Purpose: Patients with primary cutaneous melanoma greater than or equal to 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival.Patients and Methods: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia, Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness greater than or equal to 3 mm.Results: Median follow-vp duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND), The impact of ILP was clearly on the occurrence - as first site of progression - of in transit metastases (ITM), which were reduced from 6.6% to 3,3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%, There was no benefit from lip in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP,Conclusion: prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma, J Clin Oncol 16:2906-2912. (C) 1998 by American Society of Clinical Oncology.

BACKGROUND:The application of bleomycin is characterized by acute side effects, such as fever, chills, and sometimes hypotension and tachypnea. Furthermore, bleomycin is known to induce pneumonitis. There are several indications that the induction of cytokines by bleomycin is involved in the development of these side effects.METHODS:In this study, the authors determined the plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and transforming growth factor-beta (TGF-beta) before and after bleomycin infusion in 14 patients treated for disseminated nonseminomatous germ cell tumor.RESULTS:Compared with the pretreatment value, TNF-alpha was significantly increased 3, 4.5, and 24 hours after bleomycin infusion. For IL-1beta and TGF-beta, no significant alterations were observed within 24 hours after administration of bleomycin.CONCLUSIONS:The increase in TNF-alpha after administration of bleomycin suggests a role for this cytokine in the development of the acute side effects and probably also in the occurrence of bleomycin-induced pulmonary toxicity. The involvement of IL-1beta and TGF-beta deserve further study.

UNLABELLED:In patients with early-stage squamous cell cancer of the vulva, inguinofemoral lymphadenectomy is performed primarily as a diagnostic procedure. The morbidity of this procedure, however, is not negligible. The aim of this study was to evaluate the feasibility of minimally invasive detection of the sentinel inguinofemoral lymph node (SILN) and to investigate whether the histopathology of the SILNs is representative of that of the other non-SILNs.METHODS:Patients with early-stage squamous cell cancer of the vulva, planned for resection of the primary tumor and uni- or bilateral inguinofemoral lymphadenectomy, were eligible for the study. Technetium-99m-labeled nanocolloid was injected intradermally at four locations around the tumor the day before operation. Images were recorded immediately and after 2.5 hr using a gamma camera. SILN locations were marked on the overlying groin skin. The next day, during general anesthesia, blue patent dye was injected intradermally at the same locations around the tumor. During the operation SILNs were identified at the place indicated using a handheld gamma-detection probe. It was noted if SILNs were found by the probe, by blue dye or by both techniques. After resection of the SILNs, a standard inguinofemoral lymphadenectomy was performed. The results of histopathology of the SILNs were compared with those of the non-SILNs.RESULTS:The procedure was well tolerated by 10 of 11 patients. One patient, initially agreeing to participate, refused the injection of tracer because of fear of pain. In all 10 patients, identification of the SILNs was successful. The mean time for identification was 11 min. Identification of SILNs was primarily performed using the hand probe in all patients, whereas in 10 of 18 removed SILNs afferent lymph channels were also blue stained (56%). In 8 patients, pathologic examination showed no metastatic disease in both SILNs and non-SILNs, whereas in 2 patients metastases in the SILNs (one and two metastatic lymph nodes, respectively), as well as in other non-SILNs, were found.CONCLUSION:This study shows that identification of SILNs in squamous cell cancer of the vulva is feasible with preoperatively administered 99mTc-labeled nanocolloid. Intraoperatively administered blue dye was only useful for confirmation of identification with nanocolloid. To date, no false-negative SILNs have been found, but expansion of the study is necessary to determine the possible clinical application of this new diagnostic technique.

Abstract. To obtain insight in the effect of TNF on the synthesis of acute phase proteins like CRP, αl‐antitrypsine, αl‐acidglycoprotein, C3 and C4 and the immunoglobulins (IgG‐M‐A), nine cancer patients who were treated with an isolated limb perfusion (ILP) with high dose recombinant TNF‐α (rTNF‐α) were investigated during a 7–day period after the end of the perfusion. Resorption of rTNF‐α from out of these limbs into the circulation after the ILP induced within 30 min to 6 h in all patients elevated serum levels of IL‐6. At the same time C‐reactive protein became detectable in serum. The highest serum levels were obtained at 48 h after ILP. The serum levels of the other acute phase proteins (α l–acidglycoprotein, αl‐antitrypsine, C3, C4), rose more slowly and the highest serum levels were found at the third day. All investigated proteins declined after they had reached their peak levels. Levels of α1‐‐acidglycoprotein and a,‐anti‐trypsin α1‐‐acid declined slower than both complement component. In regard to the immunoglobulin levels a nearly continuous increase in the serum level of specifically IgM was observed. This study clearly shows the interrelationship between TNF‐α and IL‐6 in regard to the synthesis of the different acute phase proteins; and moreover also a striking effect on IgM synthesis.

Liénard, D.; Eggermont, A. M. M.; Koops, H. Schraffordt; Lejeune, F. J. Author Information

The ploidy of carcinoma in situ and invasive germ cell tumors of the adult testis was compared by DNA flow cytometry. Irrespective of the tumor type with which it was associated, the median DNA index of carcinoma in situ was about the same as that of seminomas and higher than the DNA index of invasive nonseminomatous germ cell tumors. These data indicate that seminoma and carcinoma in situ cells are not only phenotypically similar but also have the same ploidy.

The case history is reported of a patient with an invasion of the inferior vena cava by metastases of a non-seminomatous testicular tumour. He was treated with combination chemotherapy, followed by laparotomy and resection of residual tumour tissue. Fourteen months after this operation he is in good health. For every retroperitoneal lymph node dissection it is necessary to be on the look-out for invasion of the vena cava, because of the risk of a sudden pulmonary embolism.

Carcinoma in situ (CIS) of the testis is the precursor lesion of most testicular germ cell tumors (TGCTs). Karyotyping of CIS is important for a better understanding of the pathogenesis of TGCTs and the progression to invasive cancer. We karyotyped three cases of CIS. All three cases showed a numerical abnormal chromosomal pattern. In one case, two copies of the germ cell tumor marker i(12p) were found.

To achieve adequate tissue perfusion during hyperthermic regional perfusion, perfusion pressures should be maintained at near normal mean systemic arterial pressures. During experimental as well as during clinical perfusions however, unphysiologically high perfusion flows were needed to keep the perfusion pressure at the desired level. Since both high perfusion flows and high perfusion pressures have been associated with the post-operative complications such as severe edema and tissue damage, as well as with an increased leakage of perfusate to the systemic circulation, low perfusion flows have been used in regional perfusion. High perfusion flows in our previous experimental studies were attributable to a marked reduction in vascular resistance. This decrease is believed to be caused by the release of vasodilatory constituents of damaged blood cells, and it is the extra-corporeal circuit, and in particular the bubble-oxygenator that is thought to be responsible. The superior haemocompatibility of membrane-oxygenators over bubble-oxygenators has been established in cardio-pulmonary bypass. We compared the use of a membrane-oxygenator with that of a bubble-oxygenator in regional perfusion to see if more normal haemodynamics could be maintained and vasodilatation prevented. In the experimental as well as in the clinical perfusions the use of a bubble-oxygenator required unphysiologically high perfusion flows to maintain the perfusion pressure at the level required to obtain an adequate microcirculation. In contrast the use of a membrane-oxygenator permitted a nearly physiological perfusion flow to maintain an adequate perfusion pressure as well as an adequate micro-circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

This 10-year follow-up study of 91 patients with disseminated testicular nonseminomatous cancer, treated with cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy and vinblastine plus bleomycin maintenance chemotherapy for a planned period of 2 years, shows a 63% cure rate. The predominant long-term sequelae are neurological and sexual dysfunction in 68% and 40% of patients, respectively. Two patients died of myocardial infarction. Sixteen percent of patients developed hypertension, 23% Raynaud's phenomenon, and 25% ototoxicity. Despite the long-term side effects, 90% of the patients who responded to a questionnaire are fully employed. This study shows that the maintenance chemotherapy has contributed to the incidence and/or degree of neurotoxicity, hypertension, and renal function disturbance.

A cytogenetic analysis of 13 mature residual teratomas following chemotherapy revealed modal chromosome numbers ranging from 52 to 85, in agreement with the flow cytometric determination of the DNA content of the tumors. At least one copy of an i(12p) was present in 12 tumors. One tumor, however, lacked that marker. The comparison between the chromosomal abnormalities found in mature residual teratomas following chemotherapy and those from primary testicular nonseminomas suggests that residual teratomas result from selection of clones from the primary tumor with a less abnormal karyotype.

The ploidy of testicular germ cell tumors (GCT), a heterogeneous group of neoplasms, was studied by DNA flow cytometry. The DNA index for infantile yolk sac tumor (N = 10), seminomas (N = 20), and nonseminomas (N = 36), was: 1.91, 1.66, and 1.43, respectively. These values differed significantly one from another (p less than 0.01). The seminoma and nonseminoma components of combined tumors (N = 16) had a significantly different median DNA index of 1.61 and 1.40, respectively. Three of the 10 infantile yolk sac tumors, but only one of the 72 testicular GCT of adults were diploid. The consistent aneuploidy of testicular GCTs of adults might be helpful in the differential diagnosis of primary nongerm cell tumors of the testis, and in differentiating between metastases of testicular GCTs and primary extragonadal malignant GCTs. These data fit into a model of pathogenesis of testicular GCTs of adults in which all tumors, with the possible exception of spermatocytic seminoma, pass through a seminoma stage. Tumor evolution seems to result from net loss of chromosomes from a (near)tetraploid carcinoma in situ cell. The pathogenesis of infantile yolk sac tumor might be different from that of testicular GCTs of adults.

A cytogenetic analysis of ten seminomas has been carried out after direct harvesting of the tumor cells. Modal chromosome numbers ranged from 63 to 112. These numbers were in agreement with flow cytometric determination of the DNA content of the tumors. Eight tumors had at least one copy of an i(12p) among other chromosomal abnormalities. Two seminomas lacked the i(12p).