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.

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.

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.

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.

Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer.

Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA.

Multidisciplinary service utilization pattern by advanced head and neck cancer patients: a single institution study.

Purpose. To analyze the patterns and associations of adjunctive service visits by head and neck cancer patients receiving primary, concurrent chemoradiation therapy. Methods. Retrospective chart review of patients receiving adjunctive support during a uniform chemoradiation regimen for stages III-IV head and neck squamous cell carcinoma. Univariate and multivariate models for each outcome were obtained from simple and multivariate linear regression analyses. Results. Fifty-two consecutive patients were assessed. Female gender, single marital status, and nonprivate insurance were factors associated with an increased number of social work visits. In a multivariate analysis, female gender and marital status were related to increased social work services. Female gender and stage IV disease were significant for increased nursing visits. In a multivariate analysis for nursing visits, living greater than 20 miles between home and hospital was a negative predictive factor. Conclusion. Treatment of advanced stage head and neck cancer with concurrent chemoradiation warrants a multidisciplinary approach. Female gender, single marital status, and stage IV disease were correlated with increased utilization of social work and nursing services. Distance over 20 miles from the center was a negative factor. This information may help guide the treatment team to allocate resources for the comprehensive care of patients.

Hyperfractionated radiotherapy with concurrent cisplatin/5-Fluorouracil for locoregional advanced head and neck cancer: analysis of 105 consecutive patients.

Objective. We reviewed a cohort of patients with previously untreated locoregional advanced head and neck squamous cell carcinoma (HNSCC) who received a uniform chemoradiotherapy regimen. Methods. Retrospective review was performed of 105 patients with stage III or IV HNSCC treated at Greater Baltimore Medical Center from 2000 to 2007. Radiation included 125 cGy twice daily for a total 70 Gy to the primary site. Chemotherapy consisted of cisplatin (12 mg/m(2)/h) daily for five days and 5-fluorouracil (600 mg/m(2)/20 h) daily for five days, given with weeks one and six of radiation. All but seven patients with N2 or greater disease received planned neck dissection after chemoradiotherapy. Primary outcomes were overall survival (OS), locoregional control (LRC), and disease-free survival (DFS). Results. Median followup of surviving patients was 57.6 months. Five-year OS was 60%, LRC was 68%, and DFS was 56%. Predictors of increased mortality included age ≥55, female gender, hypopharyngeal primary, and T3/T4 stage. Twelve patients developed locoregional recurrences, and 16 patients developed distant metastases. Eighteen second primary malignancies were diagnosed in 17 patients. Conclusions. The CRT regimen resulted in favorable outcomes. However, locoregional and distant recurrences cause significant mortality and highlight the need for more effective therapies to prevent and manage these events.

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.

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.

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.

Quantitative methylation profiles for multiple tumor suppressor gene promoters in salivary gland tumors.

BACKGROUND: Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. METHODOLOGY: DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. PRINCIPAL FINDINGS: The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (p<0.0003). There was a variable frequency and individual methylation quotient detected, depending on the TSG and the tumor type. When comparing normal, benign, and malignant SGTs, there was a statistically significant trend for increasing methylation in APC, Mint 1, PGP9.5, RAR-beta, and Timp3. CONCLUSIONS/SIGNIFICANCE: Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors.

Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers.

PURPOSE: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. PATIENTS AND METHODS: Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. RESULTS: Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. CONCLUSION: Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

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.

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.