Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma

2006 ◽  
Vol 24 (10) ◽  
pp. 1561-1567 ◽  
Author(s):  
William G. Richards ◽  
Lambros Zellos ◽  
Raphael Bueno ◽  
Michael T. Jaklitsch ◽  
Pasi A. Jänne ◽  
...  

Purpose To evaluate morbidity, mortality, maximum-tolerated dose (MTD), and outcome of intraoperative intracavitary hyperthermic cisplatin lavage in patients undergoing pleurectomy for malignant pleural mesothelioma (MPM). Patients and Methods Sixty-one patients were prospectively registered. Forty-four resectable patients with MPM underwent pleurectomy, followed by a 1-hour lavage of the resection cavity with dose-escalated cisplatin (50, 100, 150, 175, 200, 225, and 250 mg/m2) at 42°C and then intravenous sodium thiosulfate (16 g/m2 over 6 hours). Survival estimates were compared using the log-rank test and proportional hazards regression. Results Median age was 71 years (range, 50 to 82 years). Twenty-four patients had epithelial tumors, and 20 had sarcomatous or mixed histology. Postoperative mortality was 11% (five of 44 patients). Dose-limiting renal toxicity occurred at 250 mg/m2, establishing the MTD at 225 mg/m2. Other morbidity included atrial fibrillation (14 of 44 patients, 32%) and deep venous thrombosis (four of 44 patients, 9%). Median survival time of all registered patients was 9 months, and the median survival time of resected patients was 13 months. Survival estimates differed significantly for resectable patients exposed to low doses (50 to 150 mg/m2; n = 9; median, 6 months) versus high doses (175 to 250 mg/m2; n = 35; median, 18 months) of hyperthermic cisplatin (P = .0019); recurrence-free interval also differed significantly (4 v 9 months, respectively; P < .0001). Low dose level (relative risk = 3.418) and nonepithelial histology (relative risk = 2.336) were independent risk factors for poor survival. Twenty patients with epithelial tumors who underwent high-dose cisplatin lavage had a 26-month median survival time. Conclusion Pleurectomy and high-dose intraoperative intracavitary hyperthermic cisplatin lavage is feasible in this patient population with restricted surgical options. An apparent dose-related survival benefit warrants further study.

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Zhichao Liu ◽  
Changchun Li

Background. Neuroblastomas are the most frequent extracranial pediatric solid tumors. The prognosis of children with high-risk neuroblastomas has remained poor in the past decade. A powerful signature is required to identify factors associated with prognosis and improved treatment selection. Here, we identified a strong methylation signature that favored the earlier diagnosis of neuroblastoma in patients. Methods. Gene methylation (GM) data of neuroblastoma patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were analyzed using a multivariate Cox regression analysis (MCRA) and univariate Cox proportional hazards regression analysis (UCPHRA). Results. The methylated genes’ signature consisting of eight genes (NBEA, DDX28, TMED8, LOC151174, EFNB2, GHRHR, MIMT1, and SLC29A3) was selected. The signature divided patients into low- and high-risk categories, with statistically significant survival rates (median survival time: 25.08 vs. >128.80 months, log-rank test, P < 0.001 ) in the training group, and the validation of the signature’s risk stratification ability was carried out in the test group (log-rank test, P < 0.01 , median survival time: 30.48 vs. >120.36 months). The methylated genes’ signature was found to be an independent predictive factor for neuroblastoma by MCRA. Functional enrichment analysis suggested that these methylated genes were related to butanoate metabolism, beta-alanine metabolism, and glutamate metabolism, all playing different significant roles in the process of energy metabolism in neuroblastomas. Conclusions. The set of eight methylated genes could be used as a new predictive and prognostic signature for patients with INRG high-risk neuroblastomas, thus assisting in treatment, drug development, and predicting survival.


Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1076 ◽  
Author(s):  
Shigeo Shimose ◽  
Takumi Kawaguchi ◽  
Hideki Iwamoto ◽  
Masatoshi Tanaka ◽  
Ken Miyazaki ◽  
...  

We aimed to investigate the impact of the controlling nutritional status (CONUT) score, an immuno-nutritional biomarker, on the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). This retrospective study enrolled 164 patients with HCC and treated with LEN (median age 73 years, Barcelona Clinic Liver Cancer (BCLC) stage B/C 93/71). Factors associated with overall survival (OS) were evaluated using multivariate and decision tree analyses. OS was calculated using the Kaplan–Meier method and analyzed using the log–rank test. Independent factors for OS were albumin–bilirubin grade 1, BCLC stage B, and CONUT score <5 (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.58–5.31, p < 0.001). The CONUT score was the most important variable for OS, with OS rates of 70.0% and 29.0% in the low and high CONUT groups, respectively. Additionally, the median survival time was longer in the low CONUT group than in the high CONUT group (median survival time not reached vs. 11.3 months, p < 0.001). The CONUT score was the most important prognostic variable, rather than albumin–bilirubin grade and BCLC stage, in patients with HCC treated with LEN. Accordingly, immuno-nutritional status may be an important factor in the management of patients with HCC treated with LEN.


1997 ◽  
Vol 15 (11) ◽  
pp. 3399-3407 ◽  
Author(s):  
R P Edwards ◽  
W Gooding ◽  
B C Lembersky ◽  
K Colonello ◽  
R Hammond ◽  
...  

PURPOSE To compare the toxicity, pharmacokinetics, and efficacy seen in ovarian cancer patients treated with escalating doses of intraperitoneal (I.P.) interleukin-2 (IL-2) by two different infusion schedules. PATIENTS AND METHODS Forty-five patients were sequentially entered onto a phase I/II study in groups of four at fixed dosage tiers of 6 x 10(4), 6 x 10(5), 6 x 10(6), and 3 x 10(7) IU/m2/d in either of two schedules: (A) intermittent weekly infusions of 24 hours' duration; or (B) alternating continuous 7-day infusions followed by 7-day intervals without therapy. Eligibility criteria included > or = six courses of prior platinum-based chemotherapy and laparotomy-confirmed persistent or recurrent ovarian cancer. RESULTS Forty-one eligible patients received I.P. IL-2 and were assessable for toxicity, but six patients were not assessable for response, which left 35 patients assessable for response. Significant locoregional dose-limiting toxicity was seen with the 7-day infusions (including bowel perforation), with 600,000 IU/m2 as the maximum-tolerated dose (MTD), but catheter infection was the only significant complication seen with the 24-hour infusions, for which an MTD was not established. Among 35 assessable patients, there were six laparotomy-confirmed complete responses (CRs) and three partial responses, for an overall response rate of 25.7% (nine of 35). The median survival time of the cohort was 13.7 months and the overall 5-year survival probability was 13.9%. For the nine patients who demonstrated responses (six on the 24-hour infusion and three on the 7-day infusion), the median survival time has not been reached (range, 27 to 90+ months). CONCLUSION I.P. IL-2 is better tolerated as a weekly infusion as compared with a 7-day infusion and demonstrates evidence of possible long-term efficacy in a modest number of patients. A randomized trial is indicated to determine if the prolonged survival seen in this study is a due to I.P. IL-2 therapy or other factors that cannot be controlled for in a single-arm study.


1986 ◽  
Vol 4 (5) ◽  
pp. 685-696 ◽  
Author(s):  
D Machover ◽  
E Goldschmidt ◽  
P Chollet ◽  
G Metzger ◽  
J Zittoun ◽  
...  

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.


2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Mira Park ◽  
Jung Wun Lee ◽  
Taesung Park ◽  
SeungYeoun Lee

In this study, we propose a simple and computationally efficient method based on the multifactor dimensional reduction algorithm to identify gene-gene interactions associated with the survival phenotype. The proposed method, referred to as KM-MDR, uses the Kaplan-Meier median survival time as a classifier. The KM-MDR method classifies multilocus genotypes into a binary attribute for high- or low-risk groups using median survival time and replaces balanced accuracy with log-rank test statistics as a score to determine the best model. Through intensive simulation studies, we compared the power of KM-MDR with that of Surv-MDR, Cox-MDR, and AFT-MDR. It was found that KM-MDR has a similar power to that of Surv-MDR, with less computing time, and has comparable power to that of Cox-MDR and AFT-MDR, even when there is a covariate effect. Furthermore, we apply KM-MDR to a real dataset of ovarian cancer patients from The Cancer Genome Atlas (TCGA).


1996 ◽  
Vol 14 (7) ◽  
pp. 2167-2173 ◽  
Author(s):  
J Bladé ◽  
J F San Miguel ◽  
M Fontanillas ◽  
A Alcalá ◽  
J Maldonado ◽  
...  

PURPOSE To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy. PATIENTS AND METHODS From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report. RESULTS Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis. CONCLUSION The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients.


2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Sondus Alkhazraji ◽  
Teclegiorgis Gebremariam ◽  
Abdullah Alqarihi ◽  
Yiyou Gu ◽  
Zeinab Mamouei ◽  
...  

ABSTRACT There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium. Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 μg/ml and ranged from 0.015 to 0.03 μg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an ∼2-log10 reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds.


1996 ◽  
Vol 14 (5) ◽  
pp. 1690-1696 ◽  
Author(s):  
M Hernberg ◽  
T Muhonen ◽  
J P Turunen ◽  
M Hahka-Kemppinen ◽  
S Pyrhönen

PURPOSE As reported earlier, a chemotherapy regimen that consisted of dacarbazine, vincristine, lomustine, and bleomycin (DOBC) combined with natural leukocyte interferon (IFN) has been administered with favorable results to patients with metastatic melanoma. In this study, lymphocyte subsets (CD4+ and CD8+) were analyzed before and during treatment to elucidate if alterations in the CD4+/CD8+ ratio had any prognostic value. MATERIALS AND METHODS Blood samples were systematically obtained from 54 patients with metastatic melanoma who received this chemoimmunotherapy. The frequencies of peripheral-blood lymphocyte subsets were monitored by flow cytometry using the monoclonal antibodies OKT4 (CD4+, T-helper cells) and OKT8 (CD8+, T-suppressor cells). RESULTS Twenty-seven patients had a constantly increasing ratio, while the remaining 27 patients had a fluctuating or constantly decreasing ratio. The former group had a median survival time of 11.8 months, as compared with 6.5 months for the latter (P = .008, log-rank test). This difference was generated among patients who had an objective response. Responding patients with a constantly increasing ratio had a median survival time of 21.7 months, as compared with 10.2 months for patients with no constant increase in the ratio (P = .038, log-rank test). In nonresponders, no difference in survival was observed between the two groups. CONCLUSION The monitoring of early changes in the CD4+/CD8+ ratio can provide valuable information that predicts the prognosis of metastatic melanoma patients receiving chemoimmunotherapy.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5938-5938
Author(s):  
Paolo Bernasconi ◽  
Catherine Klersy ◽  
Anna Amelia Colombo ◽  
Daniela Caldera ◽  
Francesco Ripamonti ◽  
...  

Abstract AML patients (pts) with a normal chromosome pattern and the “Internal Tandem Duplication” (ITD) of the FLT3 gene have an overall and event-free survival (OS, EFS) inferior than those of pts with a FLT3 “wild-type” gene because of a higher relapse risk, are placed in the intermediate-1 prognostic category, and when in complete remission (CR) are candidates to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of allo-HSCT in ITD+ pts is still debated and a recent retrospective analysis has stated that FLT3/ITD adversely affected allo-HSCT outcome in the same direction as it does after chemotherapy. Thus, the present study was aimed to compare the OS, EFS and relapse risk of pts submitted to allo-HSCT in first CR or in initial relapse, defined by a 5-10% bone marrow blast cell percentage, with those of pts submitted to chemotherapy alone. The study cohort consisted of 54 chromosomally normal, ITD+ consecutive non-M3 AML pts who were included in 168 AML pts aged 18-66 years who came to our observation in the period January 2007-December 2013. At diagnosis median age was 48.6 years (range 18-66), 25 pts were males and 29 females. Median follow-up was 16.2 months (0.4-68.8): median follow-up for responsive pts was 7.15 months (range 0.26-27.6), for relapsed pts was 18.1 (range 1.9-68.8) and for transplanted pts was 9.1 months (range 2.9-26.8). All pts received the same induction treatment that consisted of standard Idarubicine+Ara-c “3+7” followed by two consolidation courses with high-dose Ara-c. Those who failed induction received other treatment schedules among which Fludarabine+Ara-c+Idarubicine was the most common. At the end of consolidation 38 pts were in first CR, achieved after 3+7 in 27 pts and after a second different course in 11. Sixteen pts had a resistant disease. After a median time of five months (range 1-21) 21/38 pts (55.2%) relapsed. All received a re-induction and 8/21 (38.1%) attained a second CR. Allo-HSCT was performed in a total of 23 pts: 12 first CRs, 6 second CRs and 5 initial relapses. The donor was a sibling in 7 pts, an unrelated donor in 13 and an haplo-identical donor in 3; the HSC source was the marrow in 6 pts, the peripheral blood in 16 and the cord blood (CB) in one. The Conditioning regimen was myeloblative (mainly Busulfan+Fludarabine) in 21 and non-myeloblative in 2; GvHD prophylaxis consisted of Cyclosporine A, steroids and methotrexate “short course”. The median number of CD34+ cells infused was 5.14x106/kg (1.3-12.7). All pts except that who received CB engrafted after a median time of 15 days (12-28); 21 were complete chimeras, two partial chimeras. Thirteen pts developed acute GvHD (grade I in 3 pts, grade II in 5, grade III in 2 and grade IV in 3) which totally/partially recovered after high dose steroids along with different immunosuppressive drugs in 4 and 9 pts respectively. Eleven pts developed a chronic GvHD which was the evolution of an aGvHD in 9, targeted different organs, was stable in 3 pts and completely/partially recovered in 4 and 2 pts respectively. Post-transplant relapse occurred in 3/12 first CRs, in none second CRs and in 3/5 initial relapse. The estimated response rate for CR pts submitted to allo-HSCT was 422.1 (95% CI: 262.4-679.1) versus 64.6 (95% CI: 40.7-102.6) for those submitted to chemotherapy alone with a median survival time of 7.2 months (range 5.3-8.8) versus not reached (1.9-not available); on univariable Cox model the HR of allo-HSCT pts was 37.9 (95% CI: 9.4-152.0) with p=0.0000. The estimated relapse rate for CR pts submitted to allo-HSCT was 8.6 (95% CI: 2.1-34.4) versus 44.3 (95% CI: 25.7-76.3) for those submitted to chemotherapy alone with a median survival time not reached (range not available) versus 13.2 (7.2-not available); on univariable Cox model the HR of allo-HSCT pts was 0.5 (95% CI: 0.2-1.1) with p=0.06. The estimated death rate for CR pts submitted to allo-HSCT was 28.7 (95% CI: 13.7-60.4) versus 49.7 (95% CI: 32.1-77.1) for those submitted to chemotherapy alone with a median survival time of 18.3 months (range 14.2-not available) versus 12.2 (8.8-18.9); on univariable Cox model the HR for allo-HSCT pts was 0.48 (95% CI: 0.2-1.1) with p=0.09. In conclusion, our series suggests that in ITD+ pts allo-HSCT significantly strengthens CR in pts who had already responded to conventional chemotherapy, but it presents only a trend towards significance when its superiority to prevent relapse was considered. Disclosures Castagnola: Gilead Sciences: Research Funding.


2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 42s-42s
Author(s):  
W. Xiang ◽  
G. Cai

Background: Appendiceal carcinoma is a rare malignant tumor with aggressive potentials. Appendiceal adenocarcinoma (AA) accounts for approximately two thirds of it. Aim: This study aimed to explore the epidemiologic changes of AA and reveal the possible influences of therapeutic advances on survival of patients with AA. Methods: We retrospectively identified 6066 patients with AA treated between 2000 and 2014 from the Surveillance, Epidemiology, and End Results (SEER) program. Pertinent data were analyzed for incidence and prevalence. Survival analysis was made by the actuarial or Kaplan-Meier and compared by log-rank test. Cox proportional hazards model was adopted for prognostic variable evaluation. Results: We identified 6066 cases with AA. Its annual age-adjusted incidence was 0.47 per 100,000 in 2000 and increased to 1.11 per 100,000 by 2014. The incidence increased the steepest in patients under 50 years old, with a threefold escalation to 0.60 per 100,000 in 2014. The elevation of the incidence was noted in all the histologic types, stages and grades. The 20-year limited-duration prevalence of AA was 6 per 100,000 on January 1, 2014. The multivariable analysis showed the median survival time was statistically different in gender, year of diagnosis, grade, stage, type of surgery performed and histologic subtype. The median survival time was prolonged from 2000-2006 to 2007-2014 (hazard ratio (HR) 0.87; 95% CI, 0.80-0.94). Conclusion: These results showed an elevation in the incidence, prevalence of AA, which may be interpreted by the advancement of examining techniques. The improvement in survival may result from the development of therapies. Furthermore, these results suggested clinicians pay more attention to AA and indicated some potential research directions.


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