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Supplementary Figures 1-11, Methods and Materials from Phosphatase PRL-3 Is a Direct Regulatory Target of TGFβ in Colon Cancer Metastasis

Genomic testing and targeted use of non-steroidal anti-inflammatory drugs (NSAIDs) may mitigate cancer recurrence risks. This study examines colorectal cancer (CRC) survivors’ interest and receptivity to these strategies. Patients diagnosed with stage I-III CRC in 2004–2012 were recruited through the New Mexico Cancer Registry to complete a cancer survivorship experiences survey. We assessed interest in genomic testing, daily aspirin (ASA) and NSAID use, and receptivity to future daily ASA/NSAIDs. Descriptive statistics and multivariable logistic regression models estimated factors associated with genomic testing interest. Receptivity to future ASA/NSAIDs use was estimated for non-users of ASA/NSAIDs. Among CRC survivors (n = 273), 83% endorsed interest in genomic testing, 25% were ASA users and 47% ASA/NSAIDs users. In our final model, genomic testing interest was associated with being uncoupled [OR = 4.11; 95% CI = 1.49–11.35], low income [OR = 0.35, 95% CI: 0.14–0.88], smoking history [OR = 0.35, 95% CI: 0.14–0.90], low [OR: 0.33, 95% CI: 0.07–1.43] and moderate [OR: 0.26, 95% CI: 0.11–0.61] health literacy, and personal CRC risk worry [OR: 2.86, 95% CI: 1.63–5.02, p = 0.0002]. In our final model, ASA use was associated with age [OR: 1.05, 95% CI: 1.01–1.10] and cardiovascular disease history [OR: 2.42, 95% CI: 1.23–4.73, p = 0.010]. Among non-users ASA/NSAIDs, 83% reported receptivity to ASA/NSAIDs to reduce cancer risks, and no significant correlates were identified. The majority of survivors’ expressed genomic testing interest and endorsed receptivity toward ASA/NSAIDs use for cancer risk management. Further research to optimize ASA/NSAIDs use guided by genomic testing is warranted. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-021-00574-9.

Robotic surgery is attractive for resection of low rectal cancer due to greater dexterity and visualization, but its benefit is poorly understood. We aimed to determine if operative approach impacts radial margin positivity (RMP) and postoperative outcomes among patients undergoing abdominoperineal resection (APR). This was a retrospective cohort study of patients from the National Surgical Quality Improvement Program who underwent APR for low rectal cancer from 2016 to 2019. Patients were stratified by operative approach: robotic, laparoscopic, and open APR (R-APR, L-APR, and O-APR). Emergent cases were excluded. The primary outcome was RMP. 30-day postoperative outcomes were also evaluated, using logistic regression analysis. Among 1,807 patients, 452 (25.0%) underwent R-APR, 474 (26.2%) L-APR, and 881 (48.8%) O-APR. No differences regarding RMP (13.5% R-APR vs. 10.8% L-APR vs. 12.3% O-APR, p = 0.44), distal margin positivity, positive nodes, readmission, or operative time were observed between operative approaches. Adjusted analysis confirmed that operative approach did not predict RMP (p > 0.05 for all). Risk factors for RMP included American Society of Anesthesiologists (ASA) classification III (ASA I-II ref; OR 1.46, p = 0.039), pT3-4 stage (T0-2 ref, OR 4.02, p

Rectal cancer treatment is often multimodal, comprising of surgery, chemotherapy, and radiotherapy. However, the impact of coordination between these modalities is currently unknown. We aimed to assess whether delivery of nonsurgical therapy within same facility as surgery impacts survival in patients with rectal cancer.A patient cohort with rectal cancer stages II to IV who received multimodal treatment between 2004 and 2016 from National Cancer Database was retrospectively analyzed. Patients were categorized into three groups: (A) surgery + chemotherapy + radiotherapy at same facility (surgery + 2); (B) surgery + chemotherapy or radiotherapy at same facility (surgery + 1); or (C) only surgery at reporting facility (chemotherapy + radiotherapy elsewhere; surgery + 0). The primary outcome was 5-year overall survival (OS), analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional-hazards models.A total of 44,716 patients (16,985 [37.98%] surgery + 2, 12,317 [27.54%] surgery + 1, and 15,414 [34.47%] surgery + 0) were included. In univariate analysis, we observed that surgery+2 patients had significantly greater 5-year OS compared to surgery + 1 or surgery + 0 patients (5-year OS: 63.46% vs 62.50% vs 61.41%, respectively; P= .002). We observed similar results in multivariable Cox proportional-hazards analysis, with surgery + 0 group demonstrating increased hazard of mortality when compared to surgery + 2 group (HR: 1.09; P.001). These results held true after stratification by stage for stage II (HR 1.10; P= .022) and stage III (HR 1.12; P.001) but not for stage IV (P= .474).Greater degree of care coordination within the same facility is associated with greater OS in patients with stage II to III rectal cancer. This finding illustrates the importance of interdisciplinary collaboration in multimodal rectal cancer therapy.

Sentinel lymph nodes (SLNs) have for centuries been recognized as reliable and effective filters of foreign material, including tumor cells. Since the mid-20th century, this principle has been applied to oncologic care through sentinel lymph node biopsy (SLNB), which detects and quantifies the extent of regional metastasis. First pioneered in parotid tumors, the technique has since expanded to many branches of oncology including breast, melanoma, head and neck, gastrointestinal, and gynecologic tumors. Across these varied pathologies, SLNB has repeatedly demonstrated non-inferiority to traditionally more extensive lymphatic dissections, which are associated with higher rates of infectious, lymphatic, and neuropathic complications. In an era of ever increasing management options, this technique also provides prognostic and predictive information key to therapeutic selection. This paper reviews the history of the practice of SLNB and its evolution over the decades in a number of oncologic disciplines.

SUMMARYCrosstalk between disparate membrane receptors is thought to drive oncogenic signaling and allow for therapeutic resistance. EGFR and RON are members of two unique receptor tyrosine kinase (RTK) subfamilies that engage in crosstalk through unknown mechanisms. We combined high resolution imaging with biochemical studies and structural mutants to understand how EGFR and RON communicate. We found that EGF stimulation results in EGFR-dependent RON phosphorylation. Crosstalk is unidirectional, since MSP stimulation of RON does not trigger EGFR phosphorylation. Two-color single particle tracking captured the formation of complexes between RON and EGFR, supporting a role for direct interactions in propagating crosstalk. We further show that RON is a substrate for EGFR kinase, and transactivation of RON requires the formation of a signaling competent EGFR dimer. These results identify critical structural features of EGFR/RON crosstalk and provide new mechanistic insights into therapeutic resistance.

Background The purpose of this study was to assess the impact of surgical delays on short- and long-term survival among colon cancer patients. Methods Adult patients undergoing surgery for stage I, II, or III colon cancer were identified from the National Cancer Database (2010-2016). After categorization by wait times from diagnosis to surgery (12 weeks), 30-day mortality, 90-day mortality, and 5-year overall survival were compared between patients both overall and after stratification by pathological disease stage. Results Among 187 394 colon cancer patients, 24.2% waited 12 weeks for surgery. Patients undergoing surgery 3-6 weeks after colon cancer diagnosis exhibited the best 30-day mortality (1.3%), 90-day mortality (2.3%), and 5-year overall survival (71.8%) ( P < .001 for all). After risk-adjusting for confounders, all wait times beyond 6 weeks were associated with worse 5-year overall survival (6-9 weeks: HR 1.10, 95% CI 1.06-1.15; 9-12 weeks: HR 1.25, 95% CI 1.18-1.33; >12 weeks: HR 1.43, 95% CI 1.35-1.52; P < .001 for all). Subgroup analysis after stratification by disease stage demonstrated that patients with stage III colon cancer were able to wait up to 9 weeks before exhibiting worse 5-year overall survival, compared to 6 weeks for patients with stage I or II disease. Conclusions Colon cancer patients should undergo surgery 3-6 weeks after diagnosis, as all surgical delays beyond 6 weeks were associated with worse 30-day mortality, 90-day mortality, and 5-year overall survival.

INTRODUCTION/BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity, measured using next-generation sequencing assays. MATERIALS AND METHODS: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2) who received nCRT. High read-depth sequencing of >400 cancer-relevant genes was performed using the Ion Ampliseq Comprehensive Cancer Panel™ assay. Tumor mutations and variant allele frequencies were used to calculate Mutant Allele Tumor Heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection. RESULTS: Biopsy samples from 21 patient tumors were analyzed. 8 patients were noted to have complete response, 2 were moderate, 4 minimal and 7 demonstrated poor response. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to those with complete response (p=0.039). CONCLUSION: The application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.

PURPOSE: Improvements in colorectal cancer (CRC) prevention, early detection, and treatment have resulted in substantial gains in survival. However, the health-related quality of life (HRQoL) of CRC survivors often depends on access to supportive care, which differs by survivors’ socioeconomic characteristics. The purpose of this study was to investigate the relationship between socioeconomic characteristics and HRQoL in a diverse group of CRC survivors. METHODS: We conducted a population-based, cross-sectional study to examine the association between socioeconomic factors (household income, health literacy, and insurance status) and HRQoL domains of pain interference, fatigue, physical function, sleep disturbance, anxiety, and depression. PROMIS(®) Short Forms v.2.0 were used to assess domains of HRQoL. Linear regression modeling was used to estimate the coefficient representing the average HRQoL domain score and its 95% confidence interval (CI). RESULTS: Three-hundred-one CRC survivors participated in the survey. Low-income (≤$30,000) CRC survivors had, on average, a 4.70-point (95% CI 1.10-8.28) higher pain interference score, a 7.02-point (95% CI 3.27-10.77) higher fatigue score, a 5.13-point (95% CI −8.56 to −1.71) lower physical function score, and a 4.44-point (95% 1.40-7.49) higher depression score than CRC survivors with an income ≥$70,000. Survivors with Medicaid insurance reported significantly greater pain interference and worse physical function than privately-insured survivors. Survivors with low health literacy reported significantly greater pain interference compared to survivors with high health literacy. CONCLUSIONS: Substantial socioeconomic disparities in HRQoL were observed in this diverse population of CRC survivors. IMPLICATIONS FOR CANCER SURVIVORS: Designing supportive care interventions to improve HRQoL among low-income and Medicaid-insured CRC survivors is critical for eliminating disparities in CRC outcomes.

Retrorectal cysts are cystic lesions located in the retrorectal space and are a distinct subset of retrorectal tumours, which are often misdiagnosed due to their rarity and mimicry of symptoms caused by common diseases. We have described the presentation and management of four patients who were diagnosed with retrorectal cysts from a 10-year retrospective chart review at our institute, a tertiary care centre. In middle-aged women, the following should raise suspicion of retrorectal cyst: gastrointestinal or urinary obstructive features, mass or fullness palpable on the posterior wall on digital rectal examination, presacral dimple, perianal fistula and/or recurrent disease. Such features should prompt an MRI evaluation of the pelvis for definitive diagnosis.

Background: Cancer survivors increasingly report financial hardship as a consequence of the high cost of cancer care, yet the financial experience of rural cancer survivors remains largely unstudied. The purpose of this study was to investigate potential rural disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy. Methods: Individuals diagnosed with localized or regional colorectal cancer between 2004 and 2012 were ascertained by the population-based New Mexico Tumor Registry. Participants completed a mailed questionnaire or telephone survey about their colorectal cancer survivorship experience, including treatment-related financial hardship and receipt of surveillance colonoscopy. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Compared with urban colorectal cancer survivors (n = 168), rural colorectal cancer survivors (n = 109) were slightly older; more likely to be married (65% vs. 59%) and have an annual income Conclusions: Substantial rural disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy exist. Impact: Treatment-related financial hardship among rural colorectal cancer survivors may negatively affect adherence to guideline-recommended follow-up care. Cancer Epidemiol Biomarkers Prev; 27(11); 1275–82. ©2018 AACR.

PURPOSE: Lifestyle factors may have a synergistic effect on health. We evaluated the correlates of poor adherence to a healthy lifestyle among a diverse sample of colorectal cancer (CRC) survivors to inform future lifestyle promotion programs. METHODS: Lifestyle questions from a cross-sectional survey were completed by 283 CRC survivors (41% Hispanic, 40% rural; 33% low income). Adherence to recommendations (yes/no) for physical activity, fruit and vegetable servings/day, avoiding tobacco, and healthy weight were summed to create an overall lifestyle quality score. Polytomous logistic regression was used to evaluate correlates of good (reference group), moderate and poor overall lifestyle quality. Potential correlates included sociodemographic characteristics, cancer-related factors, and indicators of health and well-being. RESULTS: CRC survivors with poor adherence were 2- to 3.4-fold significantly more likely to report multiple comorbidities, poor physical functioning, fatigue, anxiety/depressive symptoms, and poor social participation. In multivariable analyses, poor physical functioning was the only significant correlate of poor adherence to lifestyle recommendations, compared to good adherence (OR [95% CI] =3.4 [1.8–6.4]). The majority of survivors, 71% and 78%, indicated interest in receiving information on exercise and eating a healthy diet, respectively. CONCLUSION: Future lifestyle promotion programs for CRC survivors should carefully consider indicators of physical and psychosocial health and well-being, especially poor physical functioning, in the design, recruitment, and implementation of these health programs.

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFβ signaling by re-expression of TGFβ receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFβ, indicating that TGFβ-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFβ signaling indicated that Bim is an effector of TGFβ-mediated survival. In addition, TGFβ-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFβ, and restoration of TGFβ signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFβ signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFβ receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.

rate variability (HRV) analysis with and without interpolation were investigated. In this study, randomly selected data (with frequency of 5 samples up to 50) were removed from actual data (taking first 1000 samples) in the MIT-BIH arrhythmia RR interval database of 10 subjects having 1000 sample data points in each set. In all, the tachograms the artefacts are removed first from the 1000 samples. Poincare plot and entropy analysis were executed for the nonlinear HRV parameters, and the absolute relative errors between the data with and without the missing data duration for these parameters including the interpolation were calculated. In this process, the usefulness of reconstruction was considered when there is missed rr-interval, for which several interpolation methods (linear, delete, and zero order interpolation) were used and the best interpolation method having less error in the HRV analysis was chosen. During the work and performing all the interpolation methods, the delete interpolation gives best results for the reconstruction of data while analysing the HRV non-linear parameters.

Introduction Hispanics in New Mexico are diagnosed with more later-stage colorectal cancer (CRC) than non-Hispanic Whites (NHW). Our study evaluated the interaction of race/ethnicity and risk factors for later-stage III and IV CRC among patients in New Mexico. Method CRC patients ages 30 to 75 years ( n = 163, 46% Hispanic) completed a survey on key explanatory clinical, lifestyle, preventive health, and demographic variables for CRC risk. Adjusted logistic regression models examined whether these variables differentially contributed to later-stage CRC among NHW versus Hispanics. Results Compared with NHW, Hispanics had a higher prevalence of later-stage CRC ( p = .007), diabetes ( p = .006), high alcohol consumption ( p = .002), low education ( p = .003), and CRC diagnosis due to symptoms ( p = .06). Compared with NHW, Hispanics reporting high alcohol consumption (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.31-43.92), lower education (OR = 3.5; 95% CI = 1.28-9.65), being nondiabetic (OR = 3.23; 95% CI = 1.46-7.15), or ever smokers (OR = 2.4; 95% CI = 1.03-5.89) were at higher risk for late-stage CRC. Adjusting for CRC screening did not change the direction or intensity of the odds ratios. Conclusion The ethnicity-risk factor interactions, identified for late-stage CRC, highlight significant factors for targeted intervention strategies aimed at reducing the burden of later-stage CRC among Hispanics in New Mexico with broad applicability to other Hispanic populations.

Introduction: American Society of Clinical Oncology (ASCO) guidelines recommend that all patients with metastatic colorectal cancer (mCRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. The aim of this study was to assess for disparities in KRAS testing and mutational status. Methods: The New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the National Cancer Institute’s Surveillance, Epidemiology and End Results program, was queried to identify all incident cases of CRC diagnosed among New Mexico residents from 2010 to 2013. Results: Six hundred thirty-seven patients were diagnosed with mCRC from 2010–2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also observed. In those with metastatic disease, younger patients (≤ 64 years) were more likely to have had testing than patients 65 years and older (p < 0.0001). Patients residing in urban areas received KRAS testing more often than patients living in rural areas (p = 0.019). No significant racial/ethnic disparities were observed (p = 0.66). No significant differences were seen by year of testing. Conclusion: Age and geographic disparities exist in the rates of KRAS testing, while sex, race/ethnicity and the year tested were not significantly associated with testing. Further study is required to assess the reasons for these disparities and continued suboptimal adherence to current ASCO KRAS testing guidelines.

Lessons Learned Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer. There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. Background Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. Methods Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. Results Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively. Conclusion Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

IgG(4)-related disease (IgG(4)-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG(4) and tissue IgG(4) levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid treatment. The low incidence and the heterogeneous nature of the disease has made consensus on diagnostic criteria for IgG(4)-RD difficult. Whether sclerosing mesenteritis (SM) is considered a manifestation of IgG(4)-RD is strongly debated. We present the case of a patient with a history of rheumatoid arthritis who presented with a calcified abdominal mass. She was found to have an isolated, pedunculated mesenteric mass positive for IgG(4) and concurrently elevated serum IgG(4) levels. Clinical features did not classify her disease as either SM or IgG(4)-RD as currently described in consensus statements. Concurrent diagnoses of IgG(4)-RD, SM and other autoimmune disorders, as well as postoperative recommendations for resected isolated IgG(4)-positive masses, are discussed.

Colorectal cancer (CRC) is the second largest cause of cancer deaths in the United States. A key barrier that prevents better outcomes for this type of cancer as well as other solid tumors is the lack of effective therapies against the metastatic disease. Thus there is an urgent need to fill this gap in cancer therapy. We utilized a 2D-DIGE proteomics approach to identify and characterize proteins that are differentially regulated between primary colon tumor and liver metastatic deposits of the IGF1R-dependent GEO human CRC xenograft, orthotopically implanted in athymic nude mice that may serve as potential therapeutic targets against CRC metastasis. We observed increased expression of ezrin in liver metastasis in comparison to the primary colonic tumor. Increased ezrin expression was further confirmed by western blot and microarray analyses. Ezrin, a cytoskeletal protein belonging to Ezrin-Radixin-Moesin (ERM) family plays important roles in cell motility, invasion and metastasis. However, its exact function in colorectal cancer is not well characterized. Establishment of advanced GEO cell lines with enhanced liver-metastasizing ability showed a significant increase in ezrin expression in liver metastasis. Increased phosphorylation of ezrin at the T567 site (termed here as p-ezrin T567) was observed in liver metastasis. IHC studies of human CRC patient specimens showed an increased expression of p-ezrin T567 in liver metastasis compared to the primary tumors of the same patient. Ezrin modulation by siRNA, inhibitors and T567A/D point mutations significantly downregulated inhibitors of apoptosis (IAP) proteins XIAP and survivin that have been linked to increased aberrant cell survival and metastasis and increased cell death. Inhibition of the IGF1R signaling pathway by humanized recombinant IGF1R monoclonal antibody MK-0646 in athymic mouse subcutaneous xenografts resulted in inhibition of p-ezrin T567 indicating ezrin signaling is downstream of the IGF1R signaling pathway. We identified increased expression of p-ezrin T567 in CRC liver metastasis in both orthotopically implanted GEO tumors as well as human patient specimens. We report for the first time that p-ezrin T567 is downstream of the IGF1R signaling and demonstrate that ezrin regulates cell survival through survivin/XIAP modulation.

Background Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers, including colorectal cancer (CRC). PTEN is involved in negatively regulating the phosphatidylinositol 3-kinase/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model. Methods Green fluorescent protein labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination. Results Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared with the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs ( P = 0.02). Conclusions Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and, thus, efforts to target the phosphatidylinositol 3-kinase/PTEN pathway are legitimate.

Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient’s specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.

Hibernoma is a rare, benign tumour of brown fat origin. Less than 250 cases have been reported in the literature. We present a case of a 19-year-old man referred to surgical oncology for evaluation of a large soft tissue mass near the apex of his right scapula. Complete surgical excision was performed, sparing the overlying latissimus dorsi musculature. Surgical pathology revealed findings were consistent with hibernoma, grossly showing a well-encapsulated fluctuant mass measuring 21.4×14.4×5.3 cm, and histologically composed of brown fat adipocytes. The mainstay of treatment is surgical excision of the mass. Primary goals of the operation include complete removal of the mass to prevent recurrence and sparing of adjacent structures as it is a benign, non-invasive tumour. We present a case of a large chest wall hibernoma in a young adult, diagnosed on final pathology after complete surgical excision.

Background Colorectal cancer is a leading cause of cancer-related mortality, has a very broad mutational spectrum, and there is no clinically available biomarker that can predict which patients with stage II or stage III colorectal cancer will develop metastatic disease. Patients and Methods We used a targeted next-generation sequencing approach to analyze the mutational spectra in stage II and III colon cancer patient samples. Results Amidst a broad range of acquired mutations and variants, we found evidence of tumor heterogeneity that distinguished the tumors in different groups. When heterogeneity was quantified using the Mutant-Allele Tumor Heterogeneity (MATH) score, there was a strong correlation between higher MATH score and risk of metastases. Conclusions Measures of tumor heterogeneity might be useful biomarkers for identifying patients with colon cancer who are at risk of developing metastases. This might allow for more specific, tailored follow-up and adjuvant therapies after standard surgery.

PURPOSE: To assess the feasibility of quantitative high-speed MR spectroscopic imaging (MRSI) of total Choline (tCho) as an adjunct to dynamic-contrast enhanced (DCE) MRI to improve lesion characterization and monitor treatment response in patients undergoing neoadjuvant chemotherapy. METHOD AND MATERIALS: Seven patients with biopsy-confirmed, infiltrating ductal carcinoma were studied using a clinical 3T MR scanner (Siemens Medical Solutions, Erlangen, Germany) equipped with 8- and 16-channel breast array (Hologic Inc., Bedford, MA). Measurements were performed using PRESS prelocalized 3D Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI) using TR/TE=2000ms/135ms, matrix size up to 32×16x8, voxel size=1cc, and total acquisition time of 10 minutes (including water reference scan). Additional data were collected at TE 60 ms to enhance sensitivity for detecting tCho and J-coupled resonances. TE-averaging (8 steps, ΔTE: 2.5 ms) was employed to minimize gradient sideband artifacts. Quantification of tCho in reference to tissue water was performed using spectral fitting and relaxation correction. RESULTS: Strongly elevated tCho with maximum concentration ranging from 0.3 to 4.1 mmol/kg was measured in five patients with single and multi-centric enhancing lesions larger than 2 cc volume (Table 1). The measured tCho concentration in Grade 3 tumors was higher than in lower grade untreated and treated tumors. Strong decreases in tCho concentration were measured in 2 patients undergoing neoadjuvant therapy in a follow-up scan. At short TE an additional resonance was detected that was elevated in enhancing lesions and tentatively assigned to Taurine. Two patients had lesions smaller than 2 cc with surgical clips in which tCho was not detectable due to line broadening. MRSI data sets were preferentially collected before contrast injection, since it increased spectral line width by up to 50%. CONCLUSION: This study demonstrates feasibility of quantitatively mapping tCho in invasive breast carcinoma using high-speed MRSI. The long-term goals are to utilize high-speed MRSI as an early predictor of treatment failure in women undergoing neoadjuvant therapy (i.e. chemotherapy, endocrine therapy or biologic therapy) for breast cancer and to develop an improved screening protocol for high-risk patients. Grant support: 1RC1EB010617-01 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-10-04.

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFβ signaling by re-expression of TGFβ receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFβ, indicating that TGFβ-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFβ signaling indicated that Bim is an effector of TGFβ-mediated survival. In addition, TGFβ-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFβ, and restoration of TGFβ signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFβ signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFβ receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.

Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 (phosphatase of regenerating liver) is associated with metastasis of colon cancer. Here, we show that PRL-3 is a direct target of signaling by TGFβ, which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling that caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRL-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3–mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. In addition, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3–mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for antimetastatic therapy in patients with colon cancer. Cancer Res; 71(1); 234–44. ©2010 AACR.

Introduction: Cancer survivors increasingly report financial hardship as a consequence of the high cost of cancer care, yet the financial experience of traditionally underserved patients, including racial/ethnic minorities, non-English speakers, and rural residents, remains largely unstudied. The purpose of this study was to investigate potential disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy. Methods: In this cross-sectional study, individuals diagnosed with localized or regional colorectal cancer between 2004-2012 were ascertained by the population-based New Mexico Tumor Registry. Participants completed a mailed questionnaire or telephone survey about their cancer survivorship experience, including treatment-related financial hardship and receipt of surveillance colonoscopy. Participants were considered to have experienced treatment-related financial hardship if they reported any debt accumulation, bankruptcy filing, other financial sacrifices, or inability to pay medical bills as a consequence of their illness, its treatment, or its lasting effects. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: In this sample of 277 colorectal cancer survivors, 44% of participants reported financial hardship. Individuals with low health literacy (OR 5.41, 95% CI 1.45-20.1), Spanish-speaking Hispanics (OR 3.09, 95% CI 1.39-6.87), divorced, separated or single survivors (OR 1.94, 95% CI 1.94, 95% CI 1.06-3.54), and rural residents (OR 1.86, 95% CI 1.06-3.28) were more likely to report financial hardship. Nonadherence to surveillance colonoscopy guidelines was two times as likely among participants reporting financial hardship (OR 2.17 95% CI 1.01-4.67) and among rural residents (OR 2.28, 95% CI 1.07-4.48) than those reporting no financial hardship and urban residents, respectively. Conclusions: Substantial disparities in the likelihood of financial hardship and nonadherence to surveillance colonoscopy exist. Identifying patients at risk of financial hardship and developing interventions to reduce the financial burden of cancer may improve adherence to surveillance recommendations. Citation Format: Jean A. McDougall, Matthew P. Banegas, Charles Wiggins, Ashwani Rajput, Vi K. Chiu, Kristina G. Flores, Anita Y. Kinney. Disparities in treatment-related financial hardship and adherence to surveillance colonoscopy guidelines in ethnically, linguistically, and geographically diverse colorectal cancer survivors [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C52.

PURPOSE Hyaluronan and hyaluronan synthases have been implicated in cancer progression. Hyaluronan synthase-3 is up-regulated in metastatic colon cancer cells (SW620), and its expression mediates cellular growth in vitro. We hypothesized that inhibition of hyaluronan synthase-3 would decrease tumor formation and/or alter the pattern of metastasis in mouse models of colon cancer growth. METHODS Hyaluronan synthase-3 was inhibited in SW620 cells by transfection with small interfering RNA (silenced cells); a scrambled sequence served as a negative control. To study primary tumor growth, transfected cells were injected into the flanks of BALB/c nude mice. To study metastasis, an orthotopic model was used. Metastases were confirmed histologically. Student t test and Fisher exact probability test were used for statistical analysis. RESULTS Inhibition of hyaluronan synthase-3 significantly decreased subcutaneous tumor growth; tumor weight was 0.94 +/- 0.17 g in the hyaluronan synthase-3-silenced group vs 1.70 +/- 0.26 g in the control scrambled group (P < .01). In contrast, metastases were similar in both groups: liver metastases were present in 22% of the silenced group vs 11% of the scrambled group; lung metastases were present in 6% of the silenced group vs 0% of the scrambled group (P = not significant). CONCLUSION Inhibition of hyaluronan synthase-3 expression in SW620 colon cancer cells decreases subcutaneous tumor growth in mice, but has less of an effect on lung and liver metastases. This observation suggests that hyaluronan synthase-3 may enhance primary colon cancer growth.

Background Colorectal cancer is the second leading cause of cancer related mortality, with a majority of deaths resulting from metastases. Few in vivo models allow for the study of the complex process of metastasis. The purpose of this study was to determine the effects of epidermal growth factor receptor activation and TGFβ pathway attenuation in FET, a weakly tumorigenic human colon cancer cell line, in an orthotopic model. Methods and Results Using FET, FETα, FETαDNRII, and FETDNRII cells were constructed. Tumors were orthotopically implanted onto the colons of BALB/c nude mice. After 7 wk, the mice were euthanized and organs extracted for examination. All cell lines demonstrated primary invasion. FETα was weakly metastatic compared with FETαDNRII and FETDNRII, which demonstrated metastases to the lung and liver, respectively. Conclusion Epidermal growth factor receptor (EGFR) activation transforms a nontumorigenic cell line into a tumorigenic but not metastatic one. The tumorigenic line becomes metastatic with the attenuation of TGFβ signaling. Loss of EGFR activation in the TGFβ inhibited line results in a decreased metastatic burden, but importantly, changes the organotropic homing from lung to liver. Thus, these in vivo studies demonstrate that EGFR activation and TGFβ signaling pathways play a role in tumorigenicity and in pattern of metastases.

OBJECTIVE To assess whether TNODS is an independent prognostic factor after adjusting for the lymph node ratio (LNR). SUMMARY BACKGROUND DATA The medical literature has suggested that the TNODS is associated with better survival in stage II and III colon cancer. Thus TNODS was endorsed as a quality measure for patient care by American College of Surgeons, National Quality Forum. There is, however, little biologic rationale to support this linkage. METHODS : A total of 24,477 stage III colon cancer patients were identified from Surveillance, Epidemiology, and End Results cancer registry and categorized into 4 groups, LNR1 to LNR4, according to LNR interval: 0.50. Patients were also stratified according to TNODS into high TNODS (> or = 12) and low TNODS (

Background Because of the increase in the geriatric population, an increasing number of elderly patients are being treated for colorectal cancer. The purpose of this study was to evaluate perioperative morbidity and mortality in this population. Methods A retrospective chart review was performed for patients 80 years of age or older who underwent surgery for colorectal cancer (1993–2006). Results Ninety patients were identified, with a median age of 84 years. More than 90% presented with symptoms; the remaining were diagnosed by screening colonoscopy. Emergent surgery was required in 10%. The morbidity rate was 21% and the overall 30-day mortality rate was 1.1%. Morbidity was higher in patients who required surgery emergently. Conclusions Despite advanced age, the majority of patients in this study did well. Postoperative morbidity was higher than in the general population, but we believe it was acceptably low in most patients. Colorectal surgery appears to be safe in most elderly patients.

Mutations in the PIK3CA gene are common in human cancers, including colon cancer. We compared two pairs of colon cancer cells (HCT116 and DLD1) bearing only the wild-type (WT) or mutant (MUT) PIK3CA allele for their survival capacity under stress conditions in vitro as well as their metastatic properties in an in vivo orthotopic model. When subjected to growth factor deprivation stress (GFDS), the MUT PIK3CA cells displayed resistance to GFDS-induced apoptosis relative to the WT cells. Phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT were constitutively activated during stress conditions in the MUT PIK3CA cells but not in the WT cells. The MUT cells showed hypersensitivity to PI3K inhibition. Moreover, the proapoptotic protein Bax was expressed at a very high level in the WT PIK3CA cells, whereas it was almost undetectable in the MUT cells. Inhibition of Bax expression by small interfering RNA protected the WT PIK3CA cells from GFDS-induced apoptosis, suggesting an important role of Bax in GFDS-induced apoptosis. These results indicated that the MUT PI3K confers resistance to GFDS-induced apoptosis and that the MUT cells are more dependent on the PI3K pathway for survival. In vivo studies showed that the MUT PIK3CA-bearing cells were more metastatic than the WT cells in an orthotopic model of colon cancer. Taken together, these results suggest that MUT PI3K imparts a more aggressive phenotype in colon cancer cells and could be a potential therapeutic target for treatment of colon cancer patients bearing PIK3CA mutations. [Cancer Res 2007;67(12):5851–8]

With the advent of endoscopy, the incidence of rectal carcinoid tumors has not only risen, but the majority are localized at presentation. This has led to excisional and/or ablative therapy in lieu of radical resections. A single institute's experience with rectal carcinoids was reviewed to determine the impact this approach has had on outcomes, and evaluate any selection criteria for optimizing patient survival. A single institute's tumor registry was retrospectively queried, identifying 14 patients with rectal carcinoid tumors over a 28-year period. The mean age at diagnosis was 52.1 +/- 14.4 years. Six of the 14 patients were female. Presenting symptoms included a change in bowel habits in six (38%), rectal bleeding in six (38%), and abdominal pain or distention in five (31%) patients. No patient had symptoms consistent with carcinoid syndrome. The rectal carcinoids were a mean 9.2 +/- 3.4 cm from the anal verge and a mean 9 +/- 6 mm in size. Endoscopic and/or transanal excision/fulguration techniques treated 11 (79%) patients, whereas two (14%) patients underwent a low anterior resection (LAR). Surveillance entailed periodic endoscopy for a median 65 months (range 8-281). No patient developed recurrent carcinoid disease for a 20-year overall survival of 70%.

Epidermal growth factor receptor (EGFR) is widely expressed in a number of solid tumors including colorectal cancers. Overexpression of this receptor is one means by which a cell can achieve positive signals for survival and proliferation; another effective means is by constitutive activation of EGFR. We have elucidated the role of constitutive EGFR signaling in malignant progression by stably transfecting colon cancer cells with a human transforming growth factor-α cDNA (a ligand for EGFR) under repressible control by tetracycline. We show that constitutive expression of transforming growth factor-α and its subsequent constitutive activation of EGFR allows for cancer cell survival in response to environmental stress in vitro and in vivo as well. The reversal of constitutive EGFR activation results in the loss of downstream mitogen-activated protein kinase and Akt activation, and a reduction in xenograft size that is associated with decreased proliferation and increased apoptosis. We used CI-1033, a small molecule antagonist of EGFR, to dissect an activation pathway that shows the ability of ERBb2 to activate Akt, but not Erk in the face of EGFR antagonism. This novel escape mechanism is a possible explanation of why anti-EGFR therapies have shown disappointing results in clinical trials. [Cancer Res 2007;67(2):665–73]

Palliative medicine was recognized as a unique medical specialty in 2006. Since that time, the number of hospital-based palliative care services has increased dramatically. It is unclear how palliative care consultation services (PCCS) are utilized by surgical services. The purpose of this study was to examine utilization of PCCS by surgical services compared to medical services at the University of New Mexico.A database of palliative care consultations performed at University of New Mexico Hospital between 2009 and 2013 was queried to identify consultations requested by surgical vs. medical services. Demographic, clinical, and outcome variables were compared.A total of 521 consultations were analyzed: 441 (85%) consultations from medical and 80 (15%) consultations from surgical services. Surgical patients were older than medical patients and more likely to be in an intensive care unit (ICU) at the time of consultation. There was no difference between referring services in indication for palliative care consultation or time from hospital admission to consultation. Surgical patients were more likely to die in the hospital compared to medical patients. Among patients discharged from the hospital alive, there was no difference between the groups in discharge disposition. More patients in both groups had a change from full code to do-not-resuscitate (DNR) status following palliative care consultation.Referrals for palliative care consultations are much less common from surgical than medical services. Characteristics of surgical patients suggest that palliative care consultations are reserved for older patients, critically ill patients, and those more likely to be at end-of-life. Our findings suggest the possible need for increased palliative care consultations among less critically ill patients and/or those with an improved prospect of recovery.

Death review was conducted for the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial to avoid the biases associated with causes of death entered on death certificates. An algorithm selected deaths for review. Records on diagnosis and terminal illness were perused in the coordinating center and by the chair of the death review committee (DRC). Identifying information and randomization arm was removed. Three reviewers independently determined the cause of death. Disagreement was resolved at a meeting of the DRC. This process was subsequently simplified. The cause of death was determined by one DRC member and compared to the death certificate. With agreement the case was finalized. When discordant, the records were sent to a second DRC member. If the reviewers agreed, the case was finalized. If not, a third member reviewed. If two of the three reviewers agreed, the case was sent back to the discordant reviewer. If the reviewer remained discordant the case was resolved by a conference call. Of the 4728 death reviews that were completed, the DRC confirmed the death certificate underlying cause for over 90%. Between 5% and 13% of the certified deaths were regarded as indirect causes of death, associated with the treatment of the ascertained cancer; differential for prostate cancer, 11% in the intervention arm and 6% in the control. Without review, between 1% and 6% of the deaths that occurred would not have been assigned to the relevant PLCO cancer. The DRC completed 76% of those requiring review before the process ceased.

Purpose: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. Methods and Materials: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly × 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction × 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. Results: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m 2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m 2 /week) had a dose-limiting diarrhea. One of 6 patients at DL (−)1 (capecitabine 725 mg/m 2 p.o., b.i.d.; oxaliplatin 50 mg/m 2 /week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). Conclusions: Capecitabine 725 mg/m 2 p.o., twice daily in combination with oxaliplatin 50 mg/m 2 /week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

Objectives: To investigate the incidence of carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer (MCRC) and its implications on clinical outcome. Methods: A retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CEA levels compared to baseline. The incidence of CEA surge and its association with clinical outcome was investigated. Results: Eighty-nine patients were evaluable for CEA surge. A CEA surge was documented in 10 patients. The CEA surge lasted Conclusions: CEA surges can be observed in patients receiving chemotherapy for MCRC and are often associated with a clinical benefit. None of the CEA surges satisfied the American Society of Clinical Oncology definition of CEA progression. A rise in CEA after initiation of chemotherapy, unless lasting >4 months, cannot be used as an indicator of progressive disease.

BACKGROUND An estimated 5–10% of all pancreatic adenocarcinomas have a hereditary association. The objective of the current study was to characterize the clinical and pathologic features of familial pancreatic carcinoma and to determine potential differences in demographics, risk factors, and outcomes between familial and sporadic pancreatic carcinoma populations. METHODS A retrospective review was performed to identify patients diagnosed with pancreatic carcinoma who had an associated familial disposition. Demographic analyses and assessment of clinical features and treatment outcomes were performed for the familial subgroup, and the results were compared with observations made in the nonfamilial, or ‘sporadic’, population. RESULTS Thirty of 826 patients (3.6%) had familial pancreatic carcinoma. Baseline demographics, resectability, and metastases were similar in both the familial cohort and the sporadic cohort. The mean age of onset was slightly lower in the familial cohort (57.6 years, compared with 61 years in the sporadic cohort). However, the familial population had a significantly greater proportion of patients who were diagnosed at age < 50 years compared with the sporadic population (36.7% vs. 18.3%; P = 0.017). A positive smoking history was more commonly associated with familial pancreatic carcinoma (87% vs. 66%; P = 0.06). The overall median survival durations were 7 months and 6 months for the familial group and the sporadic group, respectively. CONCLUSIONS Patients with familial pancreatic carcinoma present at an earlier age compared with their counterparts who have nonfamilial disease. Smoking may play a significant role in the risk or promotion of pancreatic carcinoma in patients with an inherited predisposition. Cancer 2004. © 2004 American Cancer Society.

INTRODUCTIONInflammatory cap polyposis (CP) is an uncommon, non-malignant condition whose pathogenesis is poorly understood. Initial presentation of CP may mimic other gastrointestinal conditions like inflammatory bowel disease, pseudomembranous colitis, irritable bowel syndrome, and colon cancer.PRESENTATION OF CASEA 42-year-old male presented with symptoms of constipation, abdominal pain and weight loss, which were suggestive of a malignancy.DISCUSSIONSince the symptoms of CP resemble closely those of other gastrointestinal diseases, particularly colon cancer, making the initial diagnosis can be challenging and it is often delayed. The mainstay of initial treatment is conservative, however symptomatic and complicated cases require prompt surgical intervention with close clinical follow-up.CONCLUSIONWe chose to report this case because it represents a rare and unique disease process that may masquerade as a colon cancer. It is important for surgeons to be aware of this non-malignant condition since inadequate surgery usually results in recurrence.

Soft tissue sarcomas are a challenging disease entity with a variety of histologic subtypes that can arise anywhere on the body. Much effort has been put forward to advance the care of patients with soft tissue sarcomas. Radical amputations have largely given way to limb-sparing procedures. With multimodality treatment, there has been progress in local control rates as well. As knowledge of the basic biology of this disease grows, there likely will be new strategies to treat soft tissue sarcomas. The development of STI-571, and its demonstrated effectiveness in GIST, represents an important advance in the treatment of these tumors and potentially a new paradigm for the development of therapeutic intervention in other sarcomas. Developing collaboration among ACOSOG other cooperative groups in the United States, Canada, and Europe may provide physicians with new venues for asking important clinical questions about these low-incidence tumors. The importance of collaboration in enrolling patients in clinical trials to evaluate these future therapies cannot be overstated.