Summary An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% (95% confidence intervals, 74%-88%). No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol.The conventional management of stage I seminoma of the testis is by adjuvant retroperitoneal node irradiation. This policy is highly successful, recurrence occuring in less than 5% of patients (Hamilton et al., 1986;Zagars, 1991). Surveillance following orchidectomy was introduced as an alternative with the rationale that a substantial proportion of patients with stage I seminoma would not need further treatment and could thus avoid the side-effects of radiotherapy. This supposition was based partly on a series of retroperitoneal lymph node dissection in stage I seminoma, which revealed microscopic nodal involvement in only 8% of patients (Maier et al., 1968), and partly on the success of a surveillance policy in stage I non-seminomatous tumours of the testis (Freedman et al., 1987;Horwich & Peckham, 1988;Cullen, 1991). Preliminary results of surveillance for stage I seminomas have been reported (Thomas et al., 1989;Duchesne et al., 1990) and it has become apparent that the policy presents some clinical difficulties, such as for example, the relatively indolent natural history of seminoma leading to a requirement for prolonged surveillance. A second problem is the lack of a sensitive serum marker for seminoma (in contrast to non-seminoma) making it difficult to monitor patients sufficiently closely to detect small volume relapse.In (median 36 years). They have been followed for a median of 5 years and 2 months from orchidectomy (range 14 months to 141 months).Initial staging investigations prior to registering the patient for surveillance always included thorough physical examination, assay of serum concentrations of the beta sub-unit of human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP), CT scan of thorax abdomen and pelvis, lymphogram and chest X-ray. The histopathology had always been reviewed in the Department of Histopathology of The Ro...

No abstract

Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8 þ and CD4 þ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.

No abstract

Human cytochrome P450 3A4is recognized as the catalyst for the oxygen-dependent metaboism of a diverse group of medicafly important chemicals, inWuding the immunosuppressive agent cyclosporin; macrolide antibiotics, such as erythromycin; drugs such as benzphetamine, nifedipine, and cocaine; and steroids, such as cortisol and testosterone to name but a few. We have engineered the cDNA for human cytochrome P450 3A4 by linkage to the cDNA for the rat or human flavoprotein, NADPH-P450 reductase (NADPH:ferrihemoprotein oxidoreductase, EC 1.6.2.4). An enzymaticafly active fusion protein (rF450[mHum3A4/mRatOR]Ll) has been expressed at high levels in Escherichia coli and purified to homogeneity.Enzymatic studies show a requirement for lipid, detergent, and cytochrome bs for the 63-hydroxylation of steroids and the N-oxidation of nifedipine. In contrast, these additions are not required for the N-demethylation of erythromycin or benzphetamine. A spectrophotometricafly detectable metabolite complex of P450 3A4 is formed during the metabolism of triacetyloleandomycin, and this has a pronounced inhibitory effect on the metabolim of both testosterone and erthromycin. These resuits relate to the interpretation of current methods used to assess the in vivo activity of P450 3A4.One ofthe most versatile ofthe cytochrome P450s is the form present in human liver called CYP3A4, which catalyzes the oxidative metabolism of a wide array of different chemicals with markedly different structural characteristics (1). Interest has centered on this P450 since it is reported to be one of the more abundant P450s in human liver (2); it is inducible by a variety of agents including glucocorticoids as well as phenobarbital (3); it appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin (4); it also catalyzes the 63-hydroxylation of a number of steroids including testosterone, progesterone, and cortisol (5). Clinical interest relates to the measurement of erythromycin metabolism by a breath test (6) and the presence of6f-hydroxylated steroids in urine (7) as indicators of CYP3A4 function for evaluation of transplant recipients.P450s ofthe 3A family were first characterized by Guzelian and colleagues (8) based on the ability ofthe catabolic steroid pregnenolone-16a-carbonitrile to induce a unique form of P450 (which they called P-450p). They also recognized the ability of the macrolide antibiotic triacetyloleandomycin (TAO) to serve as a powerful inducer of this type of P450-a result of interest because of the known ability of TAO and other compounds to form stable, metabolite-inhibitor complexes with P450 (9). Reconstitution studies using purified P450s of the 3A family have shown the need to include phospholipids, detergents, and cytochrome b5 when testing enzymatic activities (10, 11).