E. Carmack Holmes

BCG Immunotherapy of Malignant Melanoma: Summary of a Seven-year Experience

Over the past 7 years, 151 patients with malignant melanoma have been treated with BCG immunotherapy alone or as an adjunct to surgical therapy. Direct injection of metastatic melanoma lesions limited to skin resulted in 90% regression of injected lesions and 17% regression of uninjected lesions in immunocompetent patients. Approximately 25% of these patients remained free of disease for 1 to 6 years. Direct injections of BCG into nodules of patients with subcutaneous or visceral metastases resulted in a lower incidence of local control and no long term survivors. Attempts to improve the results of immunotherapy in these patients by palliative surgical resection of large metastatic lesions to lower tumor burden followed by BCG immunotherapy significantly improved the results although many patients still developed recurrent disease. Early results of a clinical trial combining BCG immunotherapy with regional lymphadenectomy in patients with melanoma metastatic to lymph nodes have been encouraging and promising. Further controlled clinical trials are necessary to elucidate the role of BCG in immunotherapy. However, since BCG is but one of a number of potential immunologic adjuvants, even more effective immunotherapy will be possible as further knowledge of the interactions of cellular and humoral immunity is acquired.

Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopathologic features

Background. Bronchioloalveolar lung carcinoma (BAC) is a unique type of lung cancer with distinguishing pathologic, biologic, epidemiologic, demographic, and perhaps etiologic features.

Prognostic factors in patients with resected stage I non-small cell lung cancer. A report from the Lung Cancer Study Group.

The authors present prognostic information on recurrence and survival for resected Stage I lung cancer patients with squamous cell carcinoma, adenocarcinoma or large cell carcinoma. The data derive from 392 carefully staged patients and include results from the history and physical examination, preoperative laboratory tests, nature of the surgery, complications, initial pathologic findings following surgical resection, and final pathologic review. A simple multivariate model of recurrence, which is used to classify patients into low, intermediate, and high‐risk groups, is based on tumor size and location (T1, T2), histologic type (squamous, nonsquamous/mixed) and nodal status (N0, N1). To model survival, the performance status and the presence of empyema, pneumonia, or wound infection were added to the previous factors. Not all factors associated with increased mortality are associated with increased risk of recurrence, and, in particular, postoperative empyema, pneumonia or wound infections carry an increased risk of death only. Serial measurements of performance status and leukocyte count have the potential for monitoring for increased risk of recurrence and death.

Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer

Purpose: To study the structure and expression of the cyclin D1 and the epidermal growth factor receptor (EGFR) genes in a cohort of 298 non-small-cell lung cancer (NSCLC) specimens. Methods: Gene structure was studied by Southern analysis, and gene expression was studied by Northern analysis and immunohistochemical analysis. Results: Amplification of the cyclin D1 locus was found in 14/298 (5%) specimens. All 12/12 specimens with amplification of the cyclin D1 gene for which RNA was available were found to express the cyclin D1 transcript, and 11/12 overexpressed the transcript to levels higher than that of uninvolved lung. The EGFR gene was amplified in 17/286 samples of NSCLC tested, and was overexpressed in 22/169 (13%) cases tested, including 12/13 cases with amplification of the gene for which RNA was available. Cyclin D1 gene amplification was associated with advanced lymph node involvement (P = 0.043), but not with larger tumor size or adverse outcome. Cyclin D1 gene amplification and overexpression occurred independently of retinoblastoma tumor-suppressor gene (RB) inactivation, but tumors with amplification of the cyclin D1 gene were more likely to have EGFR gene amplification (P<0.005). No correlation of EGFR gene amplification or overexpression with tumor size, lymph node involvement, patient demographic data, or survival was identified. Conclusions: These data indicate that the cyclin D1 and EGFR genes are amplified and overexpressed in NSCLC, and amplification of the cyclin D1 gene occurs frequently in conjunction with amplification of the EGFR gene.

Muscle-Sparing Posterolateral Thoracotomy

We have developed a technique for posterolateral thoracotomy that allows adequate exposure for most thoracic operations, yet spares both the latissimus dorsi and serratus anterior muscles. Postoperative pain is decreased, functional recovery is improved, and patients can frequently be discharged earlier from the hospital. Although the time for opening is slightly prolonged, closing time is less and the incision can easily be converted to the standard muscle-splitting approach if more room is required.

Pulmonary resection for metastatic sarcoma

Surgical resection plays an important role in the treatment of sarcoma that is metastatic to the lung. Multiple bilateral metastases are not contraindications to surgery. The rapidity of growth and the response to chemotherapy can be accurately determined by the tumor doubling time. Preoperative chemotherapy provides an in vivo measurement of tumor sensitivity, and the response to chemotherapy correlates with prognosis. Since residual microscopic pulmonary disease appears to be responsible for most failures after thoracotomy, attention should be directed toward delivering more effective adjuvant therapy to the lungs.

Changes in the surgical management of esophageal cancer from 1970 to 1993

PURPOSE To evaluate the changes since 1970 in the management and outcome of esophageal resection for cancer. METHODS The records of all 316 patients who underwent esophageal resection for cancer at University of California Los Angeles Medical Center during the years 1970 to 1993 were reviewed. RESULTS When records from 1984 to 1993 were compared to those from 1970 to 1983, significant decreases were seen in operative mortality (10% to 3%, P < 0.01), morbidity (72% to 60%, P < 0.05), anastomotic leaks (12% to 5%, P < 0.03), and reoperations (20% to 8%, P < 0.003). Time spent in hospital and in intensive care decreased 40%. These improvements in short-term outcome were most evident in patients with disease in later stages. The 5-year survival rate increased (12% to 21%, P < 0.01). A greater percentage of tumors presented in early stages (21% versus 37%). CONCLUSIONS Short-term outcome of surgical resection for esophageal carcinoma improved between 1970 and 1993, in part because of changes in perioperative and surgical management. Long-term survival improved, probably due to earlier detection of tumors.

Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2–selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease. Cancer Prev Res; 4(7); 984–93. ©2011 AACR.

Hepatic artery ligation and 5-fluorouracil infusion for metastatic colon carcinoma and primary hepatoma.

Nine patients with extensive bilateral hepatic metastases of colorectal cancer were treated with hepatic artery ligation and continuous infusion of 5-fluorouracil (5-FU). Silastic catheters were inserted into the hepatic artery at laparotomy, and continuous perfusion was effected by a Sigmamotor pump. There was no operative mortality or morbidity, and drug toxicity was acceptable. Dosage averaged 10 mg/kg/day and average time of infusion was sixty-three days. Liver function returned to preoperative values within two weeks in all patients, and four patients had improvement of preoperative liver function for three to six months after perfusion. Two patients had palpable regressions that lasted five months or more, and one patient had a slight palpable regression for two months. Five who are dead had a mean survival of 10.4 months after therapy, with a median survival of 11.5 months. Eight of the nine patients had significant clinical improvement following treatment. Seven patients with irresectable primary liver carcinoma were treated with continuous 5-FU infusion. A Silastic catheter was placed at laparotomy into the hepatic artery via the gastroduodenal artery. Ligation of the hepatic artery was not performed. There was no operative mortality or morbidity. Dosage averaged 10 mg/kg/day and the average time of infusion was 140 days. Significant clinical improvement was noted in six of the seven patients although this did not correlate with improvement of hepatic function. All six responding patients are still living (mean survival, 14 months). Prolongation of life with hepatic artery infusion of 5-FU has been significantly better than with any previously reported chemotherapy for this disease.

Surgical management and reconstruction of extensive chest wall malignancies

Seven patients aged 8 to 77 years underwent massive resection for chest wall malignancies. Two had chondrosarcoma, one recurrent breast cancer, one malignant hemangioepithelioma, one embryonal cell sarcoma, one metastatic osteogenic sarcoma, and one lymphangiosarcoma. The smallest surgical defect was 17 by 19 cm, the largest 35 by 45 cm. Closure was done with Marlex mesh, full-thickness muscle flaps, or free island pectoralis or latissimus dorsi flaps. The rotation of myocutaneous island flaps (bilateral in two patients) greatly facilitated reconstruction. No infection, pulmonary compromise, or operative morbidity or mortality was encountered. The age of the patients and the location or size of the lesions were not significant factors. Designing a surgical strategy which provides adequate full-thickness margins and immediate reconstruction is critically important. Massive chest wall resection for malignancy should be pursued aggressively whenever these lesions are encountered. The operations can be performed safely and can be curative, and the benefits to patients in terms of comfort and prolonged survival justify this extensive surgery.