Lymph node-positive prostate cancer: evaluation of the results of the combination of androgen deprivation therapy and radiation therapy.

OBJECTIVE: To evaluate the outcome of patients with pathologic stage IV prostate cancer treated with androgen ablation plus external-beam radiation therapy. PATIENTS AND METHODS: Sixty consecutive patients treated between August 1986 and February 1995 with androgen ablation plus radiation therapy for stage IV (T1-4 N1 M0) adenocarcinoma of the prostate were selected for outcome analysis in this retrospective study. Bilateral pelvic lymphadenectomy was performed in 56 patients (93%). The 4 remaining patients had pelvic adenopathy on computed tomography, which was confirmed histologically in all patients. The median pretreatment prostate-specific antigen (PSA) level was 28.8 ng/mL (mean, 55 ng/ mL; range, 0.1-428 ng/mL). All patients received radiation therapy to the prostate, and 29 (48%) had pelvic node radiation. Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology criteria of 3 successive increases in the PSA level. RESULTS: The median follow-up duration for surviving patients was 101.1 months (range, 20-134 months). Biochemical failure with (in 2 patients) or without (in 10 patients) clinically evident disease relapse was noted in 12 patients (20%). Four additional patients (7%) had clinical relapse without biochemical failure. Local recurrences were observed in 6 patients (10%), and this clinical impression was confirmed by biopsy in 4 patients. Thirteen patients (22%) died of causes related to prostate cancer. The biochemical relapse-free, clinical disease-free, overall, and cause-specific survival rates at 5 years were 82%, 84%, 76%, and 80%, respectively. CONCLUSIONS: This observational case series of patients treated with the combination of external-beam radiation therapy and permanent androgen ablation for pathologic stage IV prostate cancer suggests that the addition of androgen deprivation therapy to radiation therapy may improve disease outcome. In the absence of randomized trial results, these observations may be beneficial in clinical decision making.

Prevention and early detection of malignant melanoma.

In addressing the problem of malignant melanoma, family physicians should emphasize primary prevention. This includes educating patients about the importance of avoiding excessive sun exposure and preventing sunburns, and advising them about the importance of prompt self-referral for changing nevi. Family physicians should be able to perform an overall risk assessment for melanoma, particularly to identify persons with familial atypical mole syndrome. Patients with such high risk should be strongly considered for referral for dermatologic surveillance. Because there are no systematic studies in primary care populations, there are no data on which to base recommendations for periodic screening in this setting. However, when performing any part of the physical examination, family physicians should be alert for suspicious nevi. Nevi detected by the family physician or pointed out by the patient should be subject to excisional biopsy with accepted techniques or be referred for such a procedure.

Barrett's esophagus, apoptosis and cell cycle regulation: correlation of p53 with Bax, Bcl-2 and p21 protein expression.

Dysregulation of apoptosis plays an important role in tumor development. Mutations of the p53 gene have been reported in adenocarcinomas arising from Barrett's metaplasia. The p53 gene is important in the regulation of cell growth and apoptosis, with the loss of wild-type activity associated with uncontrolled cell-cycle progression and tumor formation. P21 is a cyclin-dependent kinase inhibitor that is activated by p53. Bax is a member of the bcl-2 family whose function is that of cell-death promoter. We investigated the hypothesis that there are significant alterations in the levels of apoptotic protein as well as p21 protein expression in the neoplastic progression associated with Barrett's metaplasia.

Seprafilm-induced peritoneal inflammation: a previously unknown complication. Report of a case.

INTRODUCTION: Various substances and agents have been evaluated to prevent postoperative adhesion formation. Recently a sodium hyaluronate-based bioresorbable membrane was introduced with promising clinical results. Its application was regarded as safe and efficient. METHODS: We present the first reported case of a severe inflammatory reaction to a bioresorbable membrane and give a review of the related literature. CONCLUSION: Bioresorbable membranes are increasingly used by general surgeons and gynecologists to reduce postoperative adhesion formation. Bioresorbable membranes may produce extensive inflammatory reactions.

Progression-related expression of beta3 integrin in melanomas and nevi.

The expression of the beta3 integrin subunit was investigated in 130 fixed, paraffin-embedded specimens of human melanomas and nevi using two different monoclonal antibodies. Expression was not observed in melanocytes and was absent or low in most nevi. In primary melanomas, expression was absent or low in the nontumorigenic radial growth phase, which includes the classes of in situ and microinvasive melanomas. In contrast, expression was high in the tumorigenic or vertical growth phase compartment of many primary melanomas and in most metastatic melanomas. Expression patterns were similar with the two antibodies, SSA6 and SAP, and was membrane-related as well as cytoplasmically expressed. In those nevi that reacted focally, the reactivity tended to occur in the dermal component of neurotized nevi, and in Spitz nevi, where the reactivity was stronger and more diffuse. A few dysplastic nevi showed focal reactivity of the junctional component. These results are consistent with tumor progression-related expression of the beta3 integrin, which is expressed in melanocytic tumors as the alphavbeta3 integrin, having affinity for matrix molecules, including vitronectin and fibronectin. In all melanomas, and in the subset of tumorigenic vertical growth phase melanomas, expression increased with thickness (P < .01). For this reason, and because ligation of this integrin has been shown in vitro to have several properties that may be related to the malignant phenotype, it is likely that expression of this marker may have prognostic value. However, because of its consistent and strong expression in Spitz nevi, the diagnostic utility of this marker will likely be limited.

The role of screening in the management of skin cancer.

The incidence of skin cancer has been rising at an alarming rate for the past several years. This poses a significant public health problem in the United States. Detection and treatment of melanoma early in its course is critical for improved outcome. Of the approaches to cancer control that can reduce mortality from melanoma and nonmelanoma skin cancer, screening holds the greatest promise for a rapid and major impact. Prevention and early detection are crucial in reducing morbidity and mortality from skin cancer. For a number of reasons, however, the full effect of screening for both melanoma and nonmelanoma skin cancers has not been achieved. Controversy exists regarding who should perform screening, who should be screened, and whether screening should be performed at all. It is clear that melanoma and nonmelanoma skin cancer control programs combining primary prevention, education, and screening are in developmental stages. This review will discuss the advantages and disadvantages of screening for skin cancer.

Colonic strictures induced by nonsteroidal anti-inflammatory drugs.

Long-term use of nonsteroidal anti-inflammatory drugs has been reported to cause small bowel and colonic ulcerations and strictures. Abdominal pain, change in bowel habits, and anemia are frequently present, mimicking other inflammatory and neoplastic diseases of the gut. We report two cases of drug-induced colonic stricture that illustrate two different spectrums of this disease. The first is a case of ascending colon ulcerated strictures and severe anemia managed conservatively, and the second is a chronic variant with obstructive-type symptoms and a tight nonulcerated colonic stricture that necessitated right hemicolectomy.

Overexpression of p53 protein in cutaneous T cell lymphoma: relationship to large cell transformation and disease progression.

The molecular mechanisms by which advanced cases of cutaneous T cell lymphoma (CTCL) (mycosis fungoides/Sezary syndrome) undergo large cell transformation (LCT) and develop the morphologic appearance of a large cell lymphoma, are undefined. We used immunohistochemical analysis and polymerase chain reaction/single strand conformational polymorphism to examine whether p53 mutations are associated with disease progression and LCT in CTCL. p53 protein immunohistochemistry was performed on 37 paraffin embedded biopsies from 27 patients with CTCL; LCT was present in 15 biopsies. Overexpression of p53 protein was found in 11 of 37 CTCL biopsies including 10 of 15 biopsies (67%) with LCT in which p53 staining was predominantly seen in large transformed cells. In contrast, p53 immunostaining was found in only one of 22 CTCL biopsies without LCT (p < 0.0004). Serial biopsies revealed acquisition of p53 expression following LCT in two patients in whom initial diagnostic biopsies without LCT were p53 negative by immunostaining. All p53 protein positive biopsies were from advanced lesions (cutaneous tumors or extracutaneous sites); none of 12 patch/plaque stage CTCL biopsies demonstrated p53 staining. Polymerase chain reaction/single strand conformational polymorphism and sequencing analysis of p53 exons 4-8 was performed in 11 cases where frozen tissue was available. No mutations were detected in six cases positive for p53 protein expression. These results suggest overexpression of p53 protein in LCT and disease progression of CTCL by a mechanism other than p53 gene mutation, in most cases.

Cutaneous necrosis associated with recombinant interferon injection. Report of three cases with interferon beta-1b and review of the literature.

Interferons are cytokines produced by cells in response to stimulation by certain antigens and infectious agents. In recent years, recombinant interferons have been developed, which have antiviral, antiproliferative, and immunomodulatory functions. Several cutaneous reactions have been reported, including cutaneous ulceration at injection sites. We now report three cases of cutaneous ulceration caused by interferon beta-1b injections. In addition, we review all of the previously reported cases of cutaneous ulceration caused by recombinant interferons and discuss the different mechanisms by which these substances may produce this effect.

Pathogenesis of cutaneous T-cell lymphoma: implications for the use of recombinant cytokines and photopheresis.

Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin invasive malignancy of CD4+ cells with the phenotype of mature helper T cells. We previously demonstrated that the leukaemic form of CTCL (Sézary), is characterized by prominent immunological defects including depressed cell-mediated immunity. We also demonstrated increased production of T-helper type 2 (Th2) cytokines (IL-4, IL-5) and deficient Th1 cytokines (IL-2 and IFN-gamma) by their peripheral blood mononuclear cells (PBMC) and detected IL-4 and IL-5 mRNA within lesional skin of patients with all stages of CTCL. A marked defect in IL-12 production has also been noted, which may also play a role in depressed cell-mediated immunity. These results suggested that the malignant CD4+ cells were Th2 cells. Thus, the immune aberrations have been attributed to the cytokine abnormalities triggered by the malignant T-cell population. Because CTCL responds to biological response modification, we focused on strategies for reversing the cytokine and immune defects by in vitro testing of novel biological response modifiers. Our results indicate that IFN-alpha potently suppresses the abnormal IL-4 and IL-5 production, that IL-12 can correct the deficient IFN-gamma production and cell-mediated cytotoxicity, and that retinoids can enhance IFN-gamma and IL-12 production. We also studied the in vitro growth characteristics of the malignant CD4+ cells and determined that IL-12 and IFN-alpha significantly suppress growth of these cells. These studies led to a phase I trial of IL-12 to treat CTCL. Also, we have determined that photopheresis produces a high clinical response rate among Sézary syndrome patients. This therapy not only augments functions of monocytes but also induces the malignant T cells to undergo a high rate of apoptosis. We discuss how these therapies might be employed in concert to produce the optimum desired anti-tumour effect.

Diagnosis of right atrial metastatic melanoma by transesophageal echocardiographic-guided transvenous biopsy.

Traditionally, tissue diagnosis of malignant melanoma metastatic to the heart necessitated thoracotomy or was done at autopsy. More recently, right or left ventricular endomyocardial biopsy under fluoroscopic guidance has been used to confirm metastatic involvement of the heart by various neoplasms including malignant melanoma; results have been excellent, and morbidity has been low. High-quality images of intracardiac masses with excellent anatomic details can be obtained by transesophageal echocardiography. Herein we describe a 73-year-old man with a history of malignant melanoma in whom cardiac metastatic involvement was documented by percutaneous transesophageal echocardiographic-guided transvenous biopsy of a right atrial mass; thus, the need for a more invasive approach to tissue documentation was avoided.

Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a single institution.

BACKGROUND: Extracorporeal photopheresis is a pheresis-based therapy that permits the direct targeting of psoralen-mediated photochemotherapy to circulating pathogenic T cells. Although photopheresis is currently used to treat cutaneous T-cell lymphoma (CTCL), limited data are available regarding overall response rates and durability of responses among patients with advanced disease. Furthermore, little is known about the effectiveness and tolerability of combined regimens employing other biologic response modifiers including interferon alfa. OBJECTIVE: Our purpose was to determine the efficacy of photopheresis among 41 patients with the clinical and laboratory diagnosis of CTCL; the majority of patients had stage III or IV disease with the presence of circulating malignant T cells. METHODS: A retrospective chart review during a 10-year period at a single university hospital was performed for all patients receiving either photopheresis monotherapy on two consecutive days every 4 weeks (one cycle) and for an additional 12 patients who also received interferon alfa 1.5 to 5 million U subcutaneously three to five times weekly. RESULTS: Thirty-one of 41 patients (76%) were treated for six or more cycles. The remaining 10 were treated with less than six cycles because of rapidly progressing disease (n = 6), death unrelated to CTCL (n = 2), or withdrawal from treatment (n = 1); one of the 10 patients had only received five cycles of treatment but is still receiving therapy. Twenty-eight of the 31 patients treated for six or more cycles received photopheresis alone. Among the 28, seven patients (25%) had a complete remission, 13 (46%) had a partial remission defined as more than 50% clearing of skin disease, and eight (29%) did not respond to treatment. The presence of Sézary cells in the peripheral blood was associated with a favorable response. Median time to treatment failure was 18 months, whereas median survival from initiation of therapy was 77 months and from the time of diagnosis exceeded 100 months. Nine of these 28 patients went on to receive combination therapy with interferon alfa and, in some cases, other agents. Among these nine patients, five had an enhanced clinical response to the combination therapy compared with treatment with photopheresis monotherapy. The combined regimen was well tolerated. CONCLUSION: These results indicate that patients with advanced CTCL can achieve a high response rate for an extended period with photopheresis and that interferon alfa combined with photopheresis is a well-tolerated regimen that appears to produce higher response rates than photopheresis alone.

Post-irradiation malignant mesothelioma.

BACKGROUND: Approximately 30 patients with malignant mesothelioma following radiotherapy have been described. Population-based studies of this occurrence have not been reported. METHODS: Patients with malignant mesothelioma of the pleura were collected. All of the patients had a prior cancer and had received radiotherapy to the region in which the malignant mesothelioma developed. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program and the Connecticut Tumor Registry were evaluated for cases of malignant mesothelioma of the pleura occurring in patients with a previous cancer. The literature on post-irradiation malignant mesotheliomas was reviewed. RESULTS: Eight patients (4 men, 4 women) with malignant mesothelioma occurring in sites of radiotherapy for a prior tumor were identified. The mean age at diagnosis of mesothelioma was 45 years (range: 22-78 years), and the average interval between radiotherapy and the mesothelioma was 21 years (range: 11-29 years). Three of the patients had also received chemotherapy. Histologically, the mesotheliomas were epithelial in five cases, biphasic in one, and sarcomatous in one. One hundred forty-two patients were identified in the epidemiologic survey. The majority were men (89%), with a mean age for all patients of 68.5 years (range: 35-86 years) and a median latency between first cancer and mesothelioma of 4.3 years (range: 2 months-29.9 years). CONCLUSIONS: Mesotheliomas rarely develop as second malignant neoplasms. Within a large, population-based survey of patients with cancer, temporal patterns and demographic features of most second primary mesotheliomas were similar to asbestos-related tumors, although the late effects of cancer treatment might have contributed to the occurrence of cancer in some patients.

Eosinophilic gastroenteritis presenting as a giant gastric ulcer.

We describe a 43-yr-old female with a giant gastric ulcer, refractory to medical treatment, that ultimately proved to be due to the mural form of eosinophilic gastroenteritis. The patient presented with a 6-month history of abdominal pain, diarrhea, and weight loss. Endoscopy showed a giant gastric ulcer, and biopsies revealed only chronic active ulcerative inflammation. The ulcer progressed on omeprazole therapy; therefore, a distal antrectomy with gastrojejunal anastomosis and bilateral vagotomy was performed. Pathology of the surgical specimen demonstrated the mural form of eosinophilic gastritis. To the best of our knowledge, this case is the first to demonstrate that refractory giant gastric ulcers may be a manifestation of the mural form of eosinophilic gastroenteritis.

Evaluation of serum prostate-specific antigen levels after postoperative radiation therapy for pathologic stage T3, N0 prostate cancer.

OBJECTIVE: To analyze freedom from progression of serum prostate-specific antigen (PSA) levels in patients who have received radiation therapy after radical prostatectomy for pathologic stage T3, N0 prostate cancer. DESIGN: We assessed the freedom from PSA progression after postoperative radiation therapy and its relationship to several potential prognostic factors during a median follow- up of 43 months. MATERIAL AND METHODS: Thirty Mayo patients received postoperative radiation therapy for pathologic stage T3, N0 prostate cancer between January 1988 and April 1993. Radiation therapy was initiated within 6 months after prostatectomy. Radiation doses ranged from 60 to 67 Gy. RESULTS: "Freedom from PSA failure" was defined as the actuarial risk of maintaining a serum PSA level at 0.3 ng/mL or less. The freedom from failure rate was 66% at 3 and 4 years. Prognostic factors significantly associated with an improved freedom from failure were a pre-radiation PSA level of 1.0 ng/mL or less and no seminal vesicle involvement. A trend toward an improved freedom from failure was noted in patients with low-grade (1 and 2) tumors in comparison with high-grade (3 and 4) tumors. Treatment-related morbidity was minimal. CONCLUSION: Radiation therapy after radical prostatectomy for pathologic stage T3, N0 prostate cancer seems to provide an improved freedom from PSA failure in comparison with that noted in other series of similar patients treated with radical prostatectomy only.

Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation and review of the literature.

There is a clear need for well-tolerated immunomodulatory agents that can aid in the prevention of acute solid organ rejection. Extracorporeal photopherosis is an apheresis-based therapy that is currently available at many medical centers worldwide. Preliminary studies utilizing photopheresis with standard immunosuppressives have shown this therapy to successfully reverse acute cellular rejection of cardiac allografts with minimal toxicity. No formal evaluation of the role of extracorporeal photopheresis had been performed in renal transplantation. In this report, photopheresis was successfully utilized to treat acute cellular rejection in a patient with a renal allograft. This lends further support to the existing literature suggesting that photopheresis may be useful for the reversal of acute solid organ rejection. Although our experience with this patient is anecdotal, photopheresis merits further study as treatment for severe renal allograft rejection.