Deepak M. Sahasrabudhe

Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia.

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.

Renal cell carcinoma treated by vaccines for active specific immunotherapy : correlation of survival with skin testing by autologous tumor cells

SummaryEighteen patients with metastatic renal cell carcinoma, who were treated by vaccines for active specific immunotherapy, also completed skin testing with autologous tumor cells, both prior to and following vaccine treatment. All patients have now been followed for more than 5 years. Ten patients who remained skin-test-negative following treatment had no clinical responses, and all had expired by 22 months. Eight patients became skin-test-positive; three of these had clinical regressions and three remain alive after more than 69 months. The survival times of the skin-test-positive group were significantly superior to those of the skin-test-negative group. The results suggest that skin testing with autologous tumor cells may accurately identify those patients who have acquired antigenspecific cell-mediated antitumor immunity.

Stereotactic Body Radiotherapy for Pulmonary Metastases From Soft-Tissue Sarcomas: Excellent Local Lesion Control and Improved Patient Survival

PURPOSE Patients with pulmonary metastases (PM) from soft-tissue sarcomas (STS) have historically been treated with surgery and/or chemotherapy. Since 2001, we have treated PM with stereotactic body radiation therapy (SBRT). We postulated that SBRT for PM from STS would yield excellent local control (LC) and overall survival (OS). METHODS AND MATERIALS Fifty-two patients with PM from STS, diagnosed between 1990 and 2006 at the University of Rochester, were retrospectively reviewed. Most patients received multimodality treatment comprising of surgery, chemotherapy, and/or radiation. SBRT used the Novalis ExacTrac patient positioning platform, vacuum bag immobilization, and relaxed end-expiratory breath hold techniques. RESULTS Leiomyosarcoma (23%), malignant fibrous histiocytoma (19%), and synovial sarcoma (15%) were the most common histologies. Forty-eight percent initially presented with PM, whereas 52% developed PM at a median of 0.7 (0.3-7.3) years after initial diagnosis. Median follow-up from diagnosis of PM was 0.9 (0.3-7.3) years. Fifteen patients underwent SBRT to 74 lesions. Median number of lesions treated was 4 (1-16) per patient and 3.5 (1-6) per session. Preferred dose and fractionation was 50 Gy in 5 Gy fractions. Three-year LC was 82%. No patients experienced Grade ≥ 3 toxicity. Median OS was 2.1 (0.8-11.5) years for patients treated with SBRT, and 0.6 (0.1-7.8) years for those who never received SBRT (p = 0.002). CONCLUSIONS SBRT provides excellent LC of PM and may extend OS. SBRT should be considered for all patients with PM from STS, particularly those who are not surgical candidates. Further investigation is warranted to establish criteria for the use of SBRT for STS patients with PM.

A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma.

Aims: Interferon-gamma (IFN-γ) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-γ gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus–interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma. Methods: Patients were enrolled at four successive dose levels: 107 infectious units (iu) (n=3), 108 iu (n=3), 109 iu (n=3), and 1010 iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated. Results: A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity. Conclusion: Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.

Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder

The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down‐staging of patients with locally advanced urothelial cancer (UC) of the bladder.

Pilot study using gabapentin for tamoxifen-induced hot flashes in women with breast cancer.

In this pilot study, 22 women with breast cancer on tamoxifen therapy with at least two hot flashes a day took oral gabapentin at 300 mg three times a day for 4 weeks. The 16 women who completed the study had a mean decrease in hot flash duration of 73.6% (P = 0.027), frequency of 44.2% (P < 0.001), and severity of 52.6% (P < 0.001), with a complete response in 8/16 women. Side effects reported by four women who did not complete 4 weeks of the study were nausea (1/4), rash (1/4) and excessive sleepiness (3/4). Two additional patients did not provide complete data. Gabapentin is a promising new agent in the treatment of tamoxifen induced hot flashes, and should be studied further.

C35 (C17orf37) is a novel tumor biomarker abundantly expressed in breast cancer

Identification of shared tumor-specific targets is useful in developing broadly applicable therapies. In a study designed to identify genes up-regulated in breast cancer, a cDNA clone corresponding to a novel gene C35 (C17orf37) was selected by representational difference analysis of tumor and normal human mammary cell lines. Abundant expression of C35 transcript in tumors was confirmed by Northern blot and real-time PCR. The C35 gene is located on chromosome 17q12, 505 nucleotides from the 3′ end of the ERBB2 oncogene, the antigenic target for trastuzumab (HerceptinTM) therapy. The chromosomal arrangement of the genes encoding C35 and ERBB2 is tail to tail. An open reading frame encodes a 12-kDa protein of unknown function. Immunohistochemical analysis detected robust and frequent expression of C35 protein, including 32% of grade 1 and 66% of grades 2 and 3 infiltrating ductal carcinomas of the breast (in contrast to 20% overexpressing HER-2/neu), 38% of infiltrating lobular carcinoma (typically HER-2/neu negative), as well as tumors arising in other tissues. C35 was not detected in 38 different normal human tissues, except Leydig cells in the testes and trace levels in a small percentage of normal breast tissue samples. The distinct and favorable expression profile of C35 spanning early through late stages of disease, including high frequency of overexpression in various breast carcinoma, abundant expression in distant metastases, and either absence or low level expression in normal human tissues, warrants further investigation of the relevance of C35 as a biomarker and/or a target for development of broadly applicable cancer-specific therapies. [Mol Cancer Ther 2006;5(11):2919–30]

Cardiovascular Disease Mortality After Chemotherapy or Surgery for Testicular Nonseminoma: A Population-Based Study

PURPOSE Increased risks of incident cardiovascular disease (CVD) in patients with testicular cancer (TC) given chemotherapy in European studies were largely restricted to long-term survivors and included patients from the 1960s. Few population-based investigations have quantified CVD mortality during, shortly after, and for two decades after TC diagnosis in the era of cisplatin-based chemotherapy. PATIENTS AND METHODS Standardized mortality ratios (SMRs) for CVD and absolute excess risks (AERs; number of excess deaths per 10,000 person-years) were calculated for 15,006 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2010) who initially received chemotherapy (n=6,909) or surgery (n=8,097) without radiotherapy and accrued 60,065 and 81,227 person-years of follow-up, respectively. Multivariable modeling evaluated effects of age, treatment, extent of disease, and other factors on CVD mortality. RESULTS Significantly increased CVD mortality occurred after chemotherapy (SMR, 1.36; 95% CI, 1.03 to 1.78; n=54) but not surgery (SMR, 0.81; 95% CI, 0.60 to 1.07; n=50). Significant excess deaths after chemotherapy were restricted to the first year after TC diagnosis (SMR, 5.31; AER, 13.90; n=11) and included cerebrovascular disease (SMR, 21.72; AER, 7.43; n=5) and heart disease (SMR, 3.45; AER, 6.64; n=6). In multivariable analyses, increased CVD mortality after chemotherapy was confined to the first year after TC diagnosis (hazard ratio, 4.86; 95% CI, 1.25 to 32.08); distant disease (P<.05) and older age at diagnosis (P<.01) were independent risk factors. CONCLUSION This is the first population-based study, to our knowledge, to quantify short- and long-term CVD mortality after TC diagnosis. The increased short-term risk of CVD deaths should be further explored in analytic studies that enumerate incident events and can serve to develop comprehensive evidence-based approaches for risk stratification and application of preventive and interventional efforts.

CD‐20 expression in post‐transplant lymphoproliferative disorders: Treatment with Rituximab

B‐cell lymphoproliferative disorders are rare but serious complications of solid organ and bone marrow transplantation. We report that these tumors frequently express the CD‐20 antigen, and immunotherapy directed at this antigen may be a well‐tolerated and effective treatment. Am. J. Hematol. 65:171–173, 2000.

Lethality-based selection of recombinant genes in mammalian cells: application to identifying tumor antigens.

Many biological processes result in either cell death or cessation of cell growth. However, plasmid- and retrovirus-based mammalian expression vectors in which it has been possible to construct representative cDNA libraries cannot be readily recovered from cells that are not actively dividing. This has limited the efficiency of selection of recombinant genes that mediate either lytic events or growth arrest. Examples include genes that encode the target antigens of cytotoxic T cells, genes that promote stem-cell differentiation and pro-apoptotic genes. We have successfully constructed representative cDNA libraries in a poxvirus-based vector that can be recovered from cells that have undergone lethality-based selection. This strategy has been applied to selection of a gene that encodes a cytotoxic T-cell target antigen common to several independently derived tumors.