Clinical significance of macroscopic completeness of mesorectal resection in rectal cancer.

AIM: Local recurrence after resection of rectal cancer is usually regarded as being due to a 'failure' of surgery. The completeness of resection of the mesorectum has been proposed as an indicator of the 'quality' of the resection. We determined the prognostic value of macroscopic evaluation of rectal cancer resection specimens and the circumferential resection margin (CRM) after curative surgery. METHOD: From 1999 to 2006, the macroscopic quality of the mesorectum and the CRM were prospectively assessed in 127 patients who underwent rectal cancer resection with curative intent (R0+R1). Chemoradiotherapy was administered for 61 tumours staged as locally advanced tumours (T3, T4 and N+). Univariate analysis of time to local recurrence and cancer-free survival were tested (Kaplan-Meier) and multivariate analysis calculated with a Cox regression model. RESULTS: The mesorectum was incomplete in 34 (26.8%) patients. At a median follow up of 34 months (range, 9-96 months), in the group with an adequate mesorectal excision, the cumulative risk of local recurrence at 5 years was 10%. This was 25% if the mesorectum was incomplete (P < 0.01). Five-year cancer-free survival was 65% if the mesorectal excision was adequate and 47% if it was not (P < 0.05). Multivariate analysis identified T status, the CRM and the mesorectal score as independent factors for local recurrence, and T and N status and the mesorectal score as independent factors for disease-free survival. CONCLUSION: The outcome of surgical treatment of rectal cancer is related to the completeness of mesorectal excision. It is a more discriminative prognostic factor than the classic tumour-node-metastasis (TNM) system.

Cholestasis induced by chronic treatment with alpha-naphthyl-isothiocyanate (ANIT) affects rat renal mitochondrial bioenergetics.

Chronic cholestasis is characteristic of many human liver diseases. Renal injury has been often associated with this type of disease. The aim of this study was to evaluate the effect of cholestasis on kidney mitochondrial bioenergetics following in vivo chronic administration of alpha-naphthyl-isothiocyanate (ANIT), a known cholestatic agent. Serum markers of renal injury, kidney morphology and endogenous adenine nucleotides were measured in ANIT-treated rats (80 mg/kg per week s.c. for 16 weeks). Changes in membrane potential and mitochondrial respiration as well as alterations in mitochondrial calcium homeostasis were monitored. Cholestatic animals shown no alterations in renal morphology when compared with control. Additionally, following chronic ANIT administration, no significant alterations in mitochondrial respiratory function have been shown. The phosphorylation capacity of cholestatic kidney mitochondria was enhanced. Associated with these parameters, mitochondria from treated animals exhibited a decreased susceptibility to disruption of mitochondrial calcium homeostasis, due to permeability transition induction. These data suggest that, despite being submitted to chronic treatment with ANIT, kidney mitochondria from cholestasis-induced rats present some defense mechanisms to circumvent this aggression. They show improved phosphorylative capacity and, moreover, a decreased susceptibility to mitochondrial permeability transition induction, probably due to adaptative mechanisms of calcium transport.

Trichilemmal carcinoma: review of 8 cases.

Clinical and histological data from 8 trichilemmal carcinomas are reviewed. The tumors occurred mainly on sun-exposed skin of the face of elderly people as small solitary, frequently ulcerated nodules. Histologically, they consisted of multilobulate, infiltrative growths, connected to the epidermis and pilosebaceous structures and showing features reminiscent of the outer root sheath of the hair follicle. The presence of lobules of clear, glycogen-rich cells with peripheral palisading, hyaline basement membranes, trichilemmal keratinization, and abortive follicular sheaths and the absence of ductal or acinar differentiation allow distinction from other clear cell tumors of the skin. Although the histological picture suggests a high-grade malignant neoplasm, trichilemmal carcinoma has an indolent course. No recurrence or metastases have been observed.

[Eccrine porocarcinoma. A review of 24 cases]. / Porocarcinome eccrine. Revue de 24 cas.

From 1982 to 1992, 24 cases of eccrine porocarcinomas were recorded in our files. They always present as solitary well circumscribed nodules or plaques of 0.5 to 2 cm and they are mainly located on the face and the lower limbs in patients, predominantly females, aged of more than 5 decades. The average evolution time before diagnosis was 2 years; a case was observed in a 12-y-old patient with xeroderma pigmentosum. After surgical removal, only one local recurrence and one case with lymph node metastases were observed. The lesions showed two different histological types: the former is initially characterized by the intra-epidermal spreading of well circumscribed cell nests and by a secondary invasion of the dermis, the latter exhibits a trabecular pattern penetrating the dermis, sharing some microscopic aspects with the benign eccrine poroma. Whatever the histological type, the tumor is mainly built up by small cuboidal cells together with some large clear cells; the latter exhibit often atypias, which are focally distributed in the trabecular poroma-like variant. Dyskeratosis, malpighian metaplasia and necrotic comedo-like foci are frequently encountered. Ductal differentiation may be intracellular and occur together with focal keratinization. In one case with intra-epidermal cell islets, lymph node metastases showed the same cellular pattern; this superficial spreading type of porocarcinoma has the same malignant behaviour as the trabecular penetrating type. The eccrine porocarcinomas derive from the acrosyringeal cells: the ductal structures and the foci of keratinization express the epithelial membrane antigen (EMA), the carcino-embryonic antigen (CEA) and the alpha-lactalbumine related antigen; the tumor cells are S100 proteine negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas.

BACKGROUND: Treatment of cancer with multiple-drug chemotherapy regimens or radiation therapy can cause either temporary azoospermia of various durations or permanent azoospermia in young men. METHODS: To identify which drugs in which doses contribute to long-term or permanent azoospermia, semen analyses were done on patients with Ewing and soft tissue sarcomas before, during, and after treatment with either CYADIC (cyclophosphamide, doxorubicin, and dacarbazine), or CYVADIC (vincristine added to CYADIC). Some patients also received other drugs or radiation therapy. RESULTS: From pretreatment levels that were similar to those of control subjects, sperm production declined to azoospermia within 4 months of treatment. Sperm production returned in some patients after treatment; 40% of men recovered to normospermic levels by 5 years after treatment. Few patients showed continued recovery of sperm production after that time. The cumulative dose of cyclophosphamide was the most significant determinant of recovery to normospermic levels; approximately 70% of those who had received doses less than 7.5 g/m2 (median, 4.1 g/m2) recovered, but only 10% recovered when doses exceeded 7.5 g/m2. CONCLUSIONS: Thus, a risk of permanent sterility is associated with the use of the CYADIC and CYVADIC regimens in young men, especially when the cumulative dose of cyclophosphamide is greater than 7.5 mg/m2.

Infeccao do parceiro sexual pelo papilomavirus humano / Partner infection by human papillomavirus

Foram examinados 60 parceiros sexuais, de mulheres diagnosticadas como portadoras de infeccao genital pelo papilomavirus, sob protocolo de investigacao. O objetivo era identificar colposcopicamente, lesoes acetobrancas na genitalia externa masculina, biopsia-las e estuda-las histopatologicamente. Predominava como sinal patognomonico, a coilocitose celular. A biopsia foi positiva em 77,1 por cento e negativa em 22,9 por cento. Os resultados da pesquisa fecham a hipotese de que o parceiro sexual masculino e, de fato, um elemento de risco, agindo como transmissor de infeccao genital pelo papilomavirus humano.

Recovery of sperm production after chemotherapy for osteosarcoma.

Because treatment with surgery and combination chemotherapy produces a high cure rate in young men with osteosarcoma, their subsequent reproductive function is an important concern. Semen analyses of osteosarcoma patients, therefore, were performed before, during, and after treatment with the PADIC regimen consisting of cisplatin, Adriamycin (doxorubicin), and dacarbazine or, in some cases, the PADIC regimen plus additional drugs. Results showed that semen volume was not affected and that sperm motility was reduced only during treatment. Although nearly all patients were rendered azoospermic during treatment, sperm production resumed in 30 of 32 patients examined at least 2 years after treatment. Analysis with correction for censored data indicates that, in 78% of treated men, sperm counts will return to more than 10 million/ml. The percentage of men whose sperm counts recovered to normal was lower for those receiving cisplatin dosages greater than or equal to 600 mg/m2; no trends were observed with Adriamycin and dacarbazine dosages. The inclusion of additional drugs such as methotrexate, bleomycin, dactinomycin, or cyclophosphamide (less than 4 g/m2) did not significantly affect the recovery of spermatogenesis. We conclude that the risk of long-term infertility from treatment with the PADIC regimen is low.

Absence of testicular protection by a gonadotropin-releasing hormone analogue against cyclophosphamide-induced testicular cytotoxicity in the mouse.

Protection of testicular integrity against damage from cyclophosphamide (CY) by simultaneous treatment with a gonadotropin-releasing hormone (GnRH) analogue was reported in BALB/c mice (L.M. Glode et al., Lancet, 1: 1132-1134, 1981). This approach has been used as the basis for clinical trials in various treatment centers (D. H. Johnson et al., Blood, 65:832-836, 1985) in an attempt to prevent iatrogenic sterility in males. This study aims at duplicating the original findings and obtaining quantitative data on spermatogonial killing by CY, and possible protection by GnRH, of differentiating and stem cell spermatogonia. Mice were treated with 23 daily injections of 0.4 micrograms D-leucine-6 GnRH, and with 200 mg/kg CY on Days 8, 15, and 22. Three additional groups of mice received phosphate-buffered saline and bovine serum albumin only, GnRH only, and CY only. Animals were killed at 29 days after the last injection to determine the number of late spermatids in testicular homogenates, and at 56 days for histological measurement of the ratio of elongated spermatids to Sertoli cells in the tubules. The twenty-ninth day assay was a measure of damage to differentiating spermatogonia, whose killing results in temporary sterility. The fifty-sixth day point assay assessed damage to stem spermatogonia, whose killing results in long-term or permanent sterility. Sperm counts at 29 days were identical in saline-treated control mice and GnRH-treated mice; no sperm were present in the CY-treated mice, both with and without GnRH. Thus, killing of differentiating spermatogonia by CY is not prevented by GnRH treatment. Similarly, counts of spermatids at 56 days showed no difference between saline- and GnRH-treated groups; a reduction to approximately 40% of control counts was observed equally with CY and CY plus GnRH treatments. Since GnRH treatment did not alter spermatogonial kinetics in BALB/c mice, it is not surprising that it did not protect against CY-induced damage. Thus, the mouse is not a suitable model for analyzing such effects of GnRH on spermatogenesis, and further studies in other experimental animals are needed if they are to be used as a rationale for clinical administration of GnRH to cancer patients.

Effects of AMSA, an antineoplastic agent, on spermatogenesis in the mouse.

The stages of spermatogenic cells killed by the single and fractionated administration of AMSA, an acridine derivative used in cancer chemotherapy, have been identified in the mouse. A wide range of doses, up to a total of 30 mg/kg, which is the LD50 for AMSA given in three daily injections, was employed. Survival of differentiating (types A1 through Intermediate) and stem spermatogonia was measured by sperm counts performed 29 and 56 days after treatment, respectively. The sensitivity of germ cells to AMSA at other stages of differentiation was determined by semiquantitative histologic analysis at 11 days after treatment. Significant killing of differentiating spermatogonia, types A2 through B, but only minor killing of stem cells and no toxicity to post-spermatogonial stages were observed with all treatment schedules. This pattern of differential sensitivity can explain the temporary azoospermia observed in man during AMSA treatment, which was followed by a return to normal sperm counts after cessation of therapy.

Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy.

The sperm production of 25 patients with Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy was studied retrospectively. All but two patients also received radiotherapy treatment to pelvic and/or non-pelvic fields. Sperm counts were obtained from patients treated either with three or fewer (MOPP-2 group) or with five or more (MOPP-6 group) chemotherapy cycles. Recovery of spermatogenesis following treatment-induced azoospermia was significantly higher among the MOPP-2 patients (Mann-Whitney rank sum test, p = 0.001). Patients in this group who did not receive pelvic irradiation appeared to have greater recovery rates (p = 0.06). The results suggest that three cycles of MOPP chemotherapy represent a maximum exposure compatible with the recovery of spermatogenesis.

Active sperm production after cancer chemotherapy with doxorubicin.

The sperm production of 14 cancer patients who received doxorubicin was examined after cessation of therapy. Doxorubicin was used in several multiple-drug protocols for the treatment of various malignancies. Seven patients also received radiotherapy to different sites. Total cumulative doses of doxorubicin ranged from 145 to 625 mg./m.2. Sperm concentration, motility, morphology and the frequency of quinacrine-stained sperm with 2 fluorescent bodies (2F sperm) were measured 7 to 79 months after discontinuation of doxorubicin. Of the patients 6 remained azoospermic, 3 were oligospermic and 5 were normospermic. Sperm motility among the 8 patients with sperm ranged from 20 to 80 per cent. Morphology and 2F sperm distributions were not significantly different from controls. We conclude that, in contrast with the mechlorethamine, vincristine, procarbazine and prednisone protocol, active sperm production within relatively short recovery times is possible after treatment with protocols that include doxorubicin.

Temporary effects of AMSA (4'-(9-acridinylamino) methanesulfon-m-anisidide) chemotherapy on spermatogenesis.

Spermatogenesis in a melanoma patient treated with 12 courses of acridinyl anisidide (AMSA) (20 mg/m2/course) was studied by monitoring sperm concentration, motility, and morphology at various phases of treatment. Chemotherapy was interrupted for 20 weeks between the ninth and tenth course. Sperm concentration and motility began to decline after the second course. At the third course, the percentage of morphologic abnormalities had increased to 86.5% from a pretreatment value of 57.8% (P less than 0.001). Azoospermia was observed at the sixth course and persisted until 12 weeks after the ninth course, when semen levels returned to pretreatment levels: 20 million/ml; 70% motility; 60.1% abnormal forms. Three weeks after the 12th course, the sperm count was reduced to 250,000/ml, motility to 5%, and abnormalities increased to 84.0%. The rapid recovery of normal spermatogenesis observed during the chemotherapy interruption indicates that AMSA has only a temporary, reversible effect on differentiating germinal cells with no toxicity to stem cells.

Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells.

The harmful effects of 14 chemotherapeutic drugs on spermatogenesis in the mouse have been evaluated by studies of testicular cell killing and morphological and genetic damage produced. Male mice were given drugs as single injections at various doses up to the toxic levels. Prednisone and 6-mercaptopurine produced little or no cytotoxicity. All other drugs tested killed differentiated spermatogonia. Of these, methotrexate, cyclohexylchlorethylnitrosourea, cis-platinum, and mechlorethamine did not show significant stem cell killing. Bischlorethylnitrosourea, chlorambucil, 5-fluorouracil, mitomycin C, antinomycin D, and procarbazine showed some stem cell killing. Triethylenethiophosphoramide (thio-TEPA) was the only drug in this group which killed large numbers of stem cells. Only 5-fluorouracil and cis-platinum killed spermatocytes, and only cis-platinum killed spermatids. Several drugs induced chromosome breaks in treated spermatocytes. Thio-TEPA was effective in inducing chromosome translocations in treated spermatocytes and probably also in spermatocytes which originated from surviving treated stem cells. It had been our hypothesis that the cytotoxic effects of these drugs on mouse testicular stem cells would correlate with the duration of azoospermia observed in patients. This was shown not to be the case. Thus, the cytotoxic effects of single injections of single chemotherapeutic agents on the mouse testis did not appear to be predictive of which drugs will cause long-term azoospermia in humans.