pain, fever) or progression of disease were deemed treatment-related. Chi square test was used for all univariate analysis. Results: Seventy-five patients were identified. Thirty-five (46.6%) received IL-2 or IL-12, while 40 (53.4%) received cisplatin-based chemotherapy. There were 16 complications that led to treatment termination (21.3%). Immunologic therapy had an increased frequency of early termination (n=13, 37.1%) compared to cisplatin-based therapy (n=3, 7.5%) (p=0.002). There were 3 (8.6%) catheter-related complications in the immunologic group and 2 (5%) in the cisplatin-based group (p=0.54). Reasons for termination of therapy in the immunologic therapy group were progression of disease (n=5), catheter site infection (n=3), grade 3/4 nausea (n=3), and grade 3/4 abdominal pain (n=2). In the cisplatin therapy group, reasons for termination included catheter site infection (n=1), catheter site leak (n=1), and progression of disease (n=1). Conclusion: Local-regional immunotherapy produces significantly more complications and local symptoms than cisplatin-based regimens. Catheter complications were not significantly different between the two groups, and accounted for a small percentage of the treatment terminations in this series. No significant financial relationships to disclose.
Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer.
Authors: T Saphner, D C Tormey, R Gray
Journal: Journal of Clinical Oncology (1991)

The records of 2,673 patients randomized according to seven consecutive Eastern Cooperative Oncology Group (ECOG) studies of adjuvant therapy for breast cancer were reviewed for the occurrence of vascular complications. All protocols opened and closed between June 1977 and July 1987. The objectives of the present study were (1) to compare the frequency of vascular complications among patients who received adjuvant therapy for breast cancer with patients on observation, and (2) to estimate the contribution of chemotherapy and hormonal therapy to the occurrence of venous and arterial thrombi. The frequency of thrombosis, both venous and arterial combined, was 5.4% among patients who received adjuvant therapy and was 1.6% among patients on observation (P = .0002). Premenopausal patients who received chemotherapy and tamoxifen had significantly more venous complications than those who received chemotherapy without tamoxifen (2.8% v 0.8%, P = .03). Postmenopausal patients who received tamoxifen and chemotherapy had significantly more venous thrombi than those who received tamoxifen alone (8.0% v 2.3%, P = .03) or those who were observed (8.0% v 0.4%, P less than .0001). Premenopausal patients who received tamoxifen and chemotherapy had a 1.6% frequency of arterial thrombosis, significantly more than patients who received chemotherapy alone (1.6% v 0.0%, P = .004). The frequency of arterial thrombosis among postmenopausal patients was not significantly correlated with adjuvant therapy. In conclusion, patients who received adjuvant therapy for breast cancer had a 5.4% frequency of thromboembolic complications, significantly more than those who were observed. The combination of chemotherapy and tamoxifen was associated with more venous and arterial thromboembolic complications than chemotherapy alone in premenopausal patients and with more venous thrombi than tamoxifen alone among postmenopausal patients.
Abstract 12297: Relations between Baseline Physical Activity by Pedometer Counts and Future Cardiovascular Events in the NAVIGATOR Study
Authors: William E Kraus, Robert M Califf, Jaakko Tuomilehto, Jie-Lena Sun, Laine Thomas, Thomas Yates, Melanie Davies, Rury Holman, John J McMurray, Angelyn Bethel, Steven M Haffner
Journal: Circulation (2012)

Few pharmacologic trials of diabetes (DM) or cardiovascular disease (CV) have studied the effects of lifestyle (physical activity, nutrition) on defined clinical events. In NAVIGATOR, 9306 particip...
Self referral to physiotherapy and other services would empower patients and doctors
Authors: Sara Riggare
Journal: BMJ (2016)

We should make direct access easy when the benefits outweigh the risks

Healthcare systems worldwide face unprecedented challenges over the coming years as populations grow older and sicker. There is only one sustainable solution: more active patients.

Current calls for patients to have direct access to physiotherapists and to other allied health professionals such as radiographers in the NHS, without a referral from a GP, have the potential to lead to improvements for a lot of patients. As a patient with Parkinson’s disease I strongly support the idea of easier access to physiotherapists, because it’s well established that physiotherapy is essential for our wellbeing.1 With the right help we can preserve our stamina, agility, and …