Edward W. Martin

Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer

PURPOSE Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups. PATIENTS AND METHODS MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed. RESULTS Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations. CONCLUSION One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.

Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles.

The cancer microenvironment and interaction between cancer and stromal cells play critical roles in tumor development and progression. The molecular features of cancer stroma are less well understood than those of cancer cells. Cancer-associated stromal fibroblasts are the predominant component of stroma associated with colon cancer and its functions remain unclear. Fibroblast cell cultures were established from metastatic colon cancer in liver, liver away from the metastatic lesions, and skin from three patients with metastatic colorectal cancer. We generated expression profiles of cancer-associated fibroblasts using oligochip arrays and compared them to those of uninvolved fibroblasts. The conditioned media from the cancer-associated fibroblast cultures enhanced proliferation of colon cancer cell line HCT116 to a greater extent than cultures from uninvolved fibroblasts. In microarray expression analysis, cancer-associated fibroblasts clustered tightly into one group and skin fibroblasts into another. Approximately 170 of 22 000 genes were up-regulated in cancer-associated fibroblasts (fold change>2, P<0.05) as compared to skin fibroblasts, including many genes encoding cell adhesion molecules, growth factors, and COX2. By immunohistochemistry in-vivo, we confirmed COX2 and TGFB2 expression in cancer-associated fibroblasts in metastatic colon cancer. The distinct molecular expression profiles of cancer-associated fibroblasts in colon cancer metastasis support the notion that these fibroblasts form a favorable microenvironment for cancer cells.

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology.

CEA-directed second-look surgery in the asymptomatic patient after primary resection of colorectal carcinoma.

Since 1971, serial carcinoembryonic antigen (CEA) levels have been measured to monitor patients after primary resection of colorectal cancer. Based solely on a rise in CEA level above the baseline established after primary resection, 146 patients were readmitted to the hospital. Chest films, liver-spleen scan, colonoscopy, bone scan, abdominal and pelvic CAT scan, and hepatic arteriograms were performed, and elevated CEA levels were confirmed before reexploration was undertaken. In the 146 patients, 139 (95%) had recurrences, and 81 (58%) of these were resectable for potential cure. Two of the first 22 patients re-explored between 1971 and 1975 are still living 11 and 14 years after second look; of 45 patients reoperated upon from 1976 through 1979 and followed for at least 5 years, 14 (31%) are still living. A rise in CEA above the baseline established after primary resection proved to be a sensitive indicator of recurrence and prompted reexploration before symptoms developed. Early alternative therapy was begun in patients with unresectable recurrences.

Gastric partitioning for morbid obesity.

The complication rate in jejunoileal bypass for morbid obesity is unacceptably high. Gastric bypass is technically difficult. In our series, 115 patients have undergone gastric partitioning for morbid obesity. The operation consists of stapling across the stomach below the gastroesophageal junction, leaving a gastric food reservoir of 50–60 cc. A 1 cm opening is left in the central portion of the staple line, allowing slow emptying into the distal stomach. The result is a reduced eating capacity and frequency which produce loss in weight. Three-quarters of the patients are women, and the age range is 17–62 years. Preoperative weights averaged 147 kg. Mean operative time was 48 minutes, and postoperative stay was 6.2 days. All patients were extensively evaluated preoperatively with upper GI series, cholecystogram, a number of blood chemistry tests, and endocrinologic and psychiatric consultations. All patients underwent a preoperative Minnesota Multiphasic Personality Inventory test. Cholecystectomy for cholelithiasis was performed on 18% of the patients at the time of operation. Of the seven patients operated on more than one year ago, live have lost an average of 31.6% of their preoperative weight. Of the 12 operated on less than one year but more than six months ago, eight have lost an average of 21% of their initial weight. The early failure rate of 33% has been reduced to 15% at present. One death occurred from pulmonary embolus 10 days following discharge, giving a mortality rate of .08%. The complication rate is 10%, comprising two pulmonary emboli, two psychoses, one wound dehiscence, one wound hernia, and ten wound infections, six of which were minor. There have been no complications of ulcer disease, reflux esophagitis, liver disease, renal disease, or metabolic disorders. Gastric partitioning is a safe, fast effective alternative for the surgical treatment of morbid obesity.

Determinants of Survival following Hepatic Resection for Metastatic Colorectal Cancer

Abstract. Hepatic resection remains the only potentially curative treatment for metastatic colorectal cancer. This retrospective review study was undertaken in an attempt to identify factors that influence patient survival following hepatic resection for metastatic colorectal cancer. From January 1978 to December 1993, a total of 301 patients underwent a total of 345 planned hepatic resections for metastatic colorectal cancer. Of those, 245 patients had one resection, 44 had two resections, and 12 had three resections. For all patients the overall median survival was 20.6 months, operative mortality was 1.1%, and overall morbidity was 17.2%. Average hospital stay was 9 days. Statistical analysis included univariate analysis using log rank comparisons, Kaplan-Meier survival curves, and multivariate analysis using Cox proportional hazards regression. The statistically significant factors that influenced survival were distribution of liver metastases, unilobar versus bilobar (p= 0.0001), resected versus nonresected (p < 0.0001), and tumor-free surgical margins versus positive margins (p= 0.001). Surprisingly, the disease-free interval and the original stage of the primary tumor did not predict survival (p= not significant). Other factors that had no influence on survival were type of resection, size and number of liver metastases, ABO blood group, and the number of perioperative blood transfusions. For those patients who underwent resection of unilobar metastases with tumor-free margins, the 5-year survival rate was 29% with a median survival of 35 months and eight survivors > 7 years. In addition, one patient with bilobar disease had survival > 7 years and five patients who had resection of hepatic metastases and extrahepatic cancer simultaneously had survival > 3 years. Our data support the concept that patients with unilobar metastatic disease who undergo surgical resection with tumor-free surgical margins can be afforded a significant opportunity at long-term survival with acceptable morbidity, mortality, and hospital stay. Also, certain patients with bilobar or extrahepatic disease (or both) who undergo complete resection can enjoy a long-term survival. In these subgroups of patients resection should be considered on an individual basis.

The USE of CEA as an early indicator for gastrointestinal tumor recurrence and second‐look procedures

Since 1972 plasma CEA levels of 25 cancer patients have been assayed to evaluate the reliability of CEA as an early indicator of recurrent gastrointestinal cancer. Identification of significant elevations in CEA levels required definition of exactly what a given value meant. Intraassay and interassay accuracy was determined and graphed as a CEA NOMOGRAM, which measures the observed CEA level against the 95% confidence limits for that observation and thus can be used to identify statistically significant increases. A statistically significant rise above a baseline value established by the NOMOGRAM proved to be a correct indicator of tumor recurrence in 22 (88%) of 25 patients who underwent second‐look intraabdominal operations (22 colorectal, 2 gastric, and 1 pancreatic). In each case, other accepted procedures, such as liver enzymes, scans, and x‐rays, were nondiagnostic. Of the 22 patients with proved tumor recurrence, 16 (73%) had distant metastases and 6 (27%) had localized tumors. One patient remains tumor‐free three years after second‐look operation and has had no significant change in CEA levels. More frequent serial CEA determinations combined with sound clinical judgment should facilitate earlier detection of recurrent gastrointestinal cancer.

Cholecystectomy in elderly patients

Cholecystectomy was performed in 93 patients over the age of 70 years with an overall mortality of 7.5 percent. Complications occurred in 28 percent. Patients who underwent elective operations fared far better than those who required emergency surgery. Of the 50 patients who underwent elective cholecystectomy, there was 1 death (2 percent), and 10 patients (20 percent) experienced complications. In contrast, of the 43 patients who required emergency operation, 6 died (14 percent). Complications occurred in 14 (33 percent). Elective cholecystectomy in the elderly patient with symptomatic biliary tract disease is advocated before acute complications that necessitate emergency operation develop.

Method for locating, differentiating, and removing neoplasms

The present invention is addressed to a method for the improved localization, differentiation, and removal of neoplastic tissue in animals. In particular, one aspect of the present invention involves a surgical procedure wherein an animal suspected of containing neoplastic tissue is surgically accessed and the tissue therein examined visually and by palpation for evidence of neoplastic tissue. The improved methodology commences with the administering to the animal of an effective amount of a labelled antibody specific for neoplastic tissue and labelled with a radioactive isotope exhibiting specific photon emissions of energy levels. Next, and importantly, the surgial procedure is delayed for a time interval following said administering for permitting the labelled antibody to preferentially concentrate in any neoplastic tissue present in the animal so as to increase the ratio of photon emissions from neoplastic tissue to background photon emissions in said animal. Thereafter, an operative field of the animal is surgically accessed and tissue within the operative field to be examined for neoplastic tissue has the background photon emission count determined. Once the background photon emission account for tissue within the operative field has been determined, a handheld probe is manually positioned within the operative field adjacent tissue suspected of being neoplastic. The probe is configured for fascile hand positioning and maneuvering within the operative field of the animal. The probe is characterized by having a collimatable radiation detector having a selective photon entrance and having an output deriving discrete signals responsive to photon emissions when said entrance is positioned immediately adjacent thereto. The probe further comprises amplifier means having an input coupled with said radiation detector output and responsive to said discrete signals to provide corresponding amplified output pulses. Finally, the probe comprises readout means responsive to said output pulses and actuable to an initial condition for commencing the provision of a perceptible indication of an indicia corresponding to the number of said output pulses received. From the perceptible indication, the extent of tissue exhibiting a number of output pulses having a value above background output pulses is determined and such determined tissue removed surgically. Thereafter, the probe is manually positioned adjacent tissue surrounding the surgically removed tissue to determined from said perceptible indication whether any of said surrounding tissue still exhibits a number of output pulses having a value above said background output pulses. Any adjacent tissue surrounding the initial surgically removed tissue which does exhibit an increased number of output pulses is surgically removed additonally. Thereafter, the margins again are examined with the probe in order to ensure that all tissue exhibiting a number of output pulses having a value above the background output pulses has been removed.

Intraoperative detection of colorectal cancer with radioimmunoguided surgery and CC49, a second-generation monoclonal antibody

Radioimmunoguided surgery (RIGS) has been employed intra-operatively in cases of colorectal cancer to assess the extent of local tumor spread and metastatic disease. This technique uses radiolabcled monoclonal antibodies (MAbs) directed against tumor-associated antigens, and a hand-held gamma-detection probe to detect the radiolabel fixed to tumor tissue. Recently introduced is an MAb directed against tumor-associated glycoprotcin (anti-TAG), CC49. Sixty patients were entered into the initial study. Eighteen of 21 (86%) primary tumors were localized by the CC49 MAb and the gamma-detecting probe. Twenty-nine of 30 (97%) recurrent tumors were localized. Antibody dose did not affect localization. Specimens were divided into tissue types I through IV, based on antibody localization and hematoxylin and cosin (H&E) staining: type I, RIGS (-) and histologically (-); type II, RIGS (-) and histologically (+); type III, RIGS (+) and histologically (-); type IV, RIGS (+) and histologically (+). Type IV tissues were further classified by whether they were grossly apparent, IVa, or grossly inapparent, IVb (occult). Occult tumor found by RIGS and confirmed by H&E staining (type IV) had localization ratios similar to RIGS-positive, histology-negative tissue (type III). Traditionally found cancer (type IV) had significantly higher ratios. In 12 of 24 patients (50%) with primary tumors and 14 of 30 patients (47%) with recurrent tumors, RIGS with CC49 altered the planned operative procedure. Radioimmunoguidcd surgery with CC49 provides useful, immediate intraoperativc information not available by other techniques.