Carlos Manivel

Prolongation of cardiac xenograft survival by depletion of complement

Complement (C) activation is thought to be critical for the hyperacute rejection of xenografts. We investigated the role of C in the rejection of discordant cardiac xenografts by studying outcome in recipients depleted of C, using a highly purified form of cobra venom factor (CVF) in both a small (guinea pig [GP]-to-rat) and large (pig-to-baboon) animal model. A single dose of 30 or 60 units CVF given i.v. to rats completely abrogated hemolytic C activity for up to 72 hr. The lack of hemolytic C activity correlated with nearly undetectable serum levels of C3. Doses of 30 U/kg daily or 60 U/kg every other day over a 7-day period sustained C depletion without morbidity or mortality. Rats receiving GP cardiac xenografts during CVF therapy had significantly prolonged xenograft survival (88 +/- 10 hr in CVF-treated rats vs. 18.6 +/- 7.2 min in control rats, P < 0.001). Rats that rejected GP xenografts at 4 days posttransplant had higher levels of anti-GP antibodies than control rats, without hemolytic C activity at rejection. This rise in xenoreactive Ig reflected an increase in circulating IgG and IgM against GP antigens recognized before transplantation. Histologic analysis of GP cardiac xenografts taken from CVF-treated rats revealed leukocyte and monocyte margination along blood vessels, beginning at 12 hr posttransplant. Progressive cell infiltration, interstitial hemorrhage, and necrosis were observed over the next 72 hr. Rejected GP xenografts showed diffuse deposition of IgM and fibrin within blood vessels but no evidence of C3 deposition. A nonspecific pattern of IgG deposition was noted. CVF was tested in baboons. Complete C depletion was achieved with a dose of 60 U/kg, and was not associated with any morbidity or mortality. Xenotransplantation of a pig heart was performed in one baboon receiving CVF, 60 U/kg/day, for 2 consecutive days. Xenograft survival was prolonged to 68 hr, compared with 90 +/- 30 min in control baboons. Lack of hemolytic activity was noted during engraftment and at rejection. Histology showed evidence of vascular rejection. Immunopathology showed diffuse deposition of IgM, fibrin, and C4, and absence of C3 or membrane attack complex. We conclude that highly purified CVF can achieve marked C depletion with minimal morbidity and no associated fatalities. CVF alone can significantly prolong discordant cardiac xenograft survival. In the GP-to-rat model, the improvement in graft survival achieved with CVF was better than with conventional immunosuppression or isolated acute antibody depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

The Role of Ilioinguinal Lymphadenectomy and Significance of Histological Differentiation in Treatment of Carcinoma of the Penis

We reviewed retrospectively the medical records of 58 patients treated for squamous cell carcinoma of the penis who were followed for more than 3 years or until they died. Tissue sections from all patients were reviewed. Of 15 patients with stage I disease 11 underwent partial penectomy, and 4 underwent partial penectomy and immediate ilioinguinal lymphadenectomy; none died of cancer. Nine patients with stage II and 9 with stage III disease underwent partial or total penectomy and immediate ilioinguinal lymphadenectomy, and 5-year survival was 100 and 75%, respectively. Of 20 patients with clinical stage II disease who did not undergo immediate ilioinguinal lymphadenectomy 18 had metastasis to the groin. Of these 18 patients 12 underwent delayed ilioinguinal lymphadenectomy but only 1 survived more than 5 years. We evaluated the possible significance of the degree of histological differentiation of the primary tumor to the course of the disease. Of the 23 cases of carcinoma in situ or well differentiated disease only 1 became metastatic, while of the 35 cases of moderately to poorly differentiated disease 31 metastasized to the groin. Vascular invasion of cancer cells in the primary tumor was another indicator for poor prognosis.

The Occurrence of Sarcomatous Components in Primary Mediastinal Germ Cell Tumors

The occurrence of a sarcomatous component in germ cell tumors is an uncommon phenomenon; seven cases with such an association are presented. The sarcomatous elements were rhabdomyosarcomatous in four cases, angiosarcomatous in two, and a combination of these two types in one case. Immunohistochemical studies supported the endothelial and skeletal muscle differentiation of the sarcomatous components. All patients were treated surgically, and some received various chemotherapeutic agents and radiation. On follow-up, four patients had died of their disease, one developed recurrence and pulmonary metastases, one was free of disease after 4 years, and one is a recent case. Chemotherapy protocols may need to be altered to include sarcoma-oriented drugs for this particular group of patients.

Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues.

Expression of monocarboxylate transporter MCT1 was studied in archival tissues from human CNS using antibodies to the carboxyl-terminal end of MCT1. Sections of neocortex, hippocampus and cerebellum of brains from 10 adult autopsy patients who died from other than CNS disease, and from archival surgical biopsy specimens of 83 primary CNS and eight non-CNS tumors were studied. MCT1 immunoreactivity was present in microvessels and, ependymocytes of normal CNS tissues similar to that reported for MCT1 expression in rat brains. MCT1 immunoreactivity was strongest in ependymomas, hemangioblastomas and high grade glial neoplasms, and weakest in low grade gliomas. Increased MCT1 expression in high grade glial neoplasms may provide a potential therapeutic target for treatment of some CNS neoplasms.

Primary adenocarcinoma of urinary bladder Clinicopathologic study of 16 cases

The clinicopathologic and immunohistochemical features of 16 pure adenocarcinomas primary in the urinary bladder were reviewed. Only 3 patients were found to have disease confined to the urinary bladder. Of 13 cases with follow-up only 3 are free of disease. Histologically, the tumors were classified as signet ring cell (3), colloid (3), colonic type (5), clear cell (1), and not otherwise specified (NOS, 4). Immunohistochemically, all tumors but one colloid carcinoma were immunoreactive for cytokeratin and epithelial membrane antigen, and most tumors were likewise immunoreactive for carcinoembryonic antigen. Eight cases were immunoreactive for Leu M1 antigen. Prostate specific antigen, S-100 protein, and placental alkaline phosphatase were uniformly negative. No correlation between immunohistochemical profile and histologic type or clinical outcome was found. The utility of immunohistochemistry and other pathologic findings is reviewed.

Results of treatment for metastatic osteosarcoma with neoadjuvant chemotherapy and surgery.

The purpose of the current study was to define the survival outcome variables for the 85 patients with Stage IIB osteosarcoma treated with neoadjuvant chemotherapy at the authors’ institution from 1982 to 1997. A minimum 4-year followup or death was a requisite for inclusion. Forty-three patients were relapse-free survivors and 14 had no evidence of disease at followup for an overall survival of 67%. Twenty-nine patients had thoracotomy and nine have no evidence of disease with a minimum 4-year followup from last thoracotomy. The mean time to metastasis after diagnosis for patients presenting with Stage IIB disease was 12.8 months. There was no difference in the survival for any of the three chemotherapy protocols, used during the 15 years included in this analysis. There was a significant relation between length of time to relapse and survival. For each additional year without relapse, there is an 18% increase in chance of survival. In patients who were treated with thoracotomy, the number of metastatic nodules was a significant predictor of survival; specifically, each nodule increased the risk of death by 43%. A favorable outcome in this cohort of patients is related to the length of time between initiation of therapy and diagnosis of metastasis, and the number of metastatic foci.

Teratoid hepatoblastoma. The nosologic dilemma of solid embryonic neoplasms of childhood.

The presence of divergent tissue, such as bone or osteoid, is a well recognized occurrence in the hepatoblastoma. However, multiple lines of tissue differentiation in a hepatic tumor that had the overall features of hepatoblastoma have recently been observed. During the brief and eventually fatal clinical course in this case, the tumor initially displayed the features of conventional hepatoblastoma, but evolved into a neoplasm with teratoid features, terminally assuming a hepatoma‐like appearance. Immunohistochemistry and ultrastructural studies confirmed the various lines of divergent differentiation in this tumor, which the authors chose to designate as a teratoid hepatoblastoma.

Sarcomas of the retroperitoneum and genitourinary tract

A total of 62 patients with retroperitoneal or genitourinary sarcoma was treated at our institutions during the last 46 years. Of the patients 51 were followed for at least 5 years or until they died (median followup 11 years); 5 patients were lost to followup. The most common site was the retroperitoneum. Liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma were the most common tumors (74 per cent). Tumors were completely resected in 42 patients (68 per cent) and incompletely resected in 11, while a biopsy only was performed in 9. Some patients also received adjuvant radiation therapy and/or chemotherapy. There were no long-term survivors among patients with unresectable tumors. Over-all 3 and 5-year survival rates were 68 and 39 per cent, respectively. The histological type of the tumor appeared to have prognostic significance. The highest 5-year survivals were for liposarcoma (70 per cent), malignant fibrous histiocytoma (33 per cent) and leiomyosarcoma (13 per cent). The mean survival for patients after adjuvant radiation therapy or chemotherapy was similar to that after a radical operation alone. The primary cause of treatment failure was local recurrence (45 per cent of the patients), which was detected within 3 years of complete resection in most cases (82 per cent). Complete extirpation that provided adequate margins free of tumor was the most effective initial treatment and provided the best chance for cure.

Pancreaticoduodenal transplantation with enteric drainage following native total pancreatectomy for chronic pancreatitis: A case report

Pancreas transplantation is usually performed in patients with denovo type I diabetes, who have advanced secondary complications. We report a case in which whole pancreaticoduodenal transplantation, with enteric drainage, was performed to correct both endocrine and exocrine deficiencies in a patient with hyperlabile diabetes and steatorrhea, unresponsive to oral enzyme replacement therapy, following staged total pancreatectomy for idiopathic or familial chronic pancreatitis. The transplant was performed one year after completion of native pancreatectomy and immediately established an insulin-independent euglycemic state, with normal oral and intravenous glucose tolerance test results and correction of steatorrhea. Beginning one year posttransplant, the patient had intermittent episodes of steatorrhea, associated with mild elevation of blood sugar levels, which were presumed to be due to rejection and, indeed, responded to antirejection treatment with antilymphocyte globulin and temporary increases in steroids dosages. At 20 months posttransplant, steatorrhea did not respond to antirejection treatment and an acute abdomen developed. Laparotomy revealed a perforated graft duodenum, which was resected; pathology showed transmural necrosis secondary to chronic rejection. The pancreas graft itself was left in situ, disconnected from the intestinal tract. The patient remained normoglycemic after graft duodenectomy but resumed oral enzyme replacement therapy in an attempt to combat recurrence of severe steatorrhea. However, his overall situation remained improved compared to pretransplant, since the exocrine deficiency was tolerable in the absence of a diabetic state. Ten months postgraft duodenectomy (38 months posttransplant), elevations in blood sugar levels were treated with another course of antirejection treatment and levels temporarily declined. At 14 months postgraft duodenectomy (42 months posttransplant), graft endocrine function again declined and exogenous insulin was resumed. Six months later, four years after the original transplant, a new enteric-drained pancreaticoduodenal graft was placed, once again resulting in an insulin-independent, steatorrheafree state. With improvements in immunosuppression, pancreas transplantation could be offered to selected patients with hyperlabile diabetes, following total pancreatectomy for benign disease; if the enteric drainage technique is used, in the absence of rejection, exocrine deficiency could be corrected as well.

Low Prevalence of TP53 Mutations and MDM2 Amplifications in Pediatric Rhabdomyosarcoma

The tumor suppressor gene TP53 is the most commonly mutated gene in human cancer. The reported prevalence of mutations in rhabdomyosarcoma (RMS) varies widely, with recent larger studies suggesting that TP53 mutations in pediatric RMS may be extremely rare. Overexpression of MDM2 also attenuates p53 function. We have performed TP53 mutation/MDM2 amplification analyses in the largest series analyzed thus far, including DNA isolated from 37 alveolar and 38 embryonal RMS tumor samples obtained from the Cooperative Human Tissue Network (CHTN). Available samples were frozen tumor tissues (N = 48) and histopathology slides. TP53 mutations in exons 4–9 were analyzed by direct sequencing in all samples, and MDM2 amplification analysis was performed by differential PCR on a subset of 22 samples. We found only one sample (1/75, 1.3%) carrying a TP53 mutation at codon 259 (p.D259Y) and no MDM2 amplification. Two SNPs in the TP53 pathway, associated with accelerated tumor onset in germline TP53 mutation carriers, (TP53 SNP72 (rs no. 1042522) and MDM2 SNP309 (rs no. 2279744)), were not found to confer earlier tumor onset. In conclusion, we confirm the extremely low prevalence of TP53 mutations/MDM2 amplifications in pediatric RMS (1.33% and 0%, respectively). The possible inactivation of p53 function by other mechanisms thus remains to be elucidated.