Pegylated interferons: Prospects for the use in the adjuvant and palliative therapy of metastatic melanoma

Classic interferon-α formulations have antitumour activity in a variety of neoplastic diseases, including the adjuvant and palliative setting of metastatic melanoma, as single agents or in combination with chemotherapy and/or interleukin-2. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity. Moreover, the favourable pharmacokinetic properties of pegylated interferon allow the administration on a weekly basis, with sustained exposure to interferon during that entire period.Several clinical trials have been conducted testing adjuvant and palliative treatment with pegylated interferon-α in high-risk melanoma patients with promising results. The role of pegylated interferons in the setting of advanced metastatic melanoma will need further investigation in clinical trials, potentially in combination with targeted or cytotoxic agents with regard to synergistic antiangiogenic and cytotoxic effects. The use of pegylated interferons in earlier stage melanomas will be investigated in upcoming trials.     

Dysgerminoma of the ovary: A retrospective study

A retrospective analysis of 22 patients with ovarian dysgerminoma who were treated between 1980 and 1987 was carried out. The median age at presentation was 24.5 years. A total of 15 patients were in stage I, one patient was in stage II and six patients were in stage III. Bilateral ovarian involvement was present in four patients. Conservative surgery was carried out in nine patients and 11 patients underwent radical surgery. Two patients had biopsy only. Fourteen patients received adjuvant radiotherapy and three patients received salvage radiation for recurrent disease. The 10-year actuarial survival rate was 81.8%. All 15 patients in stage I were alive and disease-free at a median follow-up of 125 months. Four patients (one in stage II and three in stage III) died of progressive or recurrent abdominopelvic disease. Pelvic recurrence occurred after conservative surgery in two patients in stage IA who had a tumour size greater than 10 cm, but they were salvaged with radical surgery, chemotherapy and radiotherapy. There were seven patients aged 20 years or less. All were alive and disease-free at a median follow-up of 127 months.     

RENAL TRANSPLANTATION – AN EARLY EXPERIENCE

Renal transplant (RT) is now a therapy of choice for end stage renal disease (ESRD). The Nephrology Unit, Asvini started functioning in Dec 90 and to date 1298 sittings of hemodialysis have been given to 45 patients. Of these, 35 were in ESRD and 11 patients underwent renal transplantation at this hospital during the period Jan 91 – Dec 93. One patient expired after 18 months of transplantation due to infection. Early experience in screening patients for RT, use of immunosuppression, management of rejection episodes and protocol are presented with special emphasis on its relevance to the Armed Forces.KEY WORDS: Transplantation, Renal Failure, Immunosuppression, Rejection     

Cutaneous angiosarcoma of the scalp: a multidisciplinary approach

BACKGROUND: Angiosarcoma is a malignant tumor of vascular endothelial cells that arises in the head and neck. It is a rare, difficult to treat, and lethal tumor. METHODS: Clinical data from patients who were diagnosed with angiosarcoma of the scalp between 1975 and 2002 at the University of Michigan were reviewed. Analysis was performed to assess for factors impacting time to recurrence and survival. RESULTS: The study was comprised of 29 patients with a median age of 71.0 years. Most patients presented after a delay in diagnosis with either a bruise-like macule (48.3%) or a nonbruise-like nodule (51.7%). Seventy-five percent of patients had pathologic Stage T2 disease, and 76% of patients had high-grade tumors. Virtually all patients underwent surgical excision (96.6%); however, negative surgical margins were achieved in only 21.4% of patients. Multiple lesions on presentation were associated with a shorter time to recurrence (P = 0.02). The median actuarial survival was 28.4 months. Younger patients and patients with Stage T1 disease had improved survival (P = 0.024 and P = 0.013, respectively). Radiation therapy was associated significantly with a decreased chance of death (hazard ratio, 0.16; P = 0.006). CONCLUSIONS: Although surgery remains the first option for the treatment of patients with angiosarcoma of the scalp, achieving negative margins often is impossible. Patients who are younger and who have less extensive disease fare better. Postoperative radiation therapy should be employed routinely, as it may lead to improved survival.     

Treatment options for limited or symptomatic metastatic melanoma

BACKGROUND: Patients who develop metastatic melanoma often have limited effective treatment options. However, a select group of patients will benefit from aggressive surgery or a multidisciplinary approach, depending on the site of metastasis. METHODS: The current literature was reviewed and summarized regarding the collective recommendations for staging and treating patients with metastatic melanoma. RESULTS: A thorough preoperative staging includes positron-emission tomography, MRI of the brain, and CT of the chest, abdomen, and pelvis. Tumor biology ultimately determines the success of intervention. A long disease-free interval is a good indicator of potential benefit from resection of metastatic disease. If surgery is performed, no less than a complete resection will affect the overall survival of the patient. Surgery and other multimodality treatment options can be used for symptomatic palliation but will not affect survival. Chemotherapy and radiation are often used to control the symptoms of brain and bony metastases but have limited if any impact on survival. CONCLUSIONS: A select group of patients with metastatic melanoma will benefit from aggressive surgery. Identifying which patients will benefit from treatment requires good clinical judgment and a thorough radiologic evaluation to identify the true extent of disease.     

Inhibitors of catechol-O-methyltransferase sensitize mice to pain

BACKGROUND AND PURPOSE

Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson''s disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice.

EXPERIMENTAL APPROACH

We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone.

KEY RESULTS

After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception.

CONCLUSIONS AND IMPLICATIONS

Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.     

Cytoreductive surgery for melanoma

Cytoreductive surgery represents a therapeutic attempt to improve patient outcomes by reducing overall tumor burden to render postsurgical therapy effective or at least increase its effectiveness. The intent of cytoreduction differs from palliative or curative-intent surgery for oligometastatic melanoma. Both palliative surgery and attempted curative resection have important roles to play in the management of patients with melanoma that has spread beyond the regional nodes or recurred "in transit" between the primary and the regional nodal basin. To date, however, no evidence shows that cytoreductive surgery offers any meaningful benefit to patients with metastatic melanoma, and, outside of a clinical trial, there is no role for cytoreductive surgery in melanoma. To date, adjuvant vaccine therapy after complete resection of metastatic melanoma has not proved to be efficacious in clinical trials, so there is little reason to believe that the use of currently available immunotherapy strategies will be enhanced after incomplete tumor resections.     

Surgical therapy of cutaneous melanoma

For most solid tumors therapy has evolved from surgery alone to a multidisciplinary approach. Malignant melanoma remains an exception, with surgery maintaining the principal role not only for treatment of the primary lesion but also staging and the management of advanced disease. The surgical management of melanoma has evolved over the years, resulting in a substantial decrease in the morbidity associated with treatment without a compromise in outcome. This article will review the changes that have occurred leading to the current surgical approach to melanoma, the evidence behind these recommendations, and new questions that need to be addressed.