IFN-gamma enhances paclitaxel-induced apoptosis that is modulated by activation of caspases 8 and 3 with a concomitant down regulation of the AKT survival pathway in cultured human keratinocytes.

The aim of this study was to investigate the molecular effects of paclitaxel and IFN-gamma on cultured human keratinocyte cells (HaCaT) assessing the induction of both the apoptotic pathway and cell survival signals. Cellular cytotoxicity assays were performed by MTT dye assay. Caspases 8, 3 and AKT (Ser473 and Thr308 residues) were assessed by Western blot analysis. Morphological characteristics were examined by Wright stain analysis. Paclitaxel reduced keratinocyte growth in a 3-day bioassay with an effective ED(50) of 6-600 ng/ml. A large variation in ED(50) can be attributed to the asynchronous population of cells. Paclitaxel treatment induced activation of the AKT survival pathway in a time-dependent manner. The down-regulation of AKT signal was preceded by the subsequent activation of caspases 8 and 3 leading to apoptosis. These results indicate that paclitaxel activates both the PI3-K/AKT cell survival pathway followed by induction of apoptotic signals in cultured human keratinocytes. The induction of apoptosis in paclitaxel-treated cells is enhanced by coadministration of IFN-gamma. The synergistic effect of these two agents on HaCaT cells relies on a pathway involving caspases 8 and 3, with activity increasing by 48 h. Collectively, our data indicate that i) paclitaxel-induced apoptosis is enhanced by IFN-gamma; ii) the down-regulation of PI3-K/AKT survival pathway may help potentiate the apoptotic effects of paclitaxel and iii) the apoptotic signaling pathways are initiated with the activation of caspases 8 and 3 activities.

Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer.

HYPOTHESIS: Neoadjuvant therapy has the potential to induce regression of high-risk, locally advanced cancers and render them resectable. Preoperative chemoradiotherapy is proposed as a testable treatment concept for locally advanced pancreatic cancer. DESIGN: Fourteen patients (8 men, 6 women) with locally advanced pancreatic cancer were surgically explored to exclude distant spread of disease, to perform bypass of biliary and/or gastric obstruction, and to provide a jejunostomy feeding tube for long-term nutritional support. A course of chemotherapy with fluorouracil and cisplatin plus radiotherapy was then initiated. Reexploration and resection were planned subsequent to neoadjuvant therapy. MAIN OUTCOME MEASURES: Tumor regression and survival. INTERVENTIONS: Surgically staged patients with locally advanced pancreatic cancer were treated by preoperative chemotherapy with bolus fluorouracil, 400 mg/m2, on days 1 through 3 and 28 through 30 accompanied by a 3-day infusion of cisplatin, 25 mg m2, on days 1 through 3 and 28 through 30 and concurrent radiotherapy, 45 Gy. Enteral nutritional support was maintained via jejunostomy tube. RESULTS: Of 14 patients who enrolled in the protocol and were initially surgically explored, 3 refused the second operation and 11 were reexplored; 2 showed progressive disease and were unresectable and 9 (81%) had definitive resection. Surgical pathologic stages of the resected patients were: Ib (2 patients), II (2 patients), and III (5 patients). Pancreatic resection included standard Whipple resection in 1 patient, resection of body and neck in 1 patient, and extended resection in 6 patients (portal vein resection in 6, arterial resection in 4). One patient who was considered too frail for resection had core biopsies of the pancreatic head, node dissection, and an interstitial implant of the tumorous head. Pathologic response: 2 patients had apparent complete pathologic response; 1 patient had no residual cancer in the pancreatectomy specimen, the other patient who had an iridium 192 interstitial implant had normal core biopsies of the pancreatic head. Five patients had minimal residual cancer in the resected pancreas or microscopic foci only with extensive fibrosis, and 2 patients had fully viable residual cancer. Lymph node downstaging occurred in 2 of 4 patients who had positive peripancreatic nodes at the initial surgical staging. There was 1 postoperative death at 10 days. Sepsis, prolonged ileus, and failure to thrive were major complications. In the definitive surgery group the median survival was 19 months after beginning chemoradiotherapy and 16 months after definitive surgery. The absolute 5-year survival was 11% of 9 patients, 1 is surviving 96 months (with no evidence of disease) after chemoradiotherapy and extended pancreatic resection including resection of the superior mesenteric artery and the portal vein for stage III cancer. In the nonresected group the mean survival was 9 months (survival range, 7-12 months) after initiation of chemoradiotherapy. CONCLUSION: A pilot study of preoperative chemoradiotherapy with infusional cisplatin and radiation induced a high rate of clinical pathologic response in patients with locally advanced pancreatic cancer and merits further study in these high-risk patients.

Pelvic resection of recurrent rectal cancer: technical considerations and outcomes.

PURPOSE: Pelvic recurrence of rectal cancer is an ominous event for the patient and a formidable challenge to the managing surgeon. We reviewed the results of abdominosacral resection to manage these patients and correlated outcome (survival and recurrence) with known prognostic factors. METHODS: An abdominosacral resection was performed on 61 patients with pelvic recurrence (53 with curative intent and 6 for palliation; 2 had extended pelvic resection). Of the 53 patients (32 males; average age, 59 years) previous resection included abdominoperineal resection in 27 patients, abdominoperineal resection plus hepatic lobectomy in 2 patients, low anterior resection in 19 patients, plus trisegmentectomy in 1 patient, and advanced primary cancers in 4 patients. Initial primary stage was Dukes B (64 percent) and Dukes C (36 percent). All had been irradiated (3,000-6,500 in 50 patients, 8,300 and 11,000 in 2 patients, and unknown dose in 3 patients). Preoperative carcinoembryonic antigen was elevated (>5 ng/ml) in 54 percent. Extent of resection: high sacral resection S-1-S2 was done in 32 patients, midsacrum in 14 patients, and low S-4-S-5 in 6 patients. Twenty-eight patients (60 percent) required partial or complete bladder resection with or without adjacent viscera, and all had internal iliac and obturator node dissection. RESULTS: There were four postoperative (within 60 days) deaths, 8 percent in curative groups (5.4 percent overall). Major complications included prolonged intubation (20 percent), sepsis (34 percent), posterior wound infection or flap separation (38 percent). The survival rate in the curative group (49 postoperative survivors) was 31 percent at five years, with 13 patients surviving beyond five years. Seven of these patients survived from 5 to 21 years, whereas six patients recurred again and died within 5.5 to 7.5 years after abdominosacral resection. Disease-free survival rate at five years was 23 percent. Recent reconstruction with large composite myocutaneous gluteal flaps in 5 patients permitted complete sacral wound coverage, resulting in earlier ambulation and reduced hospital stay. CONCLUSIONS: Abdominosacral resection permits removal of pelvic recurrence of rectal cancer that is fixed to the sacrum and is associated with long-term survival in 31 percent of patients. Recent technical advances have improved the short-term outcome and have made the procedure more feasible for surgical teams familiar with these techniques.

Surgical therapy of pancreatic cancer.

Surgical resection remains the only curative modality for pancreatic cancer. Improvements in surgical technique have greatly reduced the morbidity and mortality from pancreatic resection. These results clearly justify the use of pancreatic resection for localized and resectable pancreatic cancer. New surgical techniques such as laparoscopy can aid in the proper selection of candidates for curative resection. Integration of surgery with more effective treatments to prevent systemic relapse are needed to further improve survival.

Molecular oncogene markers and their significance in cutaneous malignant melanoma.

BACKGROUND: Oncogenes and other molecular tumor markers that predict tumor aggressiveness may allow individualization and optimization of surgical therapy of intermediate-thickness malignant melanoma. We examined the expression of selected markers, including the HLA-DR antigen, the heat shock protein-70 (HSP-70), and the c-myc oncogene in primary melanoma and regional nodes and related these findings to metastatic potential and survival. METHODS: Forty patients with primary melanoma (1.5-4.0 mm) were studied, all of whom had prophylactic lymph node dissection and were followed for 18 months to 7 years. The primary tissue and nodes were examined using immunohistochemical techniques for the presence of HLA-DR antigen and HSP-70 protein and the expression of the c-myc oncogene. RESULTS: Of 40 patients, there were 23 with lesions 1 to 2.9 mm thick and 17 with lesions 3 to 4 mm thick. Nodal metastases were present in 25 of the 40 patients who had elective node dissection. HLA-DR antibody stained the primary tumor in 10 patients (25%), but there was no correlation with survival in this group. HLA-DR antibody stained the stroma and cellular infiltrates surrounding the primary tumor in 28 of 40 patients; in this group there was a correlation of HLA-DR staining of the peritumoral stroma with improved survival overall. HLA-DR staining of the peritumoral stroma also influenced survival when patients were stratified by tumor thickness groups 1 to 2.9 mm and 3 to 4 mm and presence of nodal metastases. HSP-70 was demonstrated in the primary tumor in 25% of patients, who were also shown to have significantly improved survival when compared with those whose primary tumor did not stain with HSP-70. C-myc was expressed in the primary tumor in 25%, but showed no correlation with survival. None of these proteins correlated with or predicted the presence of nodal metastases. CONCLUSION: We conclude that the use of specific molecular-oncogene markers in intermediate-thickness primary melanoma may identify patients at high risk for conventional treatment failure and reduced survival who may profit from more aggressive surgery, adjuvant therapy, or both.

Is surgical management compromised in elderly patients with breast cancer?

OBJECTIVE: The suggestion that breast cancer management is compromised in elderly patients had prompted our review of the results of policies regarding screening and early detection of breast cancer and the adequacy of primary treatment in older women (> or = 65 years of age) compared to younger women (40 to 64 years of age). SUMMARY BACKGROUND DATA: Although breast cancer in elderly patients is considered biologically less aggressive than similar staged cancer in younger counterparts, outcome still is a matter of stage and adequate treatment of primary cancer. For many reasons, physicians appear reluctant to treat elderly patients according to the same standards used for younger patients. There is even government-mandated alterations in early detection programs. Thus, since 1993, Medicare has mandated screening mammography on a biennial basis for women older than 65 year of age compared to the current accepted standard of yearly mammograms for women older than 50 years of age. Using State Health Department and tumor registry data, the authors reviewed screening practice and management of elderly patients with primary breast cancer to determine the effects of age on screening, detection policies (as reflected in stage at diagnosis), treatment strategies, and outcome. METHODS: Data were analyzed from 5962 patients with breast cancer recorded in the state-wide Tumor Registry of the Hospital Association of Rhoda Island between 1987 and 1995. The focus of the data collection was nine institutions with established tumor registries using AJCC classified tumor data. Additional data were provided by the State Health Department on screening mammography practice in 2536 women during the years 1987, 1989, and 1995. RESULTS: The frequency of mammographic screening for all averaged 40% in 1987, 52% in 1987, and 63% in 1995. In the 65-year-old and older patients, the frequency of screening was 34% in 1987, 45% in 1989, and 48% in 1995, whereas in the 40- to 49-year-old age group, the frequency of mammography was 47% in 1987, 61% in 1989, and 74% in 1995 (p < 0.001). There was a lower detection rate of preinvasive cancer in the 65-year-old and older patients, 8.8% versus 13.7% in patients within the 40- to 64-year-old age group (p < 0.001). There was a higher percentage of treatment by limited surgery among elderly patients with highly curable Stage IA and IB cancer with 26.6% having lumpectomy alone versus 9.4% in the younger patients. Five-year survival in that group was significantly worse (63%) than in patients treated by mastectomy (80%) or lumpectomy with axillary dissection and radiation (95%, < 0.001). A similar effect was seen in patients with Stage II cancer. CONCLUSIONS: Breast cancer management appears compromised in elderly patients (older than 65 years of age). Frequency of mammography screening is significantly less in elderly women older than 65 years of age. Early detection of preinvasive (curative cancers) is significantly less than in younger patients. The recent requirement by Medicare of mammography every other year may further reduce the opportunity to detect potentially curable cancers. Approximately 20% of patients had inferior treatment of favorable stage early primary cancer with worsened survival. Detection and treatment strategy changes are needed to remedy these deficiencies.

Repeat hepatic resection for recurrent colorectal cancer.

Recurrence in the liver following hepatic resection for metastatic colorectal carcinoma is a predictable phenomenon, occurring in about two-thirds of patients who develop recurrence. There are few data, however, about the value of repeated hepatic resection in patients who have a recurrence in the liver following initial resection of their hepatic metastases. We have reviewed our experience with 10 patients (of whom 9 were evaluable), culled from a series of 74 patients who had an initial hepatic resection for metastatic colorectal carcinoma. There were seven men and two women, mean age 52 (range 34-75 years). Duke's stages of the primary cancer were B1 in two patients, B2 in one patient, and C2 in six patients. Most of the patients had elevated carcinoembryonic antigen (CEA) and constitutional symptoms as indications for the second-look procedure. There was one surgical death due to hepatic failure in a patient who required a trisegmentectomy. The average interval between the first and second hepatic resections was 21 months. The estimated 1- and 5-year actuarial survivals from the second liver resection were 78% and 23%, respectively. The median survival was 41 months from the first resection (range 14-100 months) and 16 months from the second resection (range 0-92 months). In conclusion, repeat hepatectomy for recurrent liver metastases is a viable option for the well selected patient. It is a low risk surgical procedure and may augment survival in the patient with well documented metastases limited to the liver.

Therapeutic options and results for the management of minimally invasive carcinoma of the breast: influence of axillary dissection for treatment of T1a and T1b lesions.

BACKGROUND: Axillary dissection has maintained a role of primacy for the surgical therapy of invasive carcinoma of the breast for many years. More recently, early (T1) minimally invasive carcinoma of the breast has been diagnosed with increasing frequency, and the necessity of axillary dissection for sampling purposes in these small tumors has been questioned, based primarily on the finding of low rates of axillary metastases. STUDY DESIGN: The Rhode Island State Tumor Registry records of 1,126 patients with T1a or T1b tumors were examined to assess the effect of axillary dissection on patient outcome. These data span 9 years (1985 to 1992) with a median follow-up duration of 64 months. Five-year overall, disease-free, and breast cancer-specific (determinate) survival were determined according to treatment modality. Axillary node positivity was calculated for patients with minimally invasive carcinoma of the breast who underwent axillary dissection. Multivariate statistical methods were used to provide adjustment for known confounding prognostic variables. RESULTS: Omission of axillary dissection occurred in 157 cases and correlated with reductions in overall, disease-free, and breast cancer-specific survival (p < .001 in all cases). Nodal status significantly influenced disease-free survival in minimally invasive carcinoma of the breast (90 percent node-negative compared with 76 percent node-positive, p = .02). Nodal positivity was evident in 18.2 percent of patients undergoing axillary dissection for minimally invasive carcinoma of the breast (9.8 percent for T1a, 19.4 percent for T1b, p = .01). In multivariate analysis, the performance of axillary dissection with breast conservation or modified radical mastectomy were independent predictors of overall survival, as well as disease-free and breast cancer-specific survival. CONCLUSIONS: A significant number of patients with small (less than or equal to 1 cm) invasive tumors of the breast will have axillary metastases at the time of diagnosis. Omission of axillary dissection in these patients was associated with significant impairment of overall, disease-free, and breast cancer-specific survival. Axillary dissection should continue to be a standard approach for the surgical therapy of all patients with invasive carcinoma of the breast, regardless of tumor size.

Pancreatic carcinoma in perspective. A continuing challenge.

There are approximately 27,000 new cases of carcinoma of the pancreas each year and most afflicted patients will die of the disease. Although smoking is a common denominator, chronic pancreatitis is considered an important precursor lesion in a smaller number of cancers. Pancreatic cancer is primarily a disease of the pancreatic ducts. The molecular events are under intense study, but c-K-ras mutation is involved in approximately 80% of the cases and p53 to a slightly lesser degree (60-80%). Early manifestations are usually occult, but jaundice is a common manifestation in patients with cancers of the pancreatic head. Thin-slice computed tomography, portography, and endoscopic retrograde cholangiopancreatography are currently the most sensitive detection techniques. The developing use of endoscopic ultrasound and laparoscopy appear to enhance detection and are under evaluation. In many patients with advanced disease, endoscopic bypass may eliminate the need for unnecessary surgery, although gastrointestinal bypass is still required in some patients (10-15%). Curative resection is possible in selected patients (perhaps 10-15%), with expectation of extended survival ranging from 6->20% in some series. The survival differences may be related to stage, patient selection, and the expertise of the operative team. Preoperative chemotherapy/radiation is under study and may improve outcome. Clinical trial participation is essential for improvement in treatment outcomes.

Preoperative therapy for advanced pelvic malignancy by isolated pelvic perfusion with the balloon-occlusion technique.

BACKGROUND: Although the technique of isolated pelvic perfusion dates back to the time of Creech (1959) and has been used by a variety of authors to treat unresectable neoplasms, the inherent complexity of the open procedure limited its widespread use. We simplified the technique through use of the balloon-occlusion technique for aortic and caval control. Our initial efforts used this technique for unresectable pelvic cancer, but recently we used this as preoperative therapy for advanced pelvic malignancy. METHODS: Isolated pelvic perfusion was accomplished by placement of balloon-occlusion catheters (Fogerty 8) in the aorta and inferior vena cava (IVC) at L3 vertebral body level via the common femoral artery and vein and establishing inflow and outflow catheter connections to a hemodialysis pump that generated a flow rate of 150-300 ml/min. Chemotherapy drugs were infused at times 0, 10, and 20 min. 5-Fluorouracil (5-FU; 1,500 mg/M2), cis-platinum (50-100 mg/M2), and mitomycin (15-20 mg/M2) were given by normothermic perfusion over a 45-min period. Forty isolated perfusions were carried out in 25 patients. Patients were evaluated by clinical examination, biochemical tests, computed tomography (CT) and magnetic resonance imaging (MRI) scans, and surgical exploration. RESULTS: Pelvic perfusion generally achieved pelvic systemic exposure ratios (area under the curve) between 5 and 10:1 for all three drugs: mean ratios were 11.4 (5-FU), 6.0 (cisplatin), and 9.0 (mitomycin). The amount of leaking to the systemic circuit ranged from 28 to 38%. Of 15 patients treated for palliation, there was one objective partial response (PR). Ten patients had symptomatic improvement of pain, two had complete pain relief (CR), and eight had partial pain relief, ranging from 3 weeks to 3 months (median, 5 weeks). Six of 10 patients with adequate carcinoembryonic antigen (CEA) follow-up data had a reduction in CEA levels (mean change, 35 units). Of 10 preoperative patients, there was one CR among five rectal cancer patients; and four of five PRs among patients with other pelvic malignancies: two PRs in patients with epidermoid cancer and one PR each in patients with endometrial cancer and metastatic anorectal melanoma. CONCLUSION: Pelvic perfusion by a simplified balloon-occlusion technique provides palliation for most patients with advanced pelvic malignancy and may increase resectability and improve tumor control in patients amenable to resection.

Current perspectives on repeat hepatic resection for colorectal carcinoma: a review.

BACKGROUND: Recurrence occurs in 65% to 85% of patients after initial hepatectomy for metastases from colorectal cancer. Approximately one half of these have liver metastases, and in 20% to 30% only the liver is involved. Opportunity for resection is frequently limited because of diffuse liver disease or extrahepatic extension, and only 10% to 25% of these patients have conditions amenable to resection. This current review is focused on the rationale, indications, and results of resection of hepatic metastases from colorectal cancer. METHODS: The major series of liver resection were reviewed, and the cases of repeat resections were culled out. In addition to standard clinical parameters, the indications and timing after initial resection and the survival and subsequent recurrence after repeat resection were recorded. RESULTS: A comprehensive review of the 28 series showed that the mean interval between the first and second liver varied from 9 to 33 months and was about 17.5 months in the two largest series. The median survival in series reporting 10 or more patients was 19 months (mean, 24 months), which is comparable to data in single resection series. In the large French Association series containing 1626 patients with single resections and 144 patients with two resections, the 5-year survival was 25% and 16%, respectively. The recurrence rate after repeat resection is high (greater than 60%), and one half are in the liver. The prognostic factors favoring repeat resection are variable, but they include absence of extrahepatic extension of tumor and a complete resection of the liver metastases. CONCLUSIONS: Repeat hepatic liver resection for metastatic colorectal cancer in carefully selected patients appears warranted in view of reasonable survival expectations, which approach that of single liver resection. Risk of recurrence is high, however, suggesting the need for rigorous preoperative and intraoperative assessment and postoperative adjuvant therapy

Patient selection for hepatic resection of colorectal metastases.

OBJECTIVE: To determine the major factors governing patient outcome after hepatic resection of metastatic colorectal cancer and to formulate criteria for optimal resection. PATIENTS: We reviewed records of 74 patients (44 men, 30 women) who underwent resection of colorectal liver metastases. MAIN OUTCOME MEASURES: Sex, age, primary tumor location; Dukes tumor stage; disease-free interval after primary resection (synchronous vs metachronous); location, number, size, and distribution of liver metastases; operative complications; and mortality. RESULTS: The primary tumor location was rectosigmoid in 46 patients and the colon in the others. The tumor stage was Dukes A in one patient, Dukes B in 16, Dukes C in 31, and Dukes D (synchronous metastases) in 26. The disease-free interval was less than 12 months in 38 patients and 12 months or more in 36. The location of the metastases was the right lobe in 42 patients, left lobe in 22, and bilateral in seven. The cancer was unilobar in 55 patients and bilobar in 18. Surgical resection included wedge resection in 23 patients, segmentectomy in 30, lobectomy in seven, and trisegmentectomy in 12. The number of lesions resected was one in 50 patients, two or three in 18, and four or more in five. Nine patients had repeated liver resections because of recurrence. There were five postoperative deaths within 60 days (7%), four of which occurred after extended resection and were complicated by delayed liver failure and multisystem failure. An additional death occurred at 65 days after an apparently uneventful initial convalescence. Overall median survival was 35 months; actuarial 5- and 10-year survival rates were 24% and 12% respectively. There were significant relationships with survival (P<.05) for the number of metastases (three or fewer vs four or more), bilobar vs unilobar metastases, and extent of liver resection (wedge and segmental vs lobectomy and trisegmentectomy). A multiple logistic regression model (multivariate analysis) showed a significant correlation with survival (P<.05) for distribution of metastases (bilobar vs unilobar) and extent of resection (wedge and segmental vs lobectomy and trisegmentectomy). CONCLUSION: Patient selection for hepatic resection of colorectal cancer metastases based on standard clinical and tumor outcome variables should be expected to achieve long-term survival with low morbidity and mortality in bilobar disease or extended resection should generally be avoided, especially in medically compromised patients.

Pelvic exenteration for recurrent rectal cancer.

Recurrent rectal carcinoma presents a formidable problem for patient and surgeon. Isolated recurrences of rectal carcinoma have been reported from 7% to 33% with a median of 14%. Increasing recurrence is associated with increasing Dukes's stage. The reason for high recurrences is probably related to the limited anatomic margins that can be obtained in the pelvis during primary resections. Patients who have recurrence after a low-anterior resection are more likely to present with nonfixed, surgically correctable lesions versus recurrences after abdominoperineal resection. The most common symptom related to pelvic recurrence is pain, which may be perineal or radiate to the lower extremities. The 5-year survival rate among unresected patients with locoregional recurrences is 4%. These patients are often in extreme pain with lower extremity swelling and perineal lesions. Although many patients will be palliated by radiation, few will experience long-term relief (6 to 8 months). A thorough physical examination should include rectal and pelvic exams to evaluate tumor extension and fixation. Computed tomographic studies are helpful when taken serially to evaluate pelvic recurrence or liver metastases. Fineneedle biopsies may also be done under CT guidance. Additional mandatory films include plain chest roentgenograph, lumbosacral spine films, and bone scan to rule out sacral involvement, which would preclude sacral resection. Magnetic resonance imaging has recently been shown to be effective in evaluating pelvic side wall involvement and metastatic lymphadenopathy. Although extensive involvement would preclude aggressive resection, in one series, 50% of patients were amenable to resection. Pelvic exenteration should include the tumor mass, along with any involved organs and their lymphatic drainage, with a 2 cm margin. Complications are increased in patients who have undergone radiation, who have undergone procedures that include urinary diversions, and who have recurrent disease. Cure rates of 30% to 50% have been reported using pelvic exenteration for rectal cancer. Recurrent disease presents a significant problem in that normal anatomic planes have been disrupted. In one series, rectal recurrences treated with pelvic exenteration had a 66% recurrence rate. In addition, there is often a posterior component to the recurrence. Although the complication rate is high, the only chance for cure in these patients would be an abdominosacral resection. There appears to be a select group of patients with recurrent locoregional disease, who benefit from sacral resection with a 20% to 30%, 5-year survival rate.

Oncogene protein co-expression. Value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma.

OBJECTIVE: A refinement of prognostic variables using traditional pathologic markers integrated with oncogene proteins, enzymes, and hormonal factors may enhance the ability to predict for recurrence or survival in patients with mammary carcinoma. Although various oncogenes and oncogene products have been identified in human breast carcinoma, their relationship to disease outcome remains controversial. METHODS: Using the monoclonal antibodies cS93.1, 9E1.0, F235-1.7.1, and PAb 1801 against each oncogene protein studied, the avidin-biotin complex immunoperoxidase method provided immunohistochemical staining of bound oncogene protein for c-fos, c-myc, Ha-ras, and p53, respectively. Analyses were made on archival pathology tissues of 85 breast cancer patients (stages I, IIA, and IIB). Forty patients (47%) had recurrence of disease; 45 remained free of local-regional or distant disease at mean follow-up of 48 months (range 6-180 months). Molecular biological data were merged with clinicopathologic demographics 1) to determine the frequency of single or co-expression of oncogenes in this patient population; 2) to evaluate the value of these molecular protein markers to predict probability of recurrence; and 3) to determine worth of the studied oncogenes to correlate with traditional clinical pathologic parameters and overall survival. RESULTS: In this study, oncogene expression had statistical correlation for recurrence with increasing co-expression: one oncogene 17.2%, two oncogenes 56.3%, three or four oncogenes, 100% (p = 0.001). Increasing oncogene or co-oncogene expression correlated with statistically significant reduction in disease-free and overall survival; with no expression of oncogenes, disease-free survival was 30 (SE +/- 5.7) months and overall survival was 56.4 (SE +/- 4.57) months. With expression of three oncogenes, disease-free survival was 12 (SE +/- 1.23) months (p = 0.0018) and overall survival was 23.4 (SE +/- 3.38) months (p = 0.0025). In univariate Wilcoxon analysis, oncogene expression was the most significant variable to determine survival (p = 0.035); in multivariate analysis, age and oncogene co-expression each emerged as the most significant variables for overall survival. For the proportional hazards regression model, oncogene co-expression was significant (p = 0.0104, risk-ratio 1.914) and correlated with age and tumor size as significant variables. Ha-ras and c-fos both emerged as important individual oncogene proteins to affect survival (p = 0.0925, risk-ratio 3.517 and p = 0.025, risk-ratio 4.214, respectively). The proto-oncogene c-myc and the antitumor suppressor gene p53 did not have significant effects as individual oncogenes to influence survival. CONCLUSIONS: Approximately one fifth of the breast cancer patients in this analysis (disease-free and recurrent) expressed only a single oncogene marker (c-fos, c-myc, Ha-ras, or p53); one quarter of patients with recurrent disease expressed only one oncogene protein. Single oncogene expression did not possess independent prognostic significance for prediction of recurrence. Further, p53 mutations did not function as independent correlates for prognosis. The co-expression of the studied proto-oncogenes (c-myc, Ha-ras) and the nuclear transcriptional protein (c-fos) functioned as a strong prognostic correlate for recurrence and survival; the effect of individual oncogenes to predict survival was greatest for Ha-ras and c-fos. Immediate or early co-expression of three oncogene proteins in neoplastic transformation endowed cells of invasive carcinoma with an aggressive phenotype. This aggressive phenotype was evident in a small percentage of the studied population (11%) and predicted adverse disease-free and overall survival. These findings suggest that oncogene co-expression possesses significant prognostic and potential therapeutic value; incorporation of this molecular technology into future prospective randomized trials is advisable.

Management of ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is an early, localized stage of breast carcinoma that has an excellent prognosis when it is properly treated. The significant increase in the frequency of diagnosis of DCIS in recent years is the result of both better recognition of DCIS among pathologists and widespread use of screening mammography. Multicentricity, bilaterality and histologic subtype are important considerations in the management of this disease. The clinical presentation of DCIS is the presence of either a palpable mass or a mammographic abnormality, most frequently in the form of an area of microcalcifications. For several decades, total mastectomy was considered the appropriate treatment for DCIS, and it should still be considered the standard to which more conservative forms of treatment must be compared. Breast conservation surgery has been used with increasing frequency in the treatment of DCIS but the adequacy of this approach remains subject to controversy. Segmental mastectomy alone may be applied with caution in carefully selected patients, while the rest of the patients undergoing breast conservation surgery should be treated with breast irradiation. Axillary node dissection is generally considered unnecessary in the treatment of DCIS. There is no role for adjuvant chemotherapy in the management of this disease. The role of tamoxifen in the treatment of DCIS is not clearly defined and it should be given only to patients enrolled in clinical trials. Ongoing research should clarify the controversies surrounding DCIS and enable us to define the optimal management for this disease.

Pelvic resection of recurrent rectal cancer.

OBJECTIVE: The authors describe their experience with pelvic resection of recurrent rectal cancer with emphasis on patient selection for curative intent based on known tumor risk factors. SUMMARY BACKGROUND DATA: Pelvic recurrence is a formidable problem in 30% of patients who have undergone a curative resection of primary rectal cancer. Although radiation can reduce the development of local recurrence and can provide palliation to many patients with localized disease, it is not curative. The authors and others have used the technique of abdominal sacral resection (ABSR) with or without pelvic exenteration to resect pelvic recurrence and its musculoskeletal extensions in selected patients with satisfactory long-term survival. METHODS: The technique of ABSR with or without pelvic exenteration or resection of pelvic viscera, which the authors have described previously, was used in 53 patients with recurrent rectal cancer--47 patients for curative intent and 6 for palliation. Previous surgeries were abdominal perineal resections (APRs) in 26 patients, anterior resections in 19 patients, and other procedures in 2 patients; original primary Dukes' stage was B in 52% and C in 48%. Almost all patients had been irradiated previously, generally in the 4000 to 5900 cGy range. Preoperative carcinoembryonic antigen (CEA) levels (before ABSR) were elevated (> 5 ng/mL) in 54%. RESULTS: Postoperative morbidity was encountered in most patients. Mortality was 8.5% in the curative group. Long-term survival for 4 years was achieved in 14 of 43 patients (33%), and 10 patients were alive with an acceptable quality of life after 5 years. Patients who had previous anterior resections or whose preoperative CEA levels were less than 10 ng/mL had a survival rate of approximately 45%, whereas patients with previous APRs and preoperative CEA levels greater than 10 ng/mL had a survival rate of only 15% to 18%. Patients with bone marrow invasion, positive margins, or pelvic node metastases had a median survival of only 10 months. CONCLUSIONS: Pelvic recurrence of rectal cancer can be resected safely with expectation of long-term survival of 33%. Patient selection based on known risk factors can identify patients most likely to benefit from resection and eliminate those who should be treated for palliation only.