Efficacy and Safety of Curcumin in Treatment of Intestinal Adenomas in Patients With Familial Adenomatous Polyposis.

BACKGROUND & AIMS: Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis. METHODS: This study included 44 patients with familial adenomatous polyposis (18-85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle. RESULTS: After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3-27.8) and the curcumin group (22.6; 95% CI, 12.1-33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8-2.8) and the placebo group (2.1 mm; 95% CI, 1.5-2.7; P = .76). Adverse events were few, with no significant differences between groups. CONCLUSIONS: In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147.

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma. METHODS: In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR). RESULTS: A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension. CONCLUSIONS: Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

Changes in PSA kinetics predict metastasis- free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of 4 phase II trials.

BACKGROUND: Several phase II trials in men with noncastrate PSA-recurrent prostate cancer have assessed the impact of novel nonhormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS). METHODS: We performed a retrospective post hoc analysis of 146 men treated in 4 phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n = 39), imatinib (a tyrosine kinase inhibitor; n = 25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n = 22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n = 60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation. RESULTS: After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P = .05), baseline PSA slope (P = .01), on-study change in PSADT (P = .02), and on-study change in PSA slope (P = .03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% confidence interval [CI], 34.6-not reached) and 28.9 months (95% CI, 13.5-68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively. CONCLUSIONS: This hypothesis generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients.

Comparison of acute toxicities in two primary chemoradiation regimens in the treatment of advanced head and neck squamous cell carcinoma.

PURPOSE: The optimal dosage and frequency of platinum-based chemoradiotherapy (CRT) regimen for treating advanced head and neck squamous cell carcinoma remains unresolved. This study aims to compare the toxicity and efficacy of weekly versus more dose-intensive cisplatin-based CRTs. METHODS: We reviewed 155 stage III/IV head and neck squamous cell carcinoma patients with no evidence of distant metastasis treated with one of two CRT regimens from 2000 to 2010 at Greater Baltimore Medical Center. Twice-daily radiation was provided as a split course over a 45-day period. Regimen A consisted of concomitant cisplatin (30 mg/m2/1 h) weekly for 6 cycles; regimen B consisted of concomitant cisplatin (12 mg/m2/1 h) and 5-fluorouracil (600 mg/m2/20 h) on days 1 through 5 and days 29 through 33. Main outcome measures included acute toxicities (myelosuppression, neurotoxicity, nephrotoxicity, gastrointestinal dysfunction), unplanned hospitalizations, and disease control at 12 months. RESULTS: Patients on regimen A were much less likely to experience ototoxicity due to their treatment (0% vs. 9.8%, P = 0.04). They were more likely to experience thrombocytopenia acutely (46% vs. 26%, P = 0.02), but the toxicity was not limiting (grade 1­2). No significant differences exist in the incidence of other toxicities or unplanned hospitalizations. At 1 year, 97% of patients on A vs. 86% of patients on regimen B were free of disease (P = 0.11). CONCLUSIONS: With concurrent radiotherapy, low-dose, single-agent, weekly cisplatin is less likely than higher-dose daily cisplatin plus 5-fluorouracil provided at the beginning and end of treatment to be associated with ototoxicity. The preliminary data suggest at least equivalent efficacy, but longer follow-up is required.

Racial disparities in ovarian cancer surgical care: a population-based analysis.

OBJECTIVE: To investigate differences according to racial classification in the frequency of ovarian cancer-related surgical procedures and in access to high-volume surgical providers among women undergoing initial surgery for ovarian cancer. METHODS: The Maryland Health Services Cost Review Commission database was accessed for women age >18years undergoing a surgical procedure that included oophorectomy for a malignant ovarian neoplasm between 7/1/01 and 6/30/09. Multivariate logistic regression analyses were used to evaluate for differences in the likelihood of selected surgical procedures and access to high-volume surgical providers (surgeons≥10 cases/year; hospitals≥20 case/year) according racial classification. RESULTS: A total of 2487 patients were identified who underwent a primary surgical procedure that included oophorectomy for a malignant ovarian neoplasm: White=1884 (75.4%), African-American=400 (16.1%), and other/unknown=203 (8.2%). Compared to White patients, African-American patients were significantly younger (mean age 55.4years vs 59.9years, P<0.0001) and less likely to have commercial insurance (28.5% vs 39.5%, p<0.0001). Compared to White patients, African-American racial classification was associated with a statistically significant and independent lower likelihood of hysterectomy (OR=0.53, 95%CI=0.42-0.66, p<0.0001), colon resection (OR=0.65, 95%CI=0.48-0.87, p=0.004), lymphadenectomy (OR=0.67, 95%CI=0.50-0.91, p=0.01), and surgery by a high-volume surgeon (OR=0.55, 95%CI=0.44-0.69, p<0.0001). CONCLUSIONS: Among women undergoing initial surgery for ovarian cancer, African-American patients are significantly less likely to be operated on by a high-volume surgeon and to undergo important ovarian cancer-specific surgical procedures compared to White patients.

Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide.

Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes.

OBJECTIVE: To evaluate the impact of surgeon and hospital case volume, and other related variables, on short-term outcomes after surgery for ovarian cancer. METHODS: The Maryland Health Service Cost Review Commission database was accessed for ovarian cancer surgical cases including both oophorectomy and any staging/cytoreductive surgical procedure from 2001 to 2008. Multivariate logistic regression analyses and multiple linear regression models were used to evaluate for significant associations between surgeon and hospital case volume, as well as other independent variables, and the risk of in-hospital death, extent of surgery, length of hospital stay, and hospital-related cost of care. RESULTS: Overall, 1894 primary ovarian cancer operations were performed by 352 surgeons at 43 hospitals. After controlling for the effects of all variables, the only independently significant factors associated with the risk of in-hospital death were surgery by a high-volume surgeon and an APR-DRG mortality risk score of 4. Ovarian cancer surgery performed by a high-volume surgeon was associated with a 69% reduction in the risk of in-hospital death. Surgery at a high-volume hospital was an independent positive predictor of a cytoreductive procedure. A statistically significant negative correlation was observed between surgery at a high-volume hospital and both length of hospital stay and hospital-related cost. CONCLUSIONS: After controlling for other factors, ovarian cancer surgery performed by a high-volume surgeon is associated with a 69% reduction in the risk of in-hospital death, while high-volume hospital care is associated with increased likelihood of cytoreduction, shorter length of stay, and lower hospital-related cost of care.

A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers.

PURPOSE: Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment. RESULTS: Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = -0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008). CONCLUSIONS: Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

Surgical care of young women diagnosed with ovarian cancer: a population-based perspective.

OBJECTIVE: To characterize primary surgical care for women with ovarian cancer aged 50 years. METHODS: A statewide hospital discharge database was used to identify women undergoing primary surgery for ovarian cancer from 1990 to 2000. Logistic regression models were used to evaluate differences in demographic characteristics and short-term outcomes comparing women 50 years. RESULTS: Women 50 years (47.1% vs. 59.5%, P<0.0001). Younger women managed by high-volume surgeons had longer lengths of stay (5.7 days vs. 7.7 days, P<0.0001), longer ICU stays (0.2 days vs. 0.5 days, P=0.0020), more billed procedures (4.2 vs. 5.5, P<0.0001), higher adjusted cost of hospital-related care ($46,590 vs. $97,538, P<0.0001) and more comorbidities (1.0 vs. 1.6, P<0.0001) than those treated by lower-volume surgeons. Women

Feasibility and economic impact of a clinical pathway for pap test utilization in Gynecologic Oncology practice.

OBJECTIVE: To evaluate the feasibility and impact on cost to the U.S. healthcare system of implementing a clinical pathway for Pap test utilization in screening and surveillance of gynecologic cancers in a university-based gynecologic oncology practice. METHODS: Baseline data were collected for Pap test utilization between 1/1/04 and 6/30/05 and prospectively compared to Pap test utilization following the implementation of a clinical pathway (7/1/05 to 5/30/06). The clinical pathway: 1) employed ACOG guidelines for asymptomatic screening of non-cancer patients, 2) allowed testing at 4 months intervals for cervical/vaginal cancer surveillance, 3) limited testing for endometrial cancer surveillance to 2 tests/60 months, and 4) eliminated testing as part of ovarian cancer surveillance. Relevant costs were calculated using Medicare charge-to-cost ratios and adjusted to 2006 USD. For statistical analysis, differences in Pap test utilization and cost were evaluated using student's t-test. RESULTS: During the baseline period, 1725 Pap tests were collected from 5605 ambulatory encounters, for a Pap test rate of 30.8% and an annualized cost of $93,759. After implementation of the clinical pathway, 4209 ambulatory encounters yielded an annual Pap test rate of 11% and an annual cost of $35,728 (p<0.0001), a savings of $58,031. In addition, clinical pathway implementation also registered an opportunity cost savings of 180.3 nursing personnel work hours ($4,162). CONCLUSIONS: Reduction in the unnecessary use of Pap testing for asymptomatic screening and surveillance for gynecologic cancers through a straightforward clinical pathway is feasible and offers an opportunity for significant cost savings in gynecologic oncology healthcare expenditure.

A clinical pathway for patients undergoing primary cytoreductive surgery with rectosigmoid colectomy for advanced ovarian and primary peritoneal cancers.

OBJECTIVES: To evaluate the safety, feasibility, and economic impact of a clinical pathway, including rapid diet advancement, for patients undergoing rectosigmoid colectomy as part of cytoreductive surgery for advanced ovarian and primary peritoneal cancers. METHODS: Between 8/1/98 and 6/30/06, 64 consecutive patients met study inclusion criteria. Using case-control methodology, post-operative management was dictated by a prescribed clinical pathway in 19 patients (Group A) and directed by individual surgeon preference in 45 patients (Group B). Critical elements of the clinical pathway included: rapid diet advancement, early discontinuance of nasogastric suction, criteria-based utilization of parenteral nutrition, selective laboratory testing, and deferring initiation of chemotherapy until after discharge. RESULTS: Stage IIIC/IV disease was present in 94% of all patients. The median time to flatus was 6 days for both groups (p=0.95); however, the median time to tolerance of diet was 3 days for Group A and 6 days for Group B (p=0.013). Compared to Group B, patients in Group A had a significantly shorter median length of hospital stay (7 days vs 10 days, p=0.014) and lower median 30-day post-operative hospital cost ($19,700 vs $25,110, p=0.028), with no significant difference in 30-day readmission rate (21% vs 33%, p=0.379). Clinical pathway-directed management was associated with a median reduction in hospital cost of $5410 per patient. CONCLUSIONS: A critical pathway incorporating rapid diet advancement for patients undergoing primary cytoreductive surgery with rectosigmoid colectomy for ovarian and primary peritoneal cancers is feasible, safe, and associated with a significant reduction in length of hospital stay and hospital-related costs.

Survival impact of multiple bowel resections in patients undergoing primary cytoreductive surgery for advanced ovarian cancer: a case-control study.

OBJECTIVE: To evaluate clinicopathological factors and survival outcome of patients with advanced epithelial ovarian carcinoma undergoing multiple bowel resections to achieve optimal (< or = 1 cm) cytoreduction. METHODS: A case-control study was performed identifying patients undergoing optimal primary cytoreductive surgery with > or = 2 bowel resections between 10/1997 and 2/2006. The two control groups consisted of (1) patients undergoing optimal cytoreduction with < or = 1 bowel resections matched [1:2] for age and stage and (2) patients left with suboptimal disease. Cox proportional hazards model were used to evaluate the effects of demographic and surgico-pathologic factors on survival outcome. RESULTS: A total of 34 patients underwent > or = 2 bowel resections. Sixty-eight patients underwent < or = 1 bowel resections. All patients had optimal cytoreduction and 40/102 patients (39.2%) underwent complete cytoreduction. Patients undergoing multiple bowel resections experienced a higher EBL (700 v 500 mL, p=0.01) and longer LOS (10 v 7 days, p=0.01) compared to patients with < or = 1 bowel resections. Multivariate analysis revealed the amount of residual disease to be a statistically significant and radiation therapy to the right pelvic sidewall and cul-de-sac independent predictor of overall survival. The median overall survival time for patients undergoing > or = 2 bowel resections was 28.3 months, which was comparable to patients undergoing < or = 1 bowel resections, (37.8 months, p=0.09) but statistically significantly superior to patients left with suboptimal residual disease (12 months, p=0.02). CONCLUSIONS: Although primary surgery that includes > or = 2 bowel resections is associated with longer LOS and a higher EBL, such extensive procedures are warranted if they will contribute to an overall optimal residual disease state.

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma.

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1-3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS.Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate.Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22-77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9-3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7-45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7-17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0-26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9-75.6). The most common adverse events were diarrhea (84%), nausea (64%), fatigue (56%), and hypertension (52%).Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027-34. ©2017 AACR.

Risk of epithelial ovarian cancer recurrence in patients with rising serum CA-125 levels within the normal range.

PURPOSE: To evaluate the risk of epithelial ovarian cancer (EOC) recurrence in patients with rising serum cancer antigen 125 (CA-125) levels that remain below the upper limit of normal (< 35 U/mL). PATIENTS AND METHODS: All patients treated for EOC between September 1997 and March 2003 were identified and screened retrospectively for the following: (1) elevated serum CA-125 at time of diagnosis, (2) complete clinical and radiographic response (CR) to initial treatment with normalization of serum CA-125, (3) at least three serial serum CA-125 determinations that remained within the normal range, and (4) clinical and/or radiographic determination of disease status at the time of last follow-up or recurrence. For statistical analyses, univariate regression models were used to compare absolute and relative changes in CA-125 levels among patients with recurrent disease and those without EOC recurrence. RESULTS: A total of 39 patients satisfied study inclusion criteria; 22 patients manifested EOC recurrence at a median interval from complete response of 11 months. The median follow-up time from complete response to last contact was 32 months for the 17 patients in the no recurrence group. A relative increase in CA-125 of 100% (odds ratio [OR] = 23.7; 95% CI, 2.9 to 192.5; P = .003) was significantly predictive of recurrence. From baseline CA-125 nadir levels, an absolute increase in CA-125 of 5 U/mL (OR = 8.4; 95% CI, 2.2 to 32.6; P = .002) and 10 U/mL (OR = 71.2; 95% CI, 4.8 to > 999.9; P = .002) were also significantly associated with the likelihood of concurrent disease recurrence. CONCLUSION: Among patients with EOC in complete clinical remission, a progressive low-level increase in serum CA-125 levels is strongly predictive of disease recurrence.

Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology.

New biomarkers of pancreatic adenocarcinoma are needed to improve the early detection of this deadly disease. We performed surface enhanced laser desorption ionization (SELDI) mass spectrometry using ProteinChip technology (Ciphergen Biosystems, Fremont, CA) to screen for differentially expressed proteins in pancreatic juice. Pancreatic juice samples obtained from patients undergoing pancreatectomy for pancreatic adenocarcinoma were compared with juice samples from patients with other pancreatic diseases. We identified a peak approximately 16,570 daltons present in the pancreatic juice from 10/15 (67%) of the patients with pancreatic adenocarcinoma and in the pancreatic juice from 1/7 (17%) of the patients with other pancreatic diseases. Using a ProteinChip immunoassay, we identified this differentially expressed protein as hepatocarcinoma-intestine-pancreas/pancreatitis-associated-protein I (HIP/PAP-I), a protein released from pancreatic acini during acute pancreatitis and overexpressed in hepatocellular carcinoma. We then quantified by ELISA the pancreatic juice HIP/PAP-I levels in 43 patients (28 with pancreatic adenocarcinoma, 15 with other pancreatic diseases) and the serum HIP/PAP-I levels in 98 patients (53 with pancreatic adenocarcinoma, 45 with other pancreatic diseases or healthy individuals). HIP/PAP-I levels were significantly higher in both the pancreatic juice (P < 0.001) and in the serum (P < 0.001) of patients with pancreatic adenocarcinoma compared with the control group. HIP/PAP-I levels were approximately 1000-fold higher in pancreatic juice compared with serum and the magnitude of the difference between the pancreatic adenocarcinoma group and the control group was greater in the pancreatic juice samples (143.75 +/- 235.52 microg/ml versus 6.04 +/- 7.59 microg/ml) than in the serum samples (99.96 +/- 140.66 ng/ml versus 35.25 +/- 28.44 ng/ml). In our study, patients with pancreatic juice HIP/PAP-I levels > or= 20 microg/ml were 21.9 times (95% confidence interval, 3.5-136.5; P < 0.001) more likely to have pancreatic adenocarcinoma than patients with levels <20 microg/ml. Immunolabeling of tissue sections revealed that the HIP/PAP-I protein was strongly expressed in acini adjacent to the invasive adenocarcinoma, but it was only rarely (1/30; 3%) expressed in the neoplastic epithelium, which suggests that the main source of HIP/PAP-I release in the pancreatic juice is acini. This low level of HIP/PAP-I expression in pancreatic adenocarcinoma was confirmed by reverse transcription-PCR: only 1 (5%) of 19 pancreatic cancer cell lines expressed HIP/PAP-I transcripts. Taken together, these data suggest that pancreatic juice measurement of HIP/PAP-I may help to identify patients with pancreatic adenocarcinoma.

Expression and prognostic significance of 14-3-3sigma and ERM family protein expression in periampullary neoplasms.

Aberrant gene expression in pancreatic ductal adenocarcinomas contributes to the dismal outcome of patients who develop this disease. The 5' region of 14-3-3sigma (stratifin) is hypomethylated in pancreatic adenocarcinomas and is associated with gene overexpression. In multiple experimental systems, ezrin (ERM, Radixin, Moesin) has been identified as being important in the metastatic behavior of pancreatic and other cancers. We investigated the prognostic significance of aberrant expression of 14-3-3sigma and the ERM proteins (Ezrin, radixin, Moesin) in a series of invasive periampullary adenocarcinomas including 300 infiltrating pancreatic adenocarcinomas, 54 ampullary adenocarcinomas, and 33 noninvasive intraductal papillary mucinous neoplasms from patients who underwent pancreaticoduodenal resection at The Johns Hopkins Hospital, Baltimore, MD, between 1991 and 2003. Two-hundred fourty-four (82%) primary infiltrating adenocarcinomas of the pancreas demonstrated positive expression of the 14-3-3sigma, 45 (15%) showed weak immunolabelling, and 9 (3%) were negative. 201 (68%) showed positive immunolabeling of the ERM proteins, 75 (25%) demonstrated weak expression and 20 (7%) no expression. A similar proportion of ampullary cancers showed 14-3-3sigma and ERM protein expression. Expression of 14-3-3sigma and ERM protein was more likely in poorly differentiated cancers (p = 0.00005), and their expression was associated with poor survival in univariate analysis (p = 0.09). By multivariate analysis, patients whose cancers expressed 14-3-3sigma, but not ERM tended to have a poorer prognosis (Hazard ratio, 1.4; 0.9-2.2, p = 0.14). Aberrant expression of 14-3-3sigma may contribute to the outcome of patients with pancreatic ductal adenocarcinoma.

Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions.

PURPOSE: Mitochondria are highly susceptible to oxidative damage. Although mitochondrial function decreases with oxidative damage, overall mitochondrial DNA (mtDNA) content increases to compensate for general mitochondrial dysfunction. We performed quantitative polymerase chain reaction for genes specific to mitochondrial and nuclear genomes to investigate relative mitochondrial abundance in a spectrum of dysplastic head and neck lesions. EXPERIMENTAL DESIGN: DNA from mild, moderate, and severe dysplasias, as well as invasive tumors and normal mucosal cells, was extracted. Using quantitative polymerase chain reaction, mitochondrial to nuclear DNA ratios were determined by quantification of cytochrome c oxidase subunit 1 (CoxI) and beta-actin genes. RESULTS: Mean CoxI/beta-actin DNA ratios for mild, moderate, and severe premalignant lesions were 0.0529, 0.0607, and 0.1021, respectively. The mean ratio for the normal mucosal cells contained in saliva was 0.0537, whereas the mean ratio for tumors was 0.1667. As a whole, our experimental model demonstrated significance (P = 0.0358). Comparisons between individual categories showed borderline significance when compared with the normal group, with P values of 0.0673, 0.0747, and 0.0824 for moderate and severe dysplasia and invasive tumor, respectively. CONCLUSIONS: Head and neck squamous cell carcinomas arise through premalignant intermediates and may be merely morphologic manifestations of accumulated genetic alterations. In keeping with this molecular tumor progression model, our study shows that mtDNA increases according to histopathologic grade, a phenomenon that may be a feedback mechanism that compensates for a generalized decline in respiratory chain function. Therefore, high mtDNA content may be another marker of genetic alteration, a measure of relative DNA injury, and a surrogate measure of histopathologic grade.

Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.

PURPOSE: Patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis. One effective strategy likely to improve the morbidity and mortality from pancreatic cancer would be the identification of accurate, noninvasive diagnostic markers that would enable earlier diagnosis of symptomatic patients and earlier detection of cancer in asymptomatic individuals at high risk for developing pancreatic cancer. In this study, we evaluated serum macrophage inhibitory cytokine-1 (MIC-1) as a marker of pancreatic cancer. EXPERIMENTAL DESIGN: MIC-1 expression in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines was determined using the National Center for Biotechnology Information serial analysis of gene expression database, oligonucleotide microarrays analysis, in situ hybridization, and immunohistochemistry. Serum MIC-1 levels were determined by ELISA in 80 patients with pancreatic adenocarcinomas, in 30 patients with ampullary and cholangiocellular carcinomas, in 42 patients with benign pancreatic tumors, in 76 patients with chronic pancreatitis, and in 97 healthy control subjects. The diagnostic performance of serum MIC-1 as a marker of pancreatic cancer was compared with that of serum CA19-9. RESULTS: Oligonucleotide microarray and serial analysis of gene expression data demonstrated that MIC-1 RNA levels were higher in primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer cell lines than in nonneoplastic pancreatic ductal epithelium. MIC-1 expression was localized to the malignant epithelium in pancreatic adenocarcinomas by in situ hybridization. MIC-1 protein was expressed in 14 of 16 primary pancreatic adenocarcinomas (88%) by immunohistochemistry and was also expressed in some pancreata affected by pancreatitis but not in normal pancreas. Serum MIC-1 levels were significantly higher in patients with pancreatic ductal adenocarcinoma (mean +/- SD, 2428 +/- 2324 pg/ml) and in patients with ampullary and cholangiocellular carcinomas (2123 +/- 2387 pg/ml) than in those with benign pancreatic neoplasms (940 +/- 469 pg/ml), chronic pancreatitis (1364 +/- 1236 pg/ml), or in healthy controls (546 +/- 262 pg/ml). An elevated serum MIC-1 (defined as 2 SD above the mean for healthy controls) performed as well as CA19-9 (area under the receiver operating characteristic curve, 0.81 and 0.77, respectively), and the combination of MIC-1 and CA19-9 significantly improved diagnostic accuracy (P < 0.05; area under the receiver operating characteristic curve, 0.87; sensitivity, 70%; specificity, 85%). CONCLUSION: Serum MIC-1 measurement can aid in the diagnosis of pancreatic adenocarcinoma.