Rocco Ricciardi

26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS‐341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21Cip1‐Waf‐1, a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS‐341 significantly inhibited tumor growth. Both cellular apoptosis and p21Cip1‐Waf‐1 protein levels were increased in PS‐341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS‐341 was combined with the tumoricidal agent CPT‐11. Combined CPT‐11/PS‐341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF‐κB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy. J. Cell. Biochem. 82: 110–122, 2001.

Increasing Negative Lymph Node Count Is Independently Associated With Improved Long-Term Survival in Stage IIIB and IIIC Colon Cancer

PURPOSE The purpose of this study was to examine the impact of the number of negative lymph nodes on survival in patients with stage III colon cancer. PATIENTS AND METHODS Patients who underwent surgery for stage III colon cancer between January 1988 and December 1997 were identified from the Surveillance, Epidemiology and End Results cancer registry. The number of negative and positive nodes was determined for 20,702 eligible patients. Disease-specific survival was examined by substage according to the number of negative nodes identified. A proportional hazards model was constructed to determine the effect of the number of negative nodes on survival. RESULTS For stage IIIB and IIIC patients, there was a significant decrease in disease-specific mortality as the number of negative nodes increased; cumulative 5-year cancer mortality was 27% in stage IIIB patients with 13 or more negative nodes identified versus 45% in those with three or fewer negative lymph nodes evaluated (P < .0001). In patients with stage IIIC cancer, those with 13 or more negative nodes had a 5-year mortality of 42% versus 65% in those with three or fewer negative lymph nodes evaluated (P < .0001). There was no association between the number of negative nodes identified and disease-specific survival for patients with stage IIIA disease. After controlling for the number of positive nodes, a higher number of negative nodes was found to be independently associated with improved disease-specific survival. CONCLUSION The number of negative nodes is an important independent prognostic factor for patients with stage IIIB and IIIC colon cancer.

Long-Term Follow-up After an Initial Episode of Diverticulitis: What Are the Predictors of Recurrence?

PURPOSE: The purpose of our study was to determine the clinical and CT predictors of recurrent disease after a first episode of diverticulitis that was successfully managed nonoperatively. METHODS: We retrospectively analyzed 954 consecutive patients who presented to our institution with diverticulitis from 2002 to 2008. Patients were identified with International Classification of Diseases, 9th Revision/Current Procedural Terminology codes. Patients were excluded if they had subsequent colectomy based on the first attack (n = 81), or if the attack they had between 2002 and 2008 was not their first attack (n = 201). We evaluated CT variables chosen by a panel of expert gastrointestinal radiologists. These radiologists reviewed the available published literature for CT imaging characteristics thought to predict diverticulitis severity. CT variables (n = 20) were determined by prospective reevaluation of scans by blinded study radiologists. Clinical variables (n = 43) were coded based on a retrospective chart review. Univariate analysis of variables in relation to recurrent disease was performed by a log-rank test of Kaplan-Meier estimates. Multivariate analysis was performed using Cox proportional hazards modeling. Variables with P < .2 on univariate analysis were included in a stepwise selection algorithm. RESULTS: The study population included 672 patients; mean age, 61 ± 15 years; mean follow-up, 42.8 ± 24 months. The index presentation of diverticulitis was most commonly located in the sigmoid colon (72%), followed by descending colon (33%), right colon (5%), and transverse colon (3%). Overall recurrence at 5 years was 36% by (95% CI 31.4%–40.6%) Kaplan-Meier estimate. Complicated recurrence (fistula, abscess, free perforation) occurred in 3.9% (95% CI 2.2%–5.6%) of patients at 5 years by Kaplan-Meier estimate. Family history of diverticulitis (HR 2.2, 95% CI 1.4–3.2), length of involved colon >5 cm (HR 1.7, 95% CI 1.3–2.3), and retroperitoneal abscess (HR 4.5, 95% CI 1.1–18.4) were associated with diverticulitis recurrence. Right colon disease (HR 0.27, 95% CI 0.09–0.86) was associated with freedom from recurrence. CONCLUSION: Although diverticulitis recurrence is common following an initial attack that has been managed medically, complicated recurrence is uncommon. Patients who present with a family history of diverticulitis, long segment of involved colon, and/or retroperitoneal abscess are at higher risk for recurrent disease. Patients who present with right-sided diverticulitis are at low risk for recurrent disease. These findings should be taken into consideration when counseling patients regarding the potential benefits of prophylactic colectomy.

Anastomotic Leak Testing After Colorectal Resection: What Are the Data?

OBJECTIVE To determine the value of anastomotic leak testing of left-sided colorectal anastomoses. DESIGN Cohort analysis. SETTING Subspecialty practice at a tertiary care facility. PATIENTS Consecutive subjects were selected from a prospective colorectal database of 2627 patients treated between January l, 2001, and December 31, 2007. INTERVENTION Creation of left-sided colorectal anastomoses and air leak testing per surgeon preference. MAIN OUTCOMES MEASURES Anastomosis type, method (handsewn vs stapled), performance of air leak testing, repair method of anastomoses after air leak tests yielding positive results, and development of postoperative clinical leak. RESULTS A total of 998 left-sided colorectal anastomoses were performed without proximal diversion; 90.1% were stapled and 9.9% were handsewn. Intraoperative air leaks were noted in 65 of 825 tested anastomoses (7.9%), that is, 7.8% of stapled anastomoses and 9.5% of handsewn anastomoses. A clinical leak developed in 48 patients (4.8%). Clinical leaks were noted in 7.7% of anastomoses with positive air leak test results compared with 3.8% of anastomoses with negative air leak test results and 8.1% of all untested anastomoses (P < .03). If air leak testing yielded positive results, suture repair alone was associated with the highest rate of postoperative clinical leak compared with diversion or reanastomosis, 12.2% vs 0% vs 0%, respectively (P = .19). CONCLUSIONS Our data indicate a high rate of air leaks at air leak testing of left-sided colorectal anastomoses. In addition, the high rate of clinical leaks in untested anastomoses leads us to recommend air leak testing of all left-sided anastomoses, whether stapled or handsewn.

An evaluation of the relationship between lymph node number and staging in pT3 colon cancer using population-based data.

PURPOSE: The number of lymph nodes examined has been proposed as a quality benchmark for colon cancer surgery, although it is unknown whether this strategy reduces understaging. METHODS: We identified 11,044 patients who underwent surgery for colon cancer with pT3 wall penetration between 1988 and 2003 from the Surveillance, Epidemiology and End Results cancer registry. We determined the proportion of patients who were node positive for each node count. We used logistic regression to predict the odds of being node positive by node count after adjusting for confounders. We used joinpoint analysis to determine whether there was a consistent relationship between node count and the odds of being node positive. RESULTS: The proportion of patients found to be node positive increased with node count at low counts (≤5–6 nodes), but patients with 7 nodes identified were as likely to be node positive as patients with 30 or more nodes (odds ratio = 0.97; 95% CI = 0.90–1.05). Joinpoint analysis demonstrated a dramatic increase in odds of node positivity with increasing node count to 5 nodes (slope = 0.2; P < .0001). Between 6 and 13 nodes there was a marginal increase in odds of positive nodes (slope = 0.03; P = .006), but when more nodes were evaluated, odds of node positivity actually declined (slope = −0.01; P = .04). CONCLUSIONS: Staging of pT3 colon cancer improves with increasing node count, but only when the node count is low (<5–7 nodes). At higher counts, an increased node count has marginal effects on staging.

Current Status of Surgical Management of Acute Cholecystitis in the United States

BackgroundWe attempted to determine population-based outcomes of laparoscopic (LC) and open cholecystectomy (OC) for acute cholecystitis (AC).MethodsWe used the National Hospital Discharge Surveys from 2000 through 2005. Annual medical and demographic data from a national sample of discharge records from nonfederal, short-stay hospitals were queried. We identified all patients who underwent LC or OC for AC. The main outcome measures were the rate of LC or OC and in-hospital morbidity and mortality. One million patients underwent cholecystectomy (859,747 LCs; 152,202 OCs) for AC during 2000–2005.ResultsOf the cases started laparoscopically, 9.5% were converted to OC. Compared to OC, patients who underwent LC were more likely to be discharged home (91% vs. 70%), carry private insurance (47% vs. 30%), suffer less morbidity (16% vs. 36%), and have a lower unadjusted mortality (0.4% vs. 3.0%). OC was associated with a 1.3-fold increase (95% confidence interval 1.1–1.4) in perioperative morbidity compared to LC after adjusting for patient and hospital factors.ConclusionsMost patients in the 21st century with AC undergo LC with a low conversion rate and low morbidity. In the general population with acute cholecystitis, LC results in lower morbidity and mortality rates than OC even in the setting of open conversion.

Epidemiology of clostridium difficile Colitis in Hospitalized Patients with Inflammatory Bowel Diseases

PURPOSE: A notable increase in-hospital admissions for Clostridium difficile colitis has occurred in the United States. In this paper we evaluate changes in the epidemiology of Clostridium difficile colitis in a subset of hospitalized patients with inflammatory bowel diseases. METHODS: A retrospective cohort analysis was conducted for all inflammatory bowel disease patients with Clostridium difficile colitis in the Nationwide Inpatient Sample, a 20 percent stratified random sample of national hospital discharge abstracts from 1993 through 2003. Using standard diagnostic codes, we identified yearly admissions for Clostridium difficile, other bacterial infections, and parasitic infections in inflammatory bowel disease patients. Next, we calculated prevalence, case fatality, and operative mortality for inflammatory bowel disease patients diagnosed with Clostridium difficile. RESULTS: We found that the prevalence of Clostridium difficile rose significantly in patients with ulcerative colitis and in those Crohns disease patients with some component of large bowel involvement but not in patients with Crohns disease limited to the small bowel alone. During the study period, case fatality also rose significantly in patients with ulcerative colitis and Clostridium difficile but not in patients with Crohns disease and Clostridium difficile. Operative mortality for ulcerative colitis patients with Clostridium difficile reached 25.7 percent. CONCLUSIONS: The prevalence and case fatality of patients with inflammatory bowel disease and Clostridium difficile rose significantly during the study period. Changes in Clostridium difficile epidemiology were particularly noteworthy for those patients with ulcerative colitis, who experienced elevated rates of hospitalization and case fatality.

Is the Decline in the Surgical Treatment for Diverticulitis Associated with an Increase in Complicated Diverticulitis

PURPOSE: Indications for operative intervention in the treatment of diverticulitis have become unclear. We hypothesized that surgical treatment for diverticulitis has decreased resulting in proportionately more complicated diverticulitis cases (free perforation and/or abscess). METHODS: We conducted a retrospective analysis of patients with diverticular disease in the Nationwide Inpatient Sample from 1991 through 2005. We used diagnostic codes to identify all patient discharges with diverticular disease and then determined the proportion of discharges with diverticulitis, perforated disease, diverticular abscess, and surgical treatment. RESULTS: During the study period, 685,390 diverticulitis discharges were recorded. The ratio of diverticulitis discharges increased from 5.1 cases per 1,000 inpatients in 1991 to 7.6 cases per 1,000 inpatients in 2005 (P < 0.0001). The proportion of patients who underwent colectomy for uncomplicated diverticulitis declined from 17.9% in 1991 to 13.7% in 2005 (P < 0.0.0001). During the same period, the proportion of free diverticular perforations as a fraction of all diverticulitis cases remained unchanged (1.5%). The proportion of diverticular abscess discharges as a fraction of all diverticulitis cases increased from 5.9% in 1991 to 9.6% in 2005 (P < 0.0001). Last, we noted a decrease in diverticular perforations and/or abscess treated with colectomy, 71.0% in 1991 to 55.5% in 2005 (P < 0.0001). CONCLUSIONS: Despite a significant decline in surgical treatment for diverticulitis, there has been no change in the proportion of patients discharged for free diverticular perforation. There was an increase in diverticular abscess discharges, but this finding was not associated with an increase in same stay surgical treatment.

The Status of Radical Proctectomy and Sphincter-Sparing Surgery in the United States

PurposeWorldwide, “centers of excellence” in rectal cancer surgery report high rates of anal sphincter-sparing surgery (70–90 percent) after proctectomy. The rate of sphincter-sparing surgery with reestablishment of intestinal continuity in the general population of the United Stares is unknown.MethodsWe used data from the Nationwide Inpatient Sample, a 20 percent stratified random sample of patients admitted to hospitals in the United States. We identified patients with rectal cancer from 1988 through 2003 who underwent sphincter-sparing surgery with reestablishment of intestinal continuity or proctectomy with colostomy. To determine predictors of sphincter-sparing surgery with reestablishment of intestinal continuity, we constructed a multivariate model that analyzed patients’ age, gender, race, insurance status, and income level.ResultsDuring our 16-year study period, radical extirpative procedures were performed in 41,631 patients: 16,510 (39.7 percent) sphincter-sparing surgery with reestablishment of intestinal continuity, and 25,121 (60.3 percent) sphincter-sacrificing procedures. The proportion of sphincter-sparing procedures increased from 26.9 percent in 1988 to 48.3 percent in 2003 (P < 0.001). There has been no significant change in the rate of sphincter-sparing surgery since 1999 (P = not significant). Logistic regression revealed that patients who were older, male, black, used Medicaid insurance, or lived in lower-income zip codes were less likely to have sphincter-sparing surgery with reestablishment of intestinal continuity (P < 0.001).ConclusionsDespite a significant increase in the rate of sphincter-sparing surgery with reestablishment of intestinal continuity, most radical resections for rectal cancer in hospitals in the United States result in a colostomy. Patients vulnerable to proctectomy without sphincter preservation were older, male, black, used Medicaid insurance, or lived in lower income zip codes.

Risk of Anal Cancer in a Cohort With Human Papillomavirus–related Gynecologic Neoplasm

OBJECTIVE: To assess the development of anal cancer in women diagnosed with a human papillomavirus–related cervical, vulvar, or vaginal neoplasm. METHODS: Using data from National Cancer Institutes Surveillance, Epidemiology and End Results program from 1973 through 2007, 189,206 cases with either in situ or invasive cervical, vulvar, or vaginal neoplasm were followed for 138,553,519 person-years for the development of subsequent primary anal cancer. Standardized incidence ratios were calculated from the observed number of subsequent anal cancers compared with those expected based on age-, race-, and calendar year–specific rates in the nonaffected population. RESULTS: Anal cancer developed in 255 women with a history of in situ or invasive gynecologic neoplasm, aggregate standardized incidence ratio of 13.6 (95% confidence interval [CI] 11.9–15.3), indicating a 13-fold increase in anal cancer compared with expected. The standardized incidence ratio for anal cancer incidence among women with in situ vulvar cancer was 22.2 (95% CI 16.7–28.4) and was 17.4 (95% CI 11.5–24.4) for those with invasive vulvar cancer. The standardized incidence ratio for anal cancer incidence in women with in situ cervical cancer was 16.4 (95% CI 13.7–19.2) and was 6.2 (95% CI 4.1–8.7) for women with invasive cervical cancer. The standardized incidence ratio for anal cancer incidence among women with in situ vaginal cancer was 7.6 (95% CI 2.4–15.6) and was 1.8 (95% CI 0.2–5.3) for invasive vaginal cancer. CONCLUSION: Women with human papillomavirus–related gynecologic neoplasm are at higher risk for developing anal cancer compared with the general population. This high-risk population may benefit from close observation and screening for anal cancer. LEVEL OF EVIDENCE: II