Mark W. Arnold

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.

Rectocele repair. Four years' experience.

A retrospective review of 64 rectocele repairs done over a four-year period was performed. The most common indication for repair was constipation. Thirty-five patients were repaired transanally, and 29 were repaired transvaginally. The overall morbidity was 34 percent, and the overall mortality was 0 percent. The most common complication was urinary retention in 12.5 percent. There was no difference in complications between techniques. Of 46 patients contacted for follow-up, 25 (54 percent) still complained of constipation, 17 (34 percent) had partial incontinence, 8 (17 percent) noted persistent rectal pain, 15 (32 percent) mentioned occasional rectal bleeding, and 10 (22 percent) complained of vaginal tightness or sexual dysfunction. Thirty-seven (80 percent) patients stated that they had improved after surgery. Except for persistent rectal pain, there was no difference in results between transanal and transvaginal repairs. Those undergoing transvaginal repair had a much greater problem with pain. Our relatively poor results may be due to an unselective approach to rectocele repair. The presence of both constipation and a rectocele does not imply an association, and a complete anorectal physiologic examination should precede repair. There is no functional difference between transvaginal and transanal rectocele repair.

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.

Modulation of Genetic and Epigenetic Biomarkers of Colorectal Cancer in Humans by Black Raspberries: A Phase I Pilot Study

Purpose: This study evaluated the effects of black raspberries (BRBs) on biomarkers of tumor development in the human colon and rectum including methylation of relevant tumor suppressor genes, cell proliferation, apoptosis, angiogenesis, and expression of Wnt pathway genes. Experimental Design: Biopsies of adjacent normal tissues and colorectal adenocarcinomas were taken from 20 patients before and after oral consumption of BRB powder (60 g/d) for 1–9 weeks. Methylation status of promoter regions of five tumor suppressor genes was quantified. Protein expression of DNA methyltransferase 1 (DNMT1) and genes associated with cell proliferation, apoptosis, angiogenesis, and Wnt signaling were measured. Results: The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1–9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction. Conclusions: These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted. Clin Cancer Res; 17(3); 598–610. ©2010 AACR.

Pain, Depression, and Fatigue: Loneliness as a Longitudinal Risk Factor

OBJECTIVE Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. METHOD We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. RESULTS Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. CONCLUSIONS Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.

Positron Emission Tomography Affects Surgical Management in Recurrent Colorectal Cancer Patients

Background: We determined the effect of positron emission tomography (PET) on surgical decision-making in patients with metastatic or recurrent colorectal cancer.Methods: A total of 114 patients with advanced colorectal cancer were imaged with computed tomography (CT) and PET scans. The PET and CT scans were independently interpreted before surgery and recorded.Results: Forty-two of the 114 patients had resectable disease on the basis of CT. PET altered therapy in 17 (40%) of these 42 patients on the basis of the following results: extrahepatic disease (n = 9), bilobar involvement (n = 3), thoracic involvement (n = 5), retroperitoneal lymphadenopathy (n = 2), bone involvement (n = 1), and supraclavicular disease (n = 1). In 25 patients with liver metastases only, PET found additional disease in 18 (72%), extrahepatic disease in 11, chest disease in 13, retroperitoneal lymphadenopathy in 4, and bone disease in 3. In five patients, both scans underestimated small-volume peritoneal metastases discovered at laparotomy.Conclusions: PET altered therapy in 40% of patients. In patients with isolated liver involvement, 72% had more extensive disease that precluded surgical resection. PET scans should be used in the management of patients with recurrent colorectal cancer who are being considered for potentially curative surgery.

Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases

AbstractBackground: Intraperitoneal (i.p.) metastases pose a special problem for surgical treatment because of their multiplicity and microscopic size. This study was designed to examine the feasibility and safety of i.p. hyperthermic perfusion (IPHP) with mitomycin C (MMC) for treating recurrent colorectal cancer. Methods: Fifteen patients with metastatic colon cancer were treated. All patients underwent cytoreductive procedures leaving only residual i.p. metastases <1 cm in diameter. All patients had received prior systemic chemotherapy, but their disease had progressed. Intraperitoneal chemotherapy was administered through three large catheters (28 French) using a closed system of two pumps, a heat exchanger, and two filters. After the patient’s abdominal temperature reached 41°C, 45–60 mg of MMC was circulated intraperitoneally for 1 h. Results: The majority of patients had various anastomoses: small bowel (n=11), large bowel (n=5), and urologic (n=5). No anastomotic complications occurred in any of the patients. One patient experienced severe systemic MMC toxicity, which caused cytopenia and respiratory depression. In all patients the carcinoembryonic antigen (CEA) level decreased after surgery and IPHP. Median follow-up was 10 months, and recurrence was defined as an elevation in CEA level. Disease recurred in three patients within 5 months, and disease recurred in seven other patients over the next 3 months; one patient remains clinically free of disease after 8 months. Conclusion: Our data suggest that IPHP is a safe palliative method of treatment for patients with peritoneal carcinomatosis. The median patient response duration of 6 months may warrant consideration of a repeat IPHP procedure at that time.

Radioimmunoguided surgery in primary colorectal carcinoma: An intraoperative prognostic tool and adjuvant to traditional staging

BACKGROUND The prognostic value of traditional staging classification for colorectal cancer has changed little since Dukes created the first staging scheme. Some patients with known metastatic disease are long-term survivors, while other patients with local disease die early. New intraoperative cancer detection technology, the radioimmunoguided surgery (RIGS) system, is being studied as a tool to aid in prediction of patient outcome. PATIENTS AND METHODS Thirty-one patients with primary colorectal cancer were injected with the monoclonal antibody CC49, which was radiolabeled with iodine 125 (125I). A hand-held gamma-detecting probe was used at surgery to detect the radiolabeled antibody. Patients were classified as to the presence or absence of 125I-CC49-positive residual tissue at the close of surgery. Patient survival was analyzed. RESULTS Follow-up ranged from 30 to 54 months. Survival of 11 stage I or II patients was longer than in 20 stage III or IV patients (P = 0.019). All 14 patients cleared of RIGS-positive tissue were alive at last follow-up, while 15 of 17 RIGS-positive patients died of their disease (P < 0.0001). CONCLUSIONS The RIGS system used during surgery provides the surgeon with immediate prognostic information on patients with colorectal cancer and supplements traditional pathologic staging.

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Importance Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Radioimmunoguided surgery system improves survival for patients with recurrent colorectal cancer

BACKGROUND Advanced colorectal cancer is fatal. No systemic therapies have resulted in increased patient survival. METHODS One hundred thirty-one patients with recurrent colorectal cancer enrolled in two prospective nonrandomized studies using Radioimmunoguided Surgery (RIGS) system from May 1986 to April 1992 have been analyzed. Eighty-six patients were injected with the anti-tumor-associated glycoprotein (TAG) antibody B72.3, and 45 patients were injected with the second-generation anti-TAG monoclonal antibody CC49. Both monoclonal antibodies were radiolabeled with iodine 125. Both traditional and RIGS explorations were used to determine resectability. Follow-up was a minimum of 28 months. RESULTS Forty-nine (37.4%) of the 131 patients underwent a curative resection. Twenty-seven of the patients (55%) are alive 2 to 8 years after operation. The cancers of the remaining 82 patients were unresectable, and only two patients (2%) are alive. In this unresectable group alternative intraoperative therapeutic methods (intraoperative radiation therapy, intraperitoneal hyperthermic perfusion, hepatic lines, and brachytherapy) were tried in 11 patients with two survivors. There were no survivors in 18 patients whose cancers were found to be traditionally resectable but unresectable with RIGS or in the 53 patients whose cancers were clearly unresectable by traditional exploration. Patients selected for curative resection had significantly increased survival (p < 0.0001). CONCLUSIONS As an intraoperative tool RIGS significantly improves the selection of patients for curative resection.