Biomedical subjects

S Groshen

Publications and source records attributed to S Groshen.

At least 91 records · Page 5Linked to original sources

PubMed1995

Surgery with adjuvant irradiation in patients with pathologic stage C adenocarcinoma of the prostate.

BACKGROUND: In recent years, the routine use of prostate-specific antigen (PSA) to detect cancer of the prostate (CaP) early has renewed the controversy regarding radiotherapy versus radical prostatectomy as the superior definitive treatment. Radiotherapy alone has been reported to result in a high incidence of local recurrence, whereas on the other hand surgical treatment has resulted in a high incidence of microscopic residual tumor. The purpose of this study was to review our treatment results with radical prostatectomy followed by planned courses of postoperative irradiation in patients with pathologic Stage (PS) C disease. METHODS: From 1972 to 1989, 95 patients with CaP with PS C tumors were treated with radical prostatectomy and bilateral pelvic lymphadenectomy. Pathologic stage distribution was: C1 in 26 (27%), C2 in 37 (39%), and C3 in 32 (34%) patients. The median follow-up was 6 years. All 95 study patients received postoperative pelvic irradiation as the only adjuvant treatment. Radiotherapy treated volume included the prostatic fossa and its immediate vicinity. The RT dose ranged from 33 Gy to 61.8 Gy (median, 45 Gy). RESULTS: The overall 5- and 10-year actuarial survival rates were 94% and 73%, respectively, with the 5 and 10 year disease specific survival of 98% and 91%, respectively. Clinical and/or prostate specific antigen recurrence was 31% at 5 years and 44% at 10 years. Prostate specific antigen elevation without clinical evidence of recurrent disease was recorded in 26 (27%) patients. Seminal vesicle involvement (C3) and high Gleason's score (8-10) were the most important factors predicting recurrence. Of the 95 patients treated, 2 had pelvic recurrence alone and 1 had local and distant metastatic disease. Radiotherapy was well tolerated with no clinically important morbidity. CONCLUSION: Based on this experience, moderate dose adjuvant radiotherapy after radical prostatectomy in patients with PS C CaP is recommended.

Adenocarcinoma↗

PubMed1995

Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis.

BACKGROUND: Tumor stage, histologic grade, and regional lymph node status are currently used to obtain prognostic information about bladder cancers. However, additional prognostic indicators are needed to aid clinicians in selecting patients who would benefit most from specific therapies. A majority of studies assessing the prognostic value of measuring tumor angiogenesis (i.e., measurement of tumor microvessel densities) have found a positive association between increasing microvessel densities and worsening prognosis. PURPOSE: We explored the relationship between established prognostic indicators and the extent of tumor-associated angiogenesis in patients with invasive transitional cell carcinoma (TCC) of the bladder, and we determined whether tumor microvessel density measurement could be used independently to predict bladder tumor behavior. METHODS: Tumor tissue was obtained from 164 patients with invasive primary TCC of the bladder. The extent of tumor-associated angiogenesis in this tissue was evaluated by immunohistochemical methods using HPCA-1, a mouse monoclonal antibody directed against the endothelial cell antigen, CD34. The number of microvessels in a 200x microscopic high-power field (hpf) containing the area of greatest neovascularization within or immediately adjacent to each tumor was determined. The patient population was then divided into three equivalently sized groups, with tumors containing low (< or = 64), intermediate (65-99), or high (> or = 100) numbers of microvessels per hpf. Kaplan-Meier product limit estimates of overall survival and the complement of cumulative incidence curves for recurrence-free survival were plotted. When analyzing survival or recurrence, the logrank test was used to compare groups of patients with and without stratification according to tumor stage. Analysis of variance was used to test for an association between microvessel density and established prognostic variables. Reported P values are from two-sided tests. RESULTS: Microvessel density was significantly associated with disease-free (P < .0001) and overall (P = .0007) survival. The estimated probabilities of recurrence at 5 years were 19% (95% confidence interval [CI] = 8-29), 56% (95% CI = 43-69), and 68% (95% CI = 55-81) for patients with lowest, intermediate, and highest microvessel counts, respectively. Overall survival at 5 years was estimated to be 68% (95% CI = 56-81), 44% (95% CI = 30-57), and 34% (95% CI = 21-47) for the same three patient groups. Microvessel density was associated with disease progression in patients with organ-confined tumors, tumors extending through the bladder wall, and tumors that had spread to regional lymph nodes. Tumor angiogenesis was found to be an independent prognostic indicator when evaluated in the presence of histologic grade, pathologic stage, and regional lymph node status. CONCLUSION: Tumor angiogenesis, as determined by microvessel density measurement, is an independent prognostic indicator for patients with invasive TCC of the bladder.

Adult↗

PubMed1995

Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction.

BACKGROUND: Many patients with aggressive clinically superficial bladder cancer ultimately die of their cancer, due in part to resistance to undergo radical cystectomy. Radical cystectomy is usually curative for patients with pathologic superficial tumors. Orthotopic urinary reconstruction has lessened the morbidity and lifestyle changes in patients after cystectomy, and may increase patient acceptance of cystectomy as therapy for high risk superficial tumors. METHODS: A retrospective analysis was performed on 182 patients with clinically superficial bladder cancer (Ta, Tis, T1) who had radical cystectomy between 1971 and 1989, to determine the incidence of pathologic upstaging and to assess overall survival, cause-specific survival, and recurrence free survival. Indications for cystectomy included failure of intravesical chemo- or immunotherapy, high grade lamina propria invasive tumors, presence of bladder diverticulae, spread of superficial tumors into the prostatic urethra, and endoscopically uncontrollable tumors. RESULTS: Pathologic upstaging to muscle-invasive or metastatic tumors occurred in 34% of patients, and of these, only half remained organ confined. Metastases were present in 8% of patients at the time of cystectomy. Mucosa-confined tumors were upstaged only 19% of the time, whereas tumors demonstrating lamina propria invasion (T1) were upstaged 40% of the time. Pathologic upstaging to muscle-invasive or metastatic disease was significantly associated with a decreased probability of survival (P = 0.042). With a median follow-up of 7.2 years, overall survival was estimated to be 86%, 72%, and 47%, and recurrence free survival 90%, 83%, and 77% at 2, 5, and 10 years, respectively. CONCLUSIONS: Pathologic upstaging to muscle-invasive or metastatic tumors occurs in one third of highly selected patients with clinically superficial bladder cancer who have had radical cystectomy, half of whom have extravesical disease. Survival is significantly decreased in this group of upstaged patients. With the alternative of orthotopic urinary diversion available to most men and women requiring cystectomy, radical cystectomy should be considered a viable alternative to continued conservative measures for selected patients with aggressive superficial bladder tumors.

Aged↗

PubMed1995

An alternative approach to the optimal design of an LD50 bioassay.

In this paper we propose an alternative approach to the optimal design of an LD50 bioassay. We adopt a Bayesian approach to make use of prior information about the location and scale parameters of the tolerance distribution function to select the design parameters (number of doses, total number of animals, centre of doses, space between doses), and we adopt a frequentist approach using the Spearman-Karber statistic to estimate the LD50. We define the optimal design as the one that produces the minimum expected mean squared error E(MSE) with respect to the joint prior distribution of the parameters of the tolerance distribution. For the design parameters investigated, we found: (i) the shape of the E(MSE) is relatively smooth and continuous, the magnitude of which is influenced by the underlying tolerance distribution; (ii) the amount of prior information about the location and scale parameters independently and jointly affect the optimal design; and (iii) as the amount of prior information decreases, one requires more doses and/or animals. Finally, we show the proposed method is robust for an incorrectly assumed tolerance distribution function.

Animals↗

PubMed1995

Inadequate adherence to radiotherapy in Latina immigrants with carcinoma of the cervix. Potential impact on disease free survival.

BACKGROUND: Radiation therapy plays an important role in the loco-regional control of carcinoma of the cervix. Strict adherence to the radiation protocol, without the introduction of time breaks, has been shown to favorably affect loco-regional control and survival, making adherence a crucial variable for optimal outcome. Because carcinoma of the cervix is a common disease among Latinas, with survival rates worse than those of other ethnic groups in this country, the pattern of adherence to the prescribed radiation treatment among Latina patients seen at Los Angeles County Hospital were studied. METHODS: The records of 69 consecutive Latina patients with cervical cancer who received radiation therapy at Los Angeles County Hospital were reviewed. Semi-structured interviews in a successive group of 30 similar patients were conducted to acquire preliminary information about their psychosocial characteristics. RESULTS: The results demonstrate inferior rates of optimal adherence to radiation treatment among Latina immigrant patients when compared with the rates reported in the literature for the general population of cervical cancer patients in United States (16 vs. 63%). Furthermore, a large subset of patients (20%) in the series elected to discontinue treatment without a medical reason. When a comparable group of Latina patients was interviewed, potential practical, psychologic, and cultural barriers to optimal care were identified. CONCLUSIONS: The results from this exploratory study support the need for further studies to document the pattern of adherence to radiotherapy in the rest of the country among this minority population. The results suggest that an intervention to improve information and adherence to radiation therapy may be necessary to assure Latinas a chance for rates of cure comparable with the national standards.

Adult↗

PubMed1995

Increased incidence of central venous catheter-related infections in bone marrow transplant patients.

In view of an apparent increase of central venous catheter-related infections among our bone marrow transplant (BMT) patients, a retrospective study of infectious complications of central venous catheters was conducted. During 1992, 147 central venous catheters were placed in 133 patients. The overall infection rate of all catheters was 3.3 per thousand catheter-days (bacteremia 1.8, site infection 1.5). Patients scheduled for BMT had the highest infection rate of 11.5 (bacteremia 6.7, site infection 4.8). HIV patients had an infection rate of 6.6 per thousand catheter-days (bacteremia 3.8 and site infection 2.8) and patients with other diagnoses had a rate of 2.4 (bacteremia 1.3 and site infection 1.1). The difference of infection risk among the three groups is statistically significant (logrank p < .0001). In analyzing the 11 BMT patients more carefully, 14 catheters were placed. Of these, 9 catheters were removed, 8 (89%) of which were secondary to infection. Multivariate analysis showed that patients under 50 and BMT patients were more likely to develop catheter-related infection. While the cause of this complication is not known at present, the possible association with PBSC harvest is of much concern.

Adult↗

PubMed1995

Detection of occult bone marrow micrometastases in patients with operable lung carcinoma.

OBJECTIVES: A large proportion of patients with operable lung carcinoma (no evidence of systemic spread of tumor) develop metastatic disease after primary therapy. More sensitive and specific methods are needed to identify patients at highest risk for recurrence who may benefit most from adjuvant therapy, while sparing those patients who do not require such treatment. SUMMARY BACKGROUND DATA: Using epithelial-specific monoclonal antibodies, the authors have developed an immunocytochemical assay capable of detecting as few as 2 lung cancer cells in 1 million bone marrow cells. METHODS: The assay was used to test the bone marrow (from resected ribs) of 43 patients with primary non-small cell lung carcinoma who showed no clinical or pathologic evidence of systemic disease. RESULTS: Occult bone marrow micrometastases (BMMs) were detected in 40% of patients (17/43) with non-small cell lung cancer, including 29% (5/17) of patients with stage I or II disease and 46% of whom (12/26) had stage III disease. The median follow-up was 13.6 months. Patients with occult BMMs had significantly shorter times to disease recurrence compared with patients without BMMs (7.3 vs. > 35.1 months, p = 0.0009). Furthermore, for patients with stage I or II disease, the presence of occult BMMs was significantly associated with a higher rate of recurrence (p = 0.0004). CONCLUSIONS: The detection of occult BMMs identifies patients with operable non-small cell lung carcinoma who are at significantly increased risk for recurrence, independent of tumor stage, and may be useful in evaluating patients for adjuvant treatment protocols.

Antibodies, Monoclonal↗

PubMed1995

Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens.

PURPOSE: In an attempt to identify women who may be appropriate candidates for orthotopic lower urinary tract reconstruction, archival cystectomy specimens from female patients undergoing cystectomy for primary bladder cancer were reviewed. These pathological findings should provide a better understanding of tumor involvement at the bladder neck (vesicourethral junction) and urethra in women with transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Cystectomy specimens of 67 consecutive women undergoing surgery for biopsy proved transitional cell carcinoma of the bladder between July 1982 and July 1990 were pathologically reviewed. RESULTS: Histological evidence of tumor (carcinoma in situ or gross carcinoma) involving the urethra was present in 9 patients (13%). Tumor was confined to the proximal and mid urethra, and the distal urethra was not involved. All patients with carcinoma involving the urethra had concomitant evidence of carcinoma involving the bladder neck. A total of 17 patients (25%) had tumor involvement of the bladder neck and those with an uninvolved bladder neck also had an uninvolved urethra. The association between the presence of tumor in the bladder neck and urethra was highly significant (p < or = 0.00012). Tumor involving the bladder neck and urethra tended to be more commonly associated with high grade and stage tumors, and node-positive disease. CONCLUSIONS: Although the fate of the retained urethra following cystectomy for bladder cancer in women is unknown, these results show that women with transitional cell carcinoma of the bladder without evidence of tumor involving the bladder neck are at low risk for urethral malignancy. These patients may be offered lower urinary tract reconstruction that includes preservation of and diversion through the urethra (orthotopic diversion). Urethral surveillance will be necessary, as it is in men after orthotopic urinary diversion.

Carcinoma in Situ↗

PubMed1994

Accumulation of nuclear p53 and tumor progression in bladder cancer.

BACKGROUND: We have previously demonstrated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder. METHODS: Histologic specimens of transitional-cell carcinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) from 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival. RESULTS: The detection of nuclear p53 was significantly associated with an increased risk of recurrence of bladder cancer (P < 0.001) and with decreased overall survival (P < 0.001). In patients with cancer confined to the bladder, the rates of recurrence for stage P1, P2, and P3a tumors that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. In a multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence and overall survival (P < 0.001). CONCLUSIONS: In patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence and death, independently of tumor grade, stage, and lymph-node status. Patients with transitional-cell carcinoma confirmed to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment.

Aged↗

PubMed1994

Comparative study of infectious complications of different types of chronic central venous access devices.

BACKGROUND: Various devices for central venous access are widely used in patients with cancer. The authors studied the incidence of infectious complications affecting these different devices. METHODS: A retrospective study of 111 central venous access devices (VAD) placed in 1992 was conducted. RESULTS: Subcutaneous ports were placed in 42 patients, single lumen Groshong catheters in 45, single lumen Hickman catheters in 15, double lumen Hickman catheters in 5, and double lumen Groshong catheters in 4. Prognostic factors analysis was performed with the log rank test and Cox's multivariate analysis. Different VAD types were compared with the likelihood ratio test. There was no significant difference in the risk of VAD-related infection between Hickman and Groshong catheters. Double lumen catheters were slightly more likely to cause infectious complications than single lumen catheters, although the difference was not statistically significant (P = 0.072 and 0.083 for bacteremia and site infection, respectively). No significant difference was observed in the risk of infection between subcutaneous ports and external catheters. Multivariate analysis using Cox's proportional hazards model demonstrated age younger than 50 years as the only significant risk factor, thus younger patients should be monitored more closely. CONCLUSIONS: No significant difference was observed in the risk of infection between subcutaneous ports and external catheters. There was a slightly higher risk of infection in double lumen catheters than single lumen catheters, although the difference did not reach statistical significance. Considering the small sample size, the results should be confirmed in larger prospective studies.

Adult↗

PubMed1994

Adjuvant radiation, chemotherapy, and androgen deprivation therapy for pathologic stage D1 adenocarcinoma of the prostate.

OBJECTIVES: A retrospective analysis of the results of an aggressive multimodal approach combining radical prostatectomy with adjuvant radiation, chemotherapy, or androgen deprivation therapy for patients with pathologic Stage D1 prostate carcinoma was performed to assess the impact of these therapies on survival, recurrence, local control, and morbidity. METHODS: Case records of 76 patients with pathologic Stage D1 tumors were reviewed. All had radical retropubic prostatectomy and were recommended adjuvant therapy based on the pathologic extent of the primary tumor and the number of involved lymph nodes. RESULTS: With a median follow-up of 7 years, overall survival was estimated to be 88% and 66% at 5 and 10 years, respectively, and equaled age- and race-matched controls. Prostate cancer-specific survival at 5 and 10 years was 88% and 74%, respectively. The probability of developing a clinically detectable recurrence (excluding prostate-specific antigen [PSA]) was 29% and 62% at 5 and 10 years, respectively. When PSA was added to the detection data, the probability of developing a recurrence increased to 58% and 78% at 5 and 10 years, respectively. Recurrence and cause-specific survival correlated with Gleason sum. Univariate analysis of the adjuvant therapies demonstrated no effect on survival, but adjuvant radiation alone and in combination with androgen deprivation increased the time to recurrence. Local control was excellent, surgical morbidity was equivalent to that of all patients undergoing prostatectomy during the same time period, and the morbidity of adjuvant therapy was minimal. CONCLUSIONS: Survival equivalent to age- and race-matched controls, with excellent control of the extensive primary tumor, can be achieved in patients with Stage D1 prostate carcinoma by a combination of radical prostatectomy and radiation therapy without the need for routine androgen deprivation therapy.

Acid Phosphatase↗

PubMed1994

Paclitaxel (Taxol) in heavily pretreated ovarian cancer: antitumor activity and complications.

OBJECTIVE: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens. PATIENTS AND METHODS: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression. RESULTS: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease. In addition, 27 others (40%) were stable on continued Taxol for a median time of 6.4 months and CA-125 decreased in 20 patients out of 59 patients with elevated baseline CA-125s. Twenty-seven patients progressed while receiving 1-6 cycles of treatment. Three patients were not evaluable for response. Neutropenia and its complications occurred primarily during the first two cycles of Taxol treatment. Febrile episodes requiring antibiotic treatment occurred in 44% of patients which is a higher incidence than in prior series. CONCLUSIONS: Taxol as a single agent has modest activity in heavily pretreated ovarian cancer patients but appears to be useful and is subjectively well tolerated by many. The high incidence of infection in comparison with other series of patients with ovarian cancer treated with chemotherapy suggests this pretreated patient population has enhanced susceptibility to develop complications from neutropenia. Safer treatment in this advanced setting should include more aggressive use of cytokines and/or less myelosuppressive regimens (e.g. shorter Taxol infusions).

Adult↗

PubMed1994

Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer.

Fifty-seven patients with locally advanced, clinical stage TC, adenocarcinoma of the prostate underwent treatment consisting of surgery, external beam radiation therapy and, in selected patients, early hormonal ablation and/or systemic chemotherapy. Surgical morbidity from radical retropubic prostatectomy and limited pelvic lymph node dissection was acceptable with an early complication rate of 11%. Followup ranged from 3.5 to 19.9 years (median 5.4 years). Actuarial 5 and 7.5 years survival rates for all patients was 91.2% and 77.6%, respectively. Of the 57 study patients 19 (33%) were alive with no evidence of disease, including a prostate specific antigen (PSA) less than 0.4 ng/ml at all times during follow-up. The estimated 5 year probability of clinical recurrence was 18.6% and the 5 year probability of clinical and PSA recurrence (> 0.4 ng/ml) was 54.5%. Local recurrence occurred in only 3 patients. This included 2 (4%) patients who received adjuvant radiotherapy. Our results suggest that patients with locally advanced prostate cancer can be successfully treated with low morbidity using a combination of radical prostatectomy and planned adjuvant radiotherapy.

Adenocarcinoma↗

PubMed1994

Acute myeloid leukemia subtypes and response to treatment among ethnic minorities in a large US urban hospital.

From January 1, 1987, to August 30, 1991, 86 consecutive new cases of AML diagnosed at the LAC-USC Medical Center were analyzed. A significant difference in the FAB subtypes of AML was observed among different racial groups, with AML-M3 more common in Latinos (40%) and AML-M2 in Orientals (52%). Sixty-seven patients received induction chemotherapy with TAD (thioguanine-cytosine arabinoside-daunorubicin) or like regimens. Median follow-up time of all patients was 16 months. Forty-three patients (64%) achieved complete remission. The median overall survival of those who received induction was 10.5 months. The complete remission rates and overall survival were similar among patients of different ethnic backgrounds.

Acute Disease↗

PubMed1994

Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma.

PURPOSE: To determine whether interferon alfa-2b (IFN-alfa; intron-A, Schering Corp, Kenilworth, NJ) can induce a remission in patients previously treated with active specific immunotherapy (therapeutic melanoma vaccine) without response. PATIENTS AND METHODS: Eighteen patients with disseminated melanoma who had failed to respond to at least five injections of Melacine therapeutic melanoma vaccine (Ribi ImmunoChem Research, Inc, Hamilton, MT) were then treated IFN-alfa after a 4-week interval. IFN-alfa 5 or 6 x 10(6) U/m2 was self-administered three times a week subcutaneously by melanoma patients for at least 2 months. Computed tomographic (CT) scans of the chest, abdomen, and pelvis and magnetic resonance imaging of the brain were performed within 4 weeks before treatment as a baseline, and then at 2-month intervals during treatment to evaluate response. All 18 patients were HLA-typed before treatment. The frequency of cytolytic T-cell precursors (pCTL) in the blood had been measured weekly in 13 of the patients during treatment with Melacine. RESULTS: Eight of 18 patients (44.4%) had a major objective clinical response induced by IFN-alfa, including site-specific complete remissions in five. Responses lasted a median of 11 months. The median survival duration of the responders has not been reached, and exceeds 32 months. The group as a whole had a median survival duration of 10.1 months, and nonresponders lived 7.3 months. Cytolytic T-cell precursors had been increased by immunization in all five responding patients tested, but also in five of eight nonresponders. There was no association of response to IFN-alfa with specific HLA phenotypes, in contrast to our previous results with melanoma theraccine alone. CONCLUSION: These data suggest an additive effect of active specific immunotherapy and IFN-alfa on the objective response rate, perhaps through upregulation of HLA molecules and tumor-associated antigens on the tumor cell by IFN-alfa, after immunization of the patient by Melacine. This treatment may have improved survival over that expected in metastatic melanoma.

Adult↗

PubMed1993

Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mechanisms of action.

Since 1985, we have conducted clinical trials with a therapeutic melanoma vaccine (melanoma theraccine). Mechanical lysates of two melanoma cell lines chosen for their complementary characteristics were combined with the adjuvant DETOX and injected subcutaneously on weeks 1, 2, 3, 4, and 6 for one or two courses and then monthly in patients with objective clinical responses. Of 106 patients, 20 had objective clinical regression of tumor masses, 5 with complete responses. The median duration of response was 21 months. Twelve patients lived at least 2 years, with a median survival of nearly 3 years. Two of them are free of disease for > 2 and > 6 years, respectively. However, it was not necessary to achieve complete remissions to cause an increase in survival, and most of the long-surviving patients have one or more (stable) residual nodules. The pace of the disease process was clearly slowed in those individuals. A rise in the level of cytotoxic T-lymphocyte precursors in the blood (pTC) correlated with clinical response. Only those patients who had a rise in pTC had a remission. In addition to "classical" CD8+ Tc, CD4+ Tc were cloned from the blood of immunized patients. Melanoma-specific Tc of both types that killed autologous melanoma but not matched lymphoblastoid cells were detected. Allogeneic melanoma cell lines were also killed, with mainly HLA-A2/28 and HLA-B12/44/45 degenerate restriction. CD4+ Tc were restricted by HLA Class I antigens, as judged by their killing of HLA Class II-negative melanomas and blocking by anti-class I antibodies. Other CD4+ clones were blocked by both anti-HLA Class I or anti-Class II MHC monoclonal antibodies, and only two were blocked only by anti-HLA Class II. Immunohistory revealed CD4+ and CD8+ T cells in lesions under rejection, but the predominant cells were macrophages, suggesting delayed-type hypersensitivity as a possible mechanism. Clinical responses were found most often in patients with HLA-A2/28, -B12/44/45, and -C3, particularly when two or more of those alleles were present. This may have been due either to (1) similarity of MHC antigens between one of the immunizing melanomas and the patient's melanoma or (2) the intrinsic importance of these MHC molecules in presenting melanoma-associated antigens to Tc in vivo. IFN-alpha 2 b salvaged 8 of 18 patients who failed with the theraccine, regardless of MHC phenotype, perhaps through upregulation of MHC and tumor epitopes on the autochthonous tumor.

Antibodies, Neoplasm↗

PubMed1993

Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer.

BACKGROUND: Biochemical modulation of bolus fluorouracil (5-FU) by addition of leucovorin to the treatment regimen has increased response in patients with disseminated colorectal cancer from fewer than 20% to more than 40%. In view of the short half-life of 5-FU and its cell cycle specificity, it may be that infusion rather than intravenous bolus injection would increase efficacy. Furthermore, the advent of safer indwelling intravenous catheters and pump technology, allowing home and ambulatory treatment, has made protracted infusion clinically feasible. To examine these questions, we conducted a phase I trial using protracted infusion of 5-FU by indwelling catheter and pump, with leucovorin given by bolus injection, and reported 40% partial response. PURPOSE: We have now initiated a phase II study of 5-FU given by prolonged continuous infusion with weekly bolus injections of leucovorin in previously untreated patients with measurable, disseminated colorectal cancer. METHODS: Forty-one patients were treated. The regimen consisted of treatment for 4 weeks with 5-FU at a dose of 200 mg/m2 daily as a continuous infusion by indwelling intravenous catheter and pump, followed by a 2-week rest and then by monthly cycles of 3 weeks of treatment and 1-week rest until disease progression. Leucovorin was given as a bolus injection of 20 mg/m2 at the beginning of each week of treatment with 5-FU. RESULTS: Nineteen (46%) of 41 patients had objective response: Three complete responses and 16 partial responses were seen. Overall, the median duration of response was 8 months. The median duration of survival was 16 months: 18 months for responders and 10 months for nonresponders. In general, toxic effects were mild and consisted primarily of stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome). Neither grade 4 toxic effects nor treatment-related deaths were observed. The only serious side effects were catheter thrombosis (three patients) and catheter sepsis (one patient). CONCLUSION: We conclude that this safe regimen is one of the most effective for the treatment of disseminated colorectal cancer. IMPLICATIONS: The regimen should be tested prospectively against other regimens in use for this disease. It is currently included in a phase III study of the Southwest Oncology Group for this purpose. That study will assess quality of life as well as response rates and survival duration.

Adjuvants, Pharmaceutic↗

PubMed1993

Intraperitoneal carboplatin and etoposide for persistent epithelial ovarian cancer: analysis of results by prior sensitivity to platinum-based regimens.

Eighteen women with epithelial ovarian cancer and small-volume disease within the peritoneal cavity at reassessment laparotomy after initial treatment with platinum-based regimens received treatment with a combination of intraperitoneal (ip) carboplatin and etoposide administration. The dose of carboplatin was fixed at 200 mg/m2 whereas the dose of etoposide was escalated in cohorts of 4 patients from 50 to 75 and eventually to 100 mg/m2. Hematologic toxicities appeared to be related to decreased renal function, and, in the last cohort of 10 patients, with prior treatment with systemic carboplatin. Because of this shift in patient population, escalations ceased and ip cisplatin was partly substituted for ip carboplatin in 5 patients. The study opened July 1988 and closed on July 1991: 8 patients are alive, with 4 enjoying progression-free survival and no clinical evidence of disease 1 to 4 years after onset of treatment. One patient is alive with no clinical evidence of disease 3+ years after a late relapse was treated with systemic carboplatin. Three other patients are alive with evidence of disease, having experienced improvements with taxol and ip floxuridine. Analysis of this small experience by pretreatment characteristics suggests that patients who are platinum sensitive and not allowed to relapse, have normal baseline CA-125s, and undergo successful secondary cytoreductive surgery may benefit from platinum-based ip therapy.

Adult↗