Same day discharge colon surgery: is it financially worth it?

AIM: Same day discharge (SDD) for colorectal surgery shows increasing promise in the era of enhanced recovery after surgery protocols and minimally invasive surgery. It has become increasingly relevant due to the constraints posed by the COVID-19 pandemic. The aim of this study was to compare SDD and postoperative day 1 (POD1) discharge to understand the clinical outcomes and financial impact on factors such as cost, charge, revenue, contribution margin and readmission. METHOD: A retrospective review of colectomies was performed at a single institution over a 2-year period (n = 143). Two populations were identified: SDD (n = 51) and POD1 (n = 92). Patients were selected by International Statistical Classification of Diseases and Related Health Problems-10 (ICD-10) and Diagnosis Related Grouper (DRG) codes. RESULTS: There was a statistically significant difference favouring SDD in total hospital cost (p < 0.0001), average direct costs (p < 0.0001) and average charges (p < 0.0016). SDD average hospital costs were $8699 (values in USD throughout) compared with $11 652 for POD 1 (p < 0.0001), and average SDD hospital charges were $85 506 compared with $97 008 for POD1 (p < 0.0016). The net revenue for SDD was $22 319 while for POD1 it was $26 173 (p = 0.14). Upon comparison of contribution margins (SDD $13 620 vs. POD1 $14 522), the difference was not statistically significant (p = 0.73). There were no identified statistically significant differences in operating room time, robotic console time, readmission rates or surgical complications. CONCLUSIONS: Amidst the pandemic-related constraints, we found that SDD was associated with lower hospital costs and comparable contribution margins compared with POD1. Additionally, the study was unable to identify any significant difference between operating time, readmissions, and surgical complications when performing SDD.

Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

An aberrantly sustained emergency granulopoiesis response accelerates postchemotherapy relapse in MLL1-rearranged acute myeloid leukemia in mice.

Acute myeloid leukemia (AML) with mixed lineage leukemia 1 (MLL1) gene rearrangement is characterized by increased expression of a set of homeodomain transcription factors, including homeobox A9 (HOXA9) and HOXA10. The target genes for these regulators include fibroblast growth factor 2 (FGF2) and Ariadne RBR E3 ubiquitin ligase 2 (ARIH2). FGF2 induces leukemia stem cell expansion in MLL1-rearranged AML. ARIH2 encodes TRIAD1, an E3 ubiquitin ligase required for termination of emergency granulopoiesis and leukemia suppressor function in MLL1-rearranged AML. Receptor tyrosine kinases (RTKs), including the FGF receptor, are TRIAD1 substrates that are possibly relevant to these activities. Using transcriptome analysis, we found increased activity of innate immune response pathways and RTK signaling in bone marrow progenitors from mice with MLL1-rearranged AML. We hypothesized that sustained RTK signaling, because of decreased TRIAD1 activity, impairs termination of emergency granulopoiesis during the innate immune response and contributes to leukemogenesis in this AML subtype. Consistent with this, we found aberrantly sustained emergency granulopoiesis in a murine model of MLL1-rearranged AML, associated with accelerated leukemogenesis. Treating these mice with an inhibitor of TRIAD1-substrate RTKs terminated emergency granulopoiesis, delayed leukemogenesis during emergency granulopoiesis, and normalized innate immune responses when combined with chemotherapy. Emergency granulopoiesis also hastened postchemotherapy relapse in mice with MLL1-rearranged AML, but remission was sustained by ongoing RTK inhibition. Our findings suggest that the physiological stress of infectious challenges may drive AML progression in molecularly defined subsets and identify RTK inhibition as a potential therapeutic approach to counteract this process.

Stat3 and CCAAT enhancer-binding protein ß (C/ebpß) activate Fanconi C gene transcription during emergency granulopoiesis.

Interferon consensus sequence-binding protein (Icsbp) is required for terminating emergency granulopoiesis, an episodic event responsible for granulocyte production in response to infections and a key component of the innate immune response. Icsbp inhibits the expression of Stat3 and C/ebpß, transcription factors essential for initiating and sustaining granulopoiesis, and activates transcription of Fanconi C (FANCC), a DNA repair protein. In prior studies, we noted accelerated bone marrow failure in Fancc-/- mice undergoing multiple episodes of emergency granulopoiesis, associated with apoptosis of bone marrow cells with unrepaired DNA damage. Additionally, we found increased expression of Fanconi C and F proteins during emergency granulopoiesis. These findings suggest that Icsbp protects the bone marrow from DNA damage by increasing activity of the Fanconi DNA repair pathway, but the mechanisms for FANCC activation during initiation of emergency granulopoiesis are unclear. In this study, we observed that Stat3 and C/ebpß activate FANCC transcription and contribute to DNA repair. Our findings indicate that FancC expression is increased during Stat3- and C/ebpß-induced initiation of emergency granulopoiesis by these transcription factors and is maintained through termination by Icsbp. Our work reveals that Stat3- and C/ebpß-mediated FancC expression is a critical component for initiating and sustaining key innate immune responses.

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.

OBJECTIVE: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose. METHODS: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis. RESULTS: The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 B RCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3-4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1-2 non-hematologic toxicities. CONCLUSIONS: Olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt. TRIAL REGISTRATION NUMBER: NCT01650376.

HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1.

Expression of the E3 ubiquitin ligase Triad1 is greater in mature granulocytes than in myeloid progenitor cells. HoxA10 actives transcription of the gene encoding Triad1 (ARIH2) during myeloid differentiation, but the contribution of increased Triad1 expression to granulocyte production or function is unknown. Mice with bone marrow-specific disruption of the ARIH2 gene exhibit constitutive inflammation with tissue infiltration by granulocytes and B cells. In contrast, disruption of the HOXA10 gene in mice neither constitutively activates the innate immune response nor significantly alters steady-state granulopoiesis. This study explores the impact of HoxA10-induced Triad1 expression on emergency (stress) granulopoiesis. We found that mice with HOXA10 gene disruption exhibited an overwhelming and fatal emergency granulopoiesis response that was characterized by tissue infiltration with granulocytes, but reversed by re-expression of Triad1 in the bone marrow. We determined that HoxA9 repressed ARIH2 transcription in myeloid progenitor cells, antagonizing the effect of HoxA10 on Triad1 expression. Also, we found that differentiation-stage-specific ARIH2 transcription was regulated by the tyrosine phosphorylation states of HoxA9 and HoxA10. Our studies demonstrate a previously undescribed role for HoxA10 in terminating emergency granulopoiesis, suggesting an important contribution by Hox proteins to the innate immune response.

The leukemia-associated Mll-Ell oncoprotein induces fibroblast growth factor 2 (Fgf2)-dependent cytokine hypersensitivity in myeloid progenitor cells.

The subset of acute myeloid leukemias (AML) with chromosomal translocations involving the MLL gene have a poor prognosis (referred to as 11q23-AML). The MLL fusion proteins that are expressed in 11q23-AML facilitate transcription of a set of HOX genes, including HOXA9 and HOXA10. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. In the current study we found that Mll-Ell (an MLL fusion protein) induced transcriptional activation of the FGF2 gene in a HoxA9- and HoxA10-dependent manner. FGF2 encodes fibroblast growth factor 2 (also referred to as basic fibroblast growth factor). Fgf2 influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2-expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf2 and Fgf2-dependent cytokine hypersensitivity. Therefore, our results implicated increased Fgf2 expression in progenitor proliferation and expansion in 11q23-AML. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia.

HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.

HoxA10 is a member of a highly conserved family of homeodomain transcription factors that are involved in definitive hematopoiesis and implicated in the pathogenesis of acute myeloid leukemia (AML). During normal hematopoiesis, HoxA10 facilitates myeloid progenitor expansion and impedes myeloid differentiation. To better understand the molecular mechanisms that control these events, we have been identifying and characterizing HoxA10 target genes. In this study, we identified the gene encoding fibroblast growth factor 2 (Fgf2 or basic fibroblast growth factor) as a target gene that is relevant to the biological effects of HoxA10. We identified two cis elements in the proximal FGF2 promoter that are activated by HoxA10 in myeloid progenitor cells and differentiating phagocytes. We determined that Fgf2 expression and secretion are regulated in a HoxA10-dependent manner in these cells. We found that increased Fgf2 production by HoxA10-overexpressing myeloid progenitor cells induced a phosphoinositol 3-kinase-dependent increase in ß-catenin protein. This resulted in autocrine stimulation of proliferation in HoxA10-overexpressing cells and hypersensitivity to other cytokines that share this pathway. Therefore, these studies identified expression of Fgf2 as a mechanism by which HoxA10 controls the size of the myeloid progenitor population. These studies also suggested that aberrant production of Fgf2 may contribute to leukemogenesis in the subset of AML with dysregulated Hox expression. Therapeutic targeting of Fgf2-stimulated signaling pathways might be a rational approach to this poor prognosis subset of AML.

Beyond enhanced recovery after surgery (ERAS): Evolving minimally invasive colectomy from multi-day admissions to same-day discharge.

INTRODUCTION: Early discharge is increasingly important in the resource-limited COVID era. Some groups have reported early experiences with same day discharge (SDD) after colectomy. We implemented a routine SDD protocol and report the evolution in our program's outcomes. METHODS: We studied a retrospective cohort of robotic colorectal surgeries from 2016 to 2022. Colectomies were analyzed as a sub-group and stratified by year. RESULTS: The cohort comprised 535 cases, of which 483 were colectomies. Annual case volume increased from 58 to 180 cases (p < 0.001). Operative console time concordantly decreased by 33% (p < 0.001). Average length of stay decreased from five to one days. By 2022, 58% of colectomies were selectively discharged on the same day of surgery. Complication and readmission rates remained constant. CONCLUSIONS: SDD is feasible and safe in selected patients. We illustrate the practical evolution of a surgical practice toward routine SDD, and discuss the factors we found critical to this transition.

HoxA10 influences protein ubiquitination by activating transcription of ARIH2, the gene encoding Triad1.

HoxA10 is a homeodomain transcription factor that is maximally expressed in myeloid progenitor cells. An increase in HoxA10 expression correlates with poor prognosis in human acute myeloid leukemia (AML). Consistent with this scenario, HoxA10 overexpression in murine bone marrow induces a myeloproliferative neoplasm that advances AML over time. Despite the importance of HoxA10 for leukemogenesis, few genuine HoxA10 target genes have been identified. The current study identified ARIH2, the gene encoding Triad1, as a HoxA10 target gene. We identified two distinct HoxA10-binding cis elements in the ARIH2 promoter and determined that HoxA10 activates these cis elements in myeloid cells. Triad1 has E3 ubiquitin ligase activity, and we found that HoxA10-overexpressing myeloid cells exhibited a Triad1-dependent increase in protein ubiquitination. Therefore, these studies have identified the regulation of protein ubiquitination as a novel function of Hox transcription factors. Forced overexpression of Triad1 has been show previously to inhibit colony formation by myeloid progenitor cells. In contrast, HoxA10-overexpressing myeloid progenitor cells exhibited increased proliferation in response to low doses of various cytokines. We found that Triad1 knockdown further increased cytokine-induced proliferation in HoxA10-overexpressing cells. Therefore, these studies have identified a HoxA10 target gene that antagonizes the overall influence of overexpressed HoxA10 on myeloproliferation. This result suggests that the consequences of HoxA10 overexpression reflect a balance between the target genes that facilitate and antagonize proliferation. These results have implications for understanding the mechanisms of leukemogenesis in AML with Hox overexpression.

HoxA10 regulates transcription of the gene encoding transforming growth factor beta2 (TGFbeta2) in myeloid cells.

HoxA10 is a homeodomain transcription factor that is maximally expressed in myeloid progenitor cells. HoxA10 is overexpressed in a poor prognosis subset of human acute myeloid leukemia (AML) and in vivo overexpression of HoxA10 in murine bone marrow induces myeloid leukemia. HoxA10 contributes to myeloid progenitor expansion and differentiation block, but few target genes have been identified that explain the influence of HoxA10 on these processes. The current study identifies the gene encoding transforming growth factor ß2 (TGFß2) as a HoxA10 target gene. We found that HoxA10 activated TGFß2 transcription by interacting with tandem cis elements in the promoter. We also determined that HoxA10 overexpression in myeloid progenitor cells increased Tgfß2 production by the cells. Tgfß2 stimulates proliferation of hematopoietic stem and progenitor cells. Therefore, these studies identified autocrine stimulation of myeloid progenitors by Tgfß2 as one mechanism by which HoxA10 expands this population. Because HoxA proteins had not been previously known to influence expression of pro-proliferative cytokines, this has implications for understanding molecular mechanisms involved in progenitor expansion and the pathobiology of AML.

Pelvic exenteration in the age of modern chemoradiation.

BACKGROUND: To examine outcomes after pelvic exenteration in women treated with modern chemoradiation and surgical techniques. METHODS: All patients at our institution with a diagnosis of gynecologic malignancy who underwent pelvic exenteration after treatment with chemoradiation between 1/90 and 6/08 were evaluated with a retrospective chart review. RESULTS: 44 women were identified, of whom 29 (66%) had cervical, 6 (14%) had uterine, 5 (11%) had vaginal, and 4 (9%) had vulvar cancer. The majority of patients (82%) were initially treated with external beam whole-pelvic radiation with concurrent cisplatin. 38 patients (86%) underwent exenteration for a central pelvic recurrence, and the remaining 6 patients (14%) for radiation necrosis. The most common surgical complication was transfusion requirement in 36 patients (82%), followed by wound infection in 15 (34%), small bowel obstruction in 8 (18%), and sepsis in 6 (14%). The median time spent in the ICU post-operatively was 2 days. One patient (2%) died during her post-operative hospital stay. The mean EBL overall was 2497 cc and the mean operative time was 544 min. Use of electrothermal bipolar coagulation, which was used in 64% of the exenterations, significantly reduced blood loss (3679 cc vs. 1836 cc, p=0.014). After exenteration, 21 patients (48%) were diagnosed with a recurrence of cancer, and the mean progression free survival was 31 months. Patients who received exenteration less than 2 years after their initial chemoradiation had a significantly shorter overall survival time (8 months vs. 33 months, p=0.016). CONCLUSIONS: Approximately 50% of women develop recurrence following exenterations done after chemoradiation. Survival is significantly longer in patients who necessitate exenteration greater than 2 years out from initial treatment. Electrothermal bipolar coagulation appears to significantly reduce blood loss during these surgeries.

Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases.

OBJECTIVE: We sought to examine outcomes in an expanding robotic surgery (RS) program. STUDY DESIGN: In all, 1000 women underwent RS from May 2006 through December 2009. We analyzed patient characteristics and outcomes. A total of 377 women undergoing RS for endometrial cancer staging (ECS) were compared with the historical data of 131 undergoing open ECS. RESULTS: For the entire RS cohort of 1000, the conversion rate was 2.9%. Body mass index increased over 3 time intervals: T1 = 26.2, T2 = 29.5, T3 = 30.1 (T1:T2, P = .01; T1:T3, P = .0001; T2:T3, P = .037). Increasing body mass index was not associated with increased major complications: T1 = 8.7%, T2 = 4.3%, T3 = 5.7%. In the ECS cohort, as compared with open ECS, women undergoing RS had lower blood loss (46.9 vs 197.6 mL, P < .0001), shorter hospitalization (1.4 vs 5.3 days, P < .0001), fewer major complications (6.4% vs 20.6%, P < .0001), with higher lymph node counts (15.5 vs 13.1, P = .007). CONCLUSION: RS is associated with favorable morbidity and conversion rates in an unselected cohort. Compared to laparotomy, robotic ECS results in improved outcomes.

Alternative intraperitoneal chemotherapy regimens for optimally debulked ovarian cancer.

OBJECTIVE: GOG 172 showed a survival benefit with intraperitoneal (IP) cisplatin for advanced ovarian cancer, but patients tolerated the regimen poorly. We hypothesized that women treated with alternative IP chemotherapy strategies may have less toxicity and improved compliance. METHODS: We reviewed the records of women with ovarian cancer and optimal surgical debulking who underwent IP chemotherapy at our institution. Primary outcomes analyzed were completion rates and toxicities of IP chemotherapy. Secondary outcomes were progression-free and overall survival. Statistical analysis was performed using STATA 10.0. RESULTS: Thirty-nine patients with primary ovarian or peritoneal cancer who underwent IP chemotherapy were identified over a 2 year period. Patients were treated with IV paclitaxel followed by IP cisplatin (64%) or IP carboplatin (36%). Median two cycles of intravenous (IV) taxane and carboplatin were given prior to initiating IP therapy in 77% of patients. Median number of IP chemotherapy cycles was 5 and median total number of cycles was 8. Seventy-four percent (74%) of patients received four or greater cycles of IP chemotherapy. There was a higher rate of completion of intended number of IP cycles in the carboplatin group (92%) versus 60% in the IP cisplatin group (p=0.05). Grade 3 non-hematologic toxicities were more common in the IP cisplatin group than in the IP carboplatin group (24% and 0%, p=0.046). At median follow-up of 24 months, the median progression-free interval and overall survival have not yet been reached for either group. CONCLUSION: Intraperitoneal chemotherapy regimens using carboplatin or cisplatin and dropping day 8 IP paclitaxel have less toxicity and less discontinuation of therapy.

Ovarian cancer in the elderly: outcomes with neoadjuvant chemotherapy or primary cytoreduction.

BACKGROUND: Recent studies have suggested inferior outcomes for elderly women with ovarian cancer. Our goal was to evaluate neoadjuvant chemotherapy versus primary cytoreduction in elderly women. METHODS: A retrospective chart review was performed for women aged 65+ diagnosed with ovarian cancer at our institution between 1997 and 2007. Univariate and multivariate logistic regression models were used to evaluate complication rates. Survival was evaluated with Cox regression and the Kaplan-Meier method. RESULTS: One hundred seventy-five patients were identified, 34 (19%) of whom were aged 80+. Those aged 65-79 and those 80+ received neoadjuvant chemotherapy with equal frequency (19% vs. 21%, p=0.92). Treatment with neoadjuvant chemotherapy was associated with odds ratios of 0.80 (95% CI 0.37-1.75) for surgical complications and 0.79 (95% CI 0.33-1.90) for chemotherapeutic complications. In those aged 80+, the frequency of surgical complications (OR 1.01, p=0.62) and chemotherapeutic complications (OR 1.04, p=0.78) did not differ compared to younger patients. Overall survival did not differ based on initial treatment regimen, with 34 months in the primary surgery group and 29 months in the neoadjuvant chemotherapy group (p=0.65). The median disease specific survival for those aged 65-79 was 35 months, and 24 months in those aged 80+ (p=0.15). Post-operative mortality for patients aged 80+ was zero. CONCLUSIONS: In our patient population, those aged 80+ have similar surgical and chemotherapy-related complication rates and comparable survival to those aged 65-79. The choice of initial treatment modality does not appear to impact survival when the decision is made in a selective fashion.

Can roflumilast become steroid-sparing alternative in the treatment of COVID-19?

According to WHO the worst of the COVID-19 pandemic is yet to come. Despite of the exceptional measures being undertaken by regulatory agencies to expedite vaccine development, we may be several months if not years away from an effective vaccine. In such unprecedented times, the only resort nations have at their disposal is to identify and repurpose existing drugs against COVID-19 based on their known clinical or pharmacological profile which can provide direct or corroborative evidence of favorable benefit: risk in the management of COVID-19. Immune-mediated inflammation remains the hallmark of severe complications related to COVID-19 and while corticosteroids have shown preliminary evidence of benefit, they can act like a double-edged sword for majority of COVID-19 patients. Therefore, there is a need to identify 'non-steroid' potent and safe anti-inflammatory agents for use in therapeutic armamentarium against COVID-19. This article makes a case for one such existing drug, roflumilast, that can emerge as a steroid-sparing alternative against COVID-19.

Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125.

OBJECTIVE: To evaluate the effect of ovarian cancer risk on the performance of the serum biomarkers mesothelin, human epididymis protein 4 (HE4), and CA125. METHODS: We measured mesothelin, HE4, and CA125 levels from women with invasive ovarian cancer (n = 143), benign gynecologic conditions (n = 124), and controls (n = 344). Demographic, epidemiologic, reproductive, medical, and family history data were collected using a standardized questionnaire. Pedigree and BRCA 1/2 test results were used to stratify women into average and high-risk groups. The diagnostic accuracy of each biomarker was characterized using receiver operating characteristic curve methods. RESULTS: Baseline characteristics did not vary by risk or case status. The distribution of stage and histology was similar in average and high-risk women. All three markers discriminated ovarian cancer cases from risk-matched healthy and benign controls. Marker performance did not vary by risk status. The sensitivity at 95% specificity for discriminating cases from risk-matched healthy control women in the average and high-risk groups, respectively, was 53.9% and 39.0% for mesothelin, 80.4% and 87.8% for HE4, and 79.4% and 82.9% for CA125. The performance of the markers was not as robust when cases were compared with benign controls. Area under the curve values for cases versus healthy and benign controls did not vary by risk status. CONCLUSIONS: The ability of serum mesothelin, HE4, and CA 125 levels to discriminate ovarian cancer cases from healthy and benign controls is not influenced by risk status. Our findings support the pursuit of additional studies evaluating the early detection potential of these markers in high-risk populations.

Factors affecting risk of mortality in women with vaginal cancer.

OBJECTIVE: To estimate the current effect of demographics, pathology, and treatment on mortality among women with vaginal cancer. METHODS: Using data from 17 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results program, 2,149 women diagnosed with primary vaginal cancer between 1990 and 2004 were identified. The association between various demographic factors, tumor characteristics, and treatments and risk of vaginal cancer mortality were evaluated using Cox proportional hazards modeling. RESULTS: The mean age+/-standard deviation at diagnosis was 65.7+/-14.3 years. Approximately 66% of all cases were non-Hispanic whites. Incidence was highest among African-American women (1.24 per 100,000 person-years). The 5-year disease-specific survival was 84% (stage I), 75% (stage II), and 57% (stage III/IV). In a multivariate adjusted model, women with tumors greater than 4 cm and advanced disease had elevated risks of mortality (hazard ratios 1.71 and 4.67, respectively). Compared with women with squamous cell carcinomas, patients with vaginal melanoma had a 1.51-fold (95% confidence interval 1.07-2.41) increased risk of mortality. Surgery alone as a treatment modality had the lowest risk of mortality. The risk of mortality has decreased over time, as women diagnosed after 2000 had an adjusted 17% decrease in their risk of death compared with women from 1990-1994. CONCLUSION: Stage, tumor size, histology, and treatment modality significantly affect a woman's risk of mortality from vaginal cancer. There seems to be a survival advantage that is temporally related to the advent of chemoradiation.

Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer.

OBJECTIVES: Forty percent of women with ovarian cancer have circulating free tumor DNA. We sought to determine if the tumor immune infiltrate varied based on tumor p53 mutation status or presence of circulating tumor DNA. METHODS: We performed immunohistochemistry on 119 ovarian cancer specimens with CD3 and CD8 (Intratumoral T cells (TILs)), CD68 (tumor-associated macrophages (TAMs)), and FoxP3 (T regulatory cells (Tregs)). Tumors had been previously sequenced for mutations in exons 4-10 of p53, and plasma from women characterized for free tumor DNA. RESULTS: TIL and TAM levels were positively correlated (P<0.0001). High levels of TILs were identified in 54 of 119 tumors (45.4%). No survival difference was identified according to the presence of TILs or TAMs. Patients with greater TILs were more likely to be optimally cytoreduced (P=0.005). p53 mutations were associated with more TILs (P=0.008). The presence of circulating tumor DNA did not correlate with TILs, TAMs, or Tregs. In the subgroup with a low host antitumor immune response, the intermediate response Tregs group did have a survival advantage (P=0.049). CONCLUSIONS: p53 mutations are associated with higher levels of TILs. The ratio of Tregs to TILS may be more important than absolute levels. A brisk T cell response within the tumor predicts adequacy of cytoreduction, suggesting successful cytoreduction may be partially due to underlying tumor biology and host response.