Faculty Bibliography

From May 1985 to December 1990, 93 patients with the clinical diagnosis of metastatic renal cell carcinoma and their primary tumor in place were evaluated for cytoreductive surgery as preparation for systemic therapy with regimens based on interleukin-2. These patients had typical sites of metastatic disease and manifestations of paraneoplastic syndromes. Patients underwent removal of the primary tumor, as well as debulking when this could be performed safely. Thirty-two percent of patients (30/93) had a second surgical resection in addition to their nephrectomy, frequently because of the large size of the primary tumor and its invasion of adjacent structures. Thirteen percent of patients (12/93) experienced postoperative complications. There were no perioperative mortalities. Forty percent of patients (37/93) who underwent nephrectomy could not be treated with immunotherapy, usually because of progression of disease. A preoperative ECOG status greater than or equal to 2 was the only significant risk factor associated with failure to undergo immunotherapy (P = 0.043). The response rate to immunotherapy in the 56 patients receiving interleukin-2 was 27 percent (4 CR, 11 PR)

Malignant mesothelioma (MM) is resistant to most standard forms of treatment. Accordingly, novel therapies based on the genetic and autocrine growth characteristics are being investigated. Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells, is produced by several human malignant cell lines including MM and therefore may promote tumourigenesis by an autocrine mechanism. We investigated the expression of PDGF-beta mRNA in tumour specimens excised from 18 patients with MM. Total cellular RNA was successfully extracted from 16/18 frozen tumour specimens with guanidine isothiocyanate and purified by centrifugation through a caesium chloride gradient. Northern blots were prepared and probed sequentially with 32P-labelled PDGF-beta and beta-actin cDNA. Gene expression was quantitated by optical densitometry. Freshly elutriated human peripheral blood monocytes were stimulated to induce PDGF-mRNA expression with transforming growth factor-beta-1. This positive control was assigned an expression index (EI) of 1, with the EI for the tumour sample calculated as: PDGFpatient/Actinpatient/EI positive control. In the 16 tumour specimens with useable RNA, transcripts for PDGF-beta MRNA were detected. Northern blot analyses revealed elevation of PDGF-beta expression above control in 10/16 (63%) of MM patients. A 230% increase in PDGF-beta expression (EI = 1.62 vs. EI = 0.49) was found between the lowest and highest expression samples. The specimens from which the PDGF transcripts were derived were found histologically to contain 87% tumour and 13% contaminating normal cells, predominantly lymphocytes. The elucidation of the transcriptional regulation of growth factors which are implicated in the pathogenesis of MM may guide the development of more effective biologic therapies

The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively

We performed in situ hybridization for c-myc, N-myc, and L-myc mRNA expression using 35S-labeled cRNA probes on frozen sections of 19 pairs of non-small cell lung cancers (NSCLC) and the surrounding non-neoplastic lung tissue. In non-neoplastic lung, c-myc expression was strongest in bronchial epithelium basal cells and hyperplastic alveolar type II pneumocytes, which are potential progenitor cells for bronchopulmonary epithelium and their tumors. In contrast, N-myc and L-myc mRNAs were not detected in non-neoplastic lung. In studies of freshly resected primary tumors, expression of c-myc was detected in 11 of 19 NSCLC (with the highest levels in squamous cell carcinomas), two of which also expressed L-myc, while N-myc expression was never detected. Levels of c-myc expression in tumors were significantly higher than in non-neoplastic lung samples. We conclude that: (1) c-myc expression in non-neoplastic lung tissues is highest in bronchial basal cells and hyperplastic type II cells, and (2) in NSCLC, overexpression of the myc-proto-oncogene is common

Gastric adenocarcinoma is typically diagnosed at an advanced stage, and even with 'curative' gastrectomy, most patients die of recurrent disease. Neoadjuvant chemotherapy for locally advanced gastric cancer is an experimental treatment strategy that may increase resectability and improve survival for patients afflicted with an almost uniformly fatal neoplasm. At our institution, we are evaluating the efficacy of fluorouracil, leucovorin, and interferon alfa-2A administered for three cycles, followed by surgery and consolidation therapy for patients with T3-4, N1-2, M0 gastric adenocarcinoma. The rationale for the use of neoadjuvant therapy combined with radical extirpative surgery in this setting and related issues are discussed

Chronic granulomatous disease of childhood is an inheritable disorder of phagocytic cell respiratory burst resulting in recurrent, life-threatening, catalase-positive infections. The lung is the most common site of infection, and pulmonary disease is the primary cause of death in greater than 50% of children with chronic granulomatous disease. Still, the role of surgery in management of this disease remains undefined. Between 1974 and 1990, 19 patients with chronic granulomatous disease required 31 thoracic interventions at our institution. Patients ranged in age from 2.5 to 27 years (mean age, 15 years). Seventeen of 19 patients (89%) had had previous pulmonary infections. Patients presented as toxic (temperature > 38.5 degrees C, chest pain, and cough) in 22 instances before the 31 procedures. Aggressive surgical intervention for diagnosis and extirpation of localized infections was undertaken with lobectomy/pneumonectomy with or without other procedures (5), bisegmentectomy (2), segmentectomy with or without other procedures (5), or wedge with or without other procedures (13). In five instances, an empyema was drained; a chest tube for a sterile collection was placed in one instance. There was one intraoperative death, and 3 patients died 22 to 600 days postoperatively with overwhelming sepsis. The mean hospitalization was 101 days (range, 24 to 600 days). Wound complications occurred in 5 patients, requiring 17 separate anesthetic debridements. A change in therapy was dictated by the results of the procedure in 23 of 31 instances (74%). Thoracic surgeons must be aware of this rare cause of immunosuppression in these children and, due to the unusual nature of the pulmonary infections, should follow an aggressive approach in their diagnosis and management

In photodynamic therapy (PDT), a sensitizer, light, and oxygen are used to cause photochemically induced cell death. The mechanism of cytotoxicity involves generation of singlet oxygen and other free radicals when the light-excited sensitizer loses or accepts an electron. Although selective retention of sensitizer by malignant tissue is seen in vivo, the mechanisms for this sensitizer targeting remain unclear. The first-generation sensitizers are porphyrin based and vary in lipophilicity and hydrophilicity. Targeting of the vasculature seems to be a prominent feature of the cytotoxic effect of these sensitizers in vivo, with resulting necrosis. Treatment depth varies with the wavelength of light that activates the sensitizer used, and the second-generation sensitizers are activated at longer wavelengths, allowing for a 30% increase in treatment depths. The selectivity of targeting can be increased when the sensitizer is delivered with the use of liposomes or monoclonal antibodies specific for tumor antigens. Studies have demonstrated direct effects of PDT on immune effector cells, specifically those with lineage from macrophages or other monocytes. Clinically, this therapy has been chiefly used for palliation of endobronchial and esophageal obstruction, as well as for treatment of bladder carcinomas, skin malignancies, and brain tumors. The future of PDT rests in defining its use either as an intraoperative adjuvant to marginal surgical procedures or as a primary treatment for superficial malignancies. Phase III trials in esophageal cancer and lung cancer are in progress and will help in evaluation of whether Photofrin II, the most widely used sensitizer, can be added to the oncologic armamentarium, pending approval from the U.S. Food and Drug Administration

The ability to predict which patients will derive a survival benefit from pulmonary metastasectomy is limited. Most patients remain asymptomatic until the disease becomes advanced, and therefore computerized tomography (CT) of the chest has become the standard of care for follow-up of patients at risk for pulmonary metastases. The most important predictor of post-thoracotomy survival in patients at the National Cancer Institute with soft tissue, osteogenic, and pediatric sarcomas as well as melanoma and renal cell carcinoma has been the ability to render the patient disease-free. Tumor histology, disease-free interval, and possibly number of nodules are also determinants of survival. Median sternotomy is the preferred approach for initial and repeat metastasectomies and every effort should be made to preserve pulmonary parenchyma. Resection of pulmonary metastases has become an accepted therapeutic modality, but selection of surgical candidates, and operative planning needs to be individualized