Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal.

Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse.

Impact of medical and surgical intervention on survival in patients with cholangiocarcinoma.

AIM: To examine surgical and medical outcomes for patients with cholangiocarcinoma using a population-based cancer registry. METHODS: Using the California Cancer Registry's Cancer Surveillance Program, patients with intrahepatic cholangiocarcinoma treated in Los Angeles County from 1988 to 2006 were identified and evaluated for clinical and pathologic factors and therapies received (surgery, radiation, and chemotherapy). The surgical cohort was further categorized into three treatment groups: patients who received adjuvant chemotherapy, adjuvant chemoradiation, or underwent surgery alone (no chemotherapy or radiation administered). Survival was assessed by Kaplan-Meier method; and Cox proportional hazard modeling was used in multivariate analysis. RESULTS: Of 825 patients, 60.2% received no treatment. Of the remaining 328 patients, 18.5% chemotherapy only, 7.4% chemoradiation, and 13.8% underwent surgery. More male patients underwent surgical resection (P = 0.004). Surgical patients were younger than the patients receiving chemotherapy or chemoradiation (P < 0.001). Of the surgical cohort (n = 114), 60.5% underwent surgery alone while 39.5% underwent surgery plus adjuvant therapy (chemotherapy, n = 20; chemoradiation, n = 21) (P < 0.001). Median survival for all patients in the study was 6.6 mo. Median survival was highest for patients who underwent surgery (23 mo), whereas both chemotherapy (9 mo) and chemoradiation (8 mo) alone were each less effective (P < 0.001). By multivariate analysis, extent of disease, receipt of surgery, and administration of chemotherapy (with/without surgery) were independent predictors of overall survival. CONCLUSION: This study demonstrates that surgery is a critical treatment modality. Multimodality treatment has yet to be standardized, but play a role in optimal therapy for cholangiocarcinoma.

Interaction between age and race alters predicted survival in colorectal cancer.

BACKGROUND: Racial disparities in colorectal cancer persist. Late stage at presentation and lack of stage-specific treatment may be contributing factors. We sought to evaluate the magnitude of disparity remaining after accounting for gender, stage, and treatment using predicted survival models. METHODS: We used institutional tumor registries from a public health system (two hospitals) and a not-for-profit health system (nine hospitals) from 1995 to 2011. Demographics, stage at diagnosis, treatment, and survival were recorded. Hazard ratios (HRs) and predicted HRs were determined by Cox regression and postestimation analyses. RESULTS: There were 6,990 patients: 55.7 % white, 23.6 % African American, 15.1 % Hispanic, and 5.6 % Asian/other. Predictors of survival were surgery (HR 0.57, 95 % confidence interval [CI] 0.46-0.70), chemotherapy (HR 0.7, 95 % CI 0.62-0.79), female gender (HR 0.87, 95 % CI 0.83-0.90), age (HR 1.04, 95 % CI 1.03-1.05), and African American race (HR 3.6, 95 % CI 1.5-8.4). Balancing for stage, gender, and treatment reduced the predicted HRs for African Americans by 28 % and Hispanics by 17 %. In this model, African American and Hispanics still had the worst predicted HRs at younger ages, but whites had the worst predicted HR after age 75. CONCLUSIONS: Gender, stage, and treatment partially accounted for worsened survival in African Americans and Hispanics at all ages. At younger ages, race-related disparities remained which may reflect tumor biology or other unknown factors. Once gender, stage, and treatment are balanced at older ages, the increased mortality observed in whites may be due to factors such as comorbidities. Further system- and patient-level study is needed to investigate reasons for colorectal cancer survival disparities.

An appraisal of radiofrequency ablation and surgical resection for hepatocellular carcinoma: results from the surveillance, epidemiology, and end results registry.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but only a small percentage of patients are eligible for curative surgical intervention. Over the past decade, radiofrequency ablation (RFA) has been increasingly shown to offer long-term survival benefits. Our study objective was to compare outcomes of patients with HCC who underwent surgical resection with those who received RFA. Using the Surveillance, Epidemiology, and End Results registry, we identified 1209 (21%) and 4595 (79%) patients with HCC who received RFA and surgical resection, respectively, between the years 1988 and 2008. When comparing the groups, patients undergoing RFA were older (years, 62.6 vs 58.7; P<0.001) and had smaller tumors (less than 5 cm; 84.4 vs 61.2%; P<0.001), yet patients who underwent surgical resection had improved survival over patients undergoing RFA (median survival, 5 vs 3 years, respectively; P<0.001). Univariate and multivariate analysis verified the superiority of surgical resection over ablation (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.60 to 0.80; P<0.001 and HR, 0.57; 95% CI, 0.52 to 0.63; P<0.001, respectively). In summary, our investigation demonstrates that surgical resection provides durable long-term survival for surgical candidates with HCC; however, RFA remains an appropriate alternative therapy that also provides long-term survival in select patients.

Surgical complications and pathologic complete response after neoadjuvant chemoradiation in locally advanced rectal cancer.

Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) in patients with rectal cancer is associated with improved prognosis, whereas postoperative surgical complications have been linked with poor oncologic outcomes. Our objective was to examine the association between postoperative complications and pCR. We analyzed 127 patients enrolled in a prospective multicenter study investigating rectal cancer response to CRT. Surgical complications were scored according to the Clavien-Dindo scale (Grade 1 to 4). Among the 127 patients analyzed, 28 (22%) patients had a pCR. In the pCR group, six surgical Grade 3+ complications occurred in five (18%) patients, including anastomotic leak (n = 2), ureteral injury (n = 2), pelvic abscess (n = 1), and pneumonia (n = 1). In the non-pCR group, there were 10 Grade 3+ complications in eight (8%) patients, including severe obstruction (n = 1), postoperative hemorrhage (n = 1), leak (n = 2), pelvic abscess (n = 2), ureteral injury (n = 1), and severe morbidity (stroke, n = 1; acute respiratory distress, n = 1; and cardiac event, n = 1). There was no significant difference in the frequency of total surgical complications between pCR and non-pCR patients; and no association was observed between pCR and major postoperative complications. In conclusion, postoperative complication rates do not differ between pCR and non-pCR groups. The occurrence of major postoperative complications is not associated with response to neoadjuvant CRT.

Sentinel lymph node biopsy indications and controversies in breast cancer.

Sentinel lymph node biopsy (SLNB) has become the standard of care for early breast cancer. Its use in breast cancer has been evaluated in several randomized controlled trials and validated in multiple prospective studies. Additionally, it has been verified that SLNB has decreased morbidity when compared to axillary lymph node dissection (ALND). The technique used to perform sentinel lymph node mapping was also evaluated in multiple studies and the accuracy rate increases when radiocolloid and blue dye are used in combination. As SLNB became more accepted, contraindications were delineated and are still debated. Patients who have clinically positive lymph nodes or core biopsy-proven positive lymph nodes should not have SLNB, but should have an ALND as their staging procedure. The safety of SLNB in pregnant patients is not fully established. However, patients with multifocal or multicentric breast cancer and patients having neoadjuvant chemotherapy are considered candidates for SLNB. However, the details of which specific neoadjuvant patients should have SLNB are currently being evaluated in a randomized controlled trial. Patients with ductal carcinoma in situ (DCIS) benefit from SLNB when mastectomy is planned and when there is a high clinical suspicion of invasion. With the advent of SLNB, pathologic review of breast cancer lymph nodes has evolved. The significance of occult metastasis in SLNB patients is currently being debated. Additionally, the most controversial subject with regards to SLNB is determining which patients with positive SLNs benefit from further axillary dissection.

Perineal wound complications after abdominoperineal resection.

Perineal wound complications following abdominoperineal resection (APR) is a common occurrence. Risk factors such as operative technique, preoperative radiation therapy, and indication for surgery (i.e., rectal cancer, anal cancer, or inflammatory bowel disease [IBD]) are strong predictors of these complications. Patient risk factors include diabetes, obesity, and smoking. Intraoperative perineal wound management has evolved from open wound packing to primary closure with closed suctioned transabdominal pelvic drains. Wide excision is used to gain local control in cancer patients, and coupled with the increased use of pelvic radiation therapy, we have experienced increased challenges with primary closure of the perineal wound. Tissue transfer techniques such as omental pedicle flaps, and vertical rectus abdominis and gracilis muscle or myocutaneous flaps are being used to reconstruct large perineal defects and decrease the incidence of perineal wound complications. Wound failure is frequently managed by wet to dry dressing changes, but can result in prolonged hospital stay, hospital readmission, home nursing wound care needs, and the expenditure of significant medical costs. Adjuvant therapies to conservative wound care have been suggested, but evidence is still lacking. The use of the vacuum-assisted closure device has shown promise in chronic soft tissue wounds; however, experience is lacking, and is likely due to the difficulty in application techniques.