How I treat newly diagnosed and refractory T-cell acute lymphoblastic lymphoma in children and young adults.

T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the 2 diseases and use illustrative cases to highlight key recommendations on how to best treat patients with newly diagnosed and relapsed/refractory T-LLy. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation.

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study.

BACKGROUND: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. OBJECTIVES: We sought to study HCT for p47phox CGD in North America. METHODS: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. RESULTS: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person-years (P = .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, ≥95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. CONCLUSIONS: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.

Patients' perception of the benefits of palliative systemic therapy for advanced cancer.

BACKGROUND: Patients with advanced cancer who misunderstand their prognosis and chance of cure tend to overestimate the likely benefits of palliative systemic therapy. AIM: To determine patient perceptions of palliative systemic therapy benefits in advanced cancer. METHODS: We surveyed 104 outpatients with advanced cancer receiving systemic anticancer therapy and their treating oncologists. Patients recorded their understanding of treatment impact on chance of cure and symptoms. Life expectancy was estimated by patients and oncologists. A visual analogue scale (0-10) was used to record how patients and oncologists valued quality of life (QOL) and length of life (LOL) (<4 QOL most important; 4-7 QOL and LOL equal; >7 LOL most important). Patient-oncologist discordance was defined as a ≥4-point difference. RESULTS: The main reasons patients selected for receiving treatment were to live longer (54%) and cure their cancer (36%). Most patients reported treatment was very/somewhat likely to prolong life (84%) and improve symptoms (76%), whereas 20% reported treatment was very/somewhat likely to cure their cancer. 42% of patients selected a timeframe for life expectancy (choice of four timeframes between <1 year and ≥5 years); of these, 62% selected a longer timeframe than their oncologist. When making treatment decisions, 71% of patients (52% of oncologists) valued QOL and LOL equally. Patient-oncologist discordance was 21%, mostly because of oncologists valuing QOL more than their patients (70%). CONCLUSION: At least 20% of patients receiving systemic therapy for advanced cancer reported an expectation of cure. Most patients and oncologists value QOL and LOL equally when making treatment decisions.

Screening for Bacterial Vaginosis Prior to Delivery: A Cost-Effectiveness Study.

OBJECTIVE: The objective of this study was to compare the cost and effectiveness of three strategies for screening and/or treating bacterial vaginosis (BV) during pregnancy prior to delivery: (1) the current standard of care was neither test nor treat for BV (Treat None); (2) test all patients for BV at 36 weeks' gestation; treat if positive (Test Treat); and (3) treat all patients undergoing cesarean delivery with intravenous metronidazole at time of surgery (Treat All Cesarean). Effectiveness was defined as avoidance of postpartum surgical site infection (SSI). STUDY DESIGN: A decision analytic cost-effectiveness model was designed from a third-party payer perspective using clinical and cost estimates obtained from the literature, American College of Surgeons National Surgical Quality Improvement Program participant use file (2005-2019), 2019 National Vital Statistics, Medicare costs, and wholesale drug costs. Cost estimates were inflated to 2020 U.S. dollars. For this study, effectiveness was defined as avoidance of postpartum SSIs. RESULTS: The base case analysis that is the current standard of care of not routinely testing and treating patients for BV (Treat None) was the most expensive and least effective strategy, with a mean cost of $59.16 and infection rate of 3.71%. Empirically treating all patients for BV without testing (Treat All Cesarean) was the most effective and the least expensive strategy, with a mean cost of $53.50 and an infection rate of 2.75%. Testing all patients for BV and treating those positive for BV (Test Treat) was also relatively inexpensive and effective, with an infection rate of 2.94% and mean cost of $57.05. Compared with Treat None, we would expect the Treat All Cesarean strategy to reduce the infection rate by 26%. CONCLUSION: These findings suggest that treating pregnant patients with intravenous metronidazole at time of cesarean delivery could be an effective and cost-saving strategy. Testing and treating for BV could also be considered a reasonable strategy, as it has the added benefit of preserving antibiotic stewardship. In no analysis was the standard of care strategy of neither testing nor treating for BV before delivery the preferred strategy. KEY POINTS: · BV colonization may increase surgical site infection risk after cesarean section.. · Treatment of BV before or during delivery may be cost-saving strategies as treatment could prevent costs associated with infection.. · Further study is needed to best balance the risk of surgical site infection with antibiotic stewardship..

Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells' behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

An obstetrician-gynecologist's review of hernias: risk factors, diagnosis, prevention, and repair.

Management of obstetrical and gynecologic patients with hernias poses challenges to providers. Risks for hernia development include well-described factors that impair surgical wound healing and increase abdominal pressure. Among the diverse populations cared for by obstetricians and gynecologists, pregnant patients and those with gynecologic malignancies are at the highest risk for hernia formation. This article provides an overview of the existing literature, with a focus on patients cared for by obstetrician-gynecologists and commonly encountered preoperative and intraoperative scenarios. We highlight scenarios when a hernia repair is not commonly performed, including those of patients undergoing nonelective surgeries with known or suspected gynecologic cancers. Finally, we offer multidisciplinary recommendations on the timing of elective hernia repair with obstetrical and gynecologic procedures, with attention to the primary surgical procedure, the type of preexisting hernia, and patient characteristics.

KRAS and BRAF Mutation Rates and Survival Outcomes in Colorectal Cancer in an Ethnically Diverse Patient Cohort.

KRAS and BRAF mutation rates in colorectal cancer (CRC) reported from various mono-ethnic studies vary amongst different ethnic groups. However, these differences in mutation rates may not be statistically significant or may be due to differences in environmental and/or laboratory factors across countries rather than racial genetic differences. Here, we compare the KRAS/BRAF mutation rates and survival outcomes in CRC between ethnic groups at a single institution. We also investigate the contributions of genetic, environmental, and laboratory factors to the variations in KRAS/BRAF mutation rates reported from different countries. Clinicopathological data from 453 ethnically diverse patients with CRC were retrospectively analyzed at Liverpool Hospital, NSW Australia (2014-2016). KRAS/BRAF mutations were detected using real-time PCR (Therascreen kits from Qiagen). Mismatch repair (MMR) status was determined using immunohistochemical staining. Four ethnic groups were analyzed: Caucasian, Middle Eastern, Asian, and South American. Overall survival data were available for 406 patients. There was no significant difference in KRAS mutation rates between Caucasians (41.1%), Middle Easterners (47.9%), Asians (44.8%), and South Americans (25%) (p = 0.34). BRAF mutation rates differed significantly between races (p = 0.025), with Caucasians having the highest rates (13.5%) and Middle Easterners the lowest (0%). A secondary analysis in which Caucasians were divided into three subgroups showed that ethnic grouping correlated significantly with KRAS mutation rate (p = 0.009), with central and eastern Europeans having the highest rates (58.3%). There were no significant differences in overall survival (OS) or disease-free survival (DFS) between the four races. The similarity in KRAS mutation rates across races raises the possibility that the differences in KRAS mutation rates reported from various countries may either not be statistically significant or may be due to environmental and/or laboratory factors rather than underlying racial genetic differences. In contrast, we verified that BRAF mutation rates differ significantly between races, suggesting racial genetic differences may be responsible for the discrepant BRAF mutation rates reported from different countries.

Continued Circulation of Tick-Borne Encephalitis Virus Variants and Detection of Novel Transmission Foci, the Netherlands.

Tick-borne encephalitis virus (TBEV) is an emerging pathogen that was first detected in ticks and humans in the Netherlands in 2015 (ticks) and 2016 (humans). To learn more about its distribution and prevalence in the Netherlands, we conducted large-scale surveillance in ticks and rodents during August 2018-September 2020. We tested 320 wild rodents and >46,000 ticks from 48 locations considered to be at high risk for TBEV circulation. We found TBEV RNA in 3 rodents (0.9%) and 7 tick pools (minimum infection rate 0.02%) from 5 geographically distinct foci. Phylogenetic analyses indicated that 3 different variants of the TBEV-Eu subtype circulate in the Netherlands, suggesting multiple independent introductions. Combined with recent human cases outside known TBEV hotspots, our data demonstrate that the distribution of TBEV in the Netherlands is more widespread than previously thought.

Promoting timely goals of care conversations between gynecologic cancer patients at high-risk of death and their providers.

OBJECTIVE: We designed a multi-faceted intervention to increase the rate of outpatient goals of care (GOC) conversations in women with gynecologic cancers who are at high-risk of death. METHODS AND MATERIALS: A multidisciplinary team developed an educational program around GOC conversations at end-of-life and chose criteria to prospectively identify patients at high-risk of death who might benefit from timely GOC conversations: recurrent or metastatic endometrial, cervical or vulvar cancer or platinum-resistant ovarian cancer. Gynecologic oncology provider consensus was built regarding the need to improve the quality and timing of GOC conversations. Eligible outpatients were prospectively identified and providers alerted pre-encounter; timely GOC documentation within 3 visits of high-risk identification was tracked. Our institution concurrently and subsequently tracked GOC documentation during the last 6 months of life among all established oncology patients. RESULTS: Of 220 pilot period high-risk patients (96 pre- and 124 during pilot period 2017-2018), timely GOC discussion documentation increased from 30.2% to 88.7% (p < 0.001) and this increase was sustained over time. In the post-pilot period (2019-2020), among patients seen by oncologists during last 6 months of life, compared to other cancer types, gynecologic cancer patients had a higher rate of GOC documentation (81% versus 9%; p < 0.001), a lower rate of receiving chemotherapy during the last 14 days of life (2% vs 5%; p = 0.051), and no difference in end-of-life admissions (29% vs 31%; p = NS). CONCLUSIONS: Implementation of systematic outpatient identification of high-risk gynecologic oncology patients is feasible, sustainable, and increases the timely conduct of GOC conversations.

Effect of social instability stress in adolescence or adulthood on sensitivity to sucrose concentration in a social context in male and female Long-Evans rats.

Although there is evidence of sex differences in responding to social stress, and that age when stressed matters, females are understudied and adult-stress comparisons are few. Here, we investigated stress effects on reward sensitivity by examining rats' choice of social versus sucrose reward in a continuous spatial allocation design. We predicted social instability stress (SS) in adolescence would result in greater social discounting (spend less time near a novel peer when provided access to sucrose) relative to nonstressed controls (CTLs) and relative to SS in adulthood. All increased sucrose intake as the concentration increased, with no evidence of social discounting. SS males tested soon after the stress had a decrease in intake, whereas those tested long after had an increase in both time near the peer and in intake. CTL and SS females did not differ in intake, although their dose-response curves differed when tested soon after the SS. We also tested whether SS changed the stimulus value of the rat as a social peer; when tested in triads, CTL rats spent similar time in interaction with SS versus CTL rats. In sum, effects of SS on reward sensitivity were greater for males irrespective of administered in adolescence versus adulthood.

Chemotherapy discontinuation processes in a gynecologic oncology population.

OBJECTIVE: We sought to categorize the processes by which gynecologic oncology patients stop chemotherapy and to evaluate associations between these processes and end-of-life outcome metrics. METHODS: A cohort of patients with metastatic or recurrent gynecologic cancer in an outpatient setting from January 2016 to May 2018 was identified. All deceased patients in this cohort were included for analysis. Processes of discontinuing chemotherapy were categorized as: 1) definitive decision inpatient; 2) definitive decision outpatient; 3) delayed decision (eg: treatment break and never resumed chemotherapy); 4) no decision. Associations between patient characteristics and clinical outcomes of those who made a definitive outpatient decision versus those who made any other type of decision were assessed. RESULTS: 220 patients were identified; 205 patients were deceased at time of analysis. Of these, 36.6% made a definitive decision to stop chemotherapy as an outpatient, while 41.5% never made a decision to discontinue chemotherapy. Making a definitive decision as an outpatient, when compared to all other decision types, was associated with significantly lower incidence of death in the hospital (5.6% vs 21.1%, p < 0.004) and hospitalization within 30 days of death (20.8% vs 56.6%, p < 0.001), and significantly increased median time from last chemotherapy to death (135.5 vs 62 days, p < 0.001). CONCLUSION: Only one in three women in this cohort of patients deceased from gynecologic cancer made a definitive decision to discontinue chemotherapy in an outpatient setting, and this process was associated with improved end-of-life outcomes. Future efforts should examine the impact of interventions designed to increase the proportion of patients who transition away from chemotherapy via shared decision making in the outpatient setting.

Tisagenlecleucel for treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia.

The treatment landscape for cancer therapy has changed drastically over the past decade. Tisagenlecleucel, the first genetically engineered adoptive cellular therapy approved by the United States Food and Drug Administration, has revolutionized this field by demonstrating impressive clinical success in children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Now 3 years since its approval, we have gained a deeper understanding on the basic immunobiology and clinical efficacy of this drug. This review will provide an updated summary of tisagenlecleucel in childhood and young adults with r/r B-ALL, common side effects and their associated management strategies, as well as barriers that remain to be addressed in order to realize the maximum potential of this drug.

Oocyte cryopreservation versus ovarian tissue cryopreservation for adult female oncofertility patients: a cost-effectiveness study.

PURPOSE: In December 2019, the American Society for Reproductive Medicine designated ovarian tissue cryopreservation (OTC) as no longer experimental and an alternative to oocyte cryopreservation (OC) for women receiving gonadotoxic therapy. Anticipating increased use of OTC, we compare the cost-effectiveness of OC versus OTC for fertility preservation in oncofertility patients. METHODS: A cost-effectiveness model to compare OC versus OTC was built from a payer perspective. Costs and probabilities were derived from the literature. The primary outcome for effectiveness was the percentage of patients who achieved live birth. Strategies were compared using incremental cost-effectiveness ratios (ICER). All inputs were varied widely in sensitivity analyses. RESULTS: In the base case, the estimated cost for OC was $16,588 and for OTC $10,032, with 1.56% achieving live birth after OC, and 1.0% after OTC. OC was more costly but more effective than OTC, with an ICER of $1,163,954 per live birth. In sensitivity analyses, OC was less expensive than OTC if utilization was greater than 63%, cost of OC prior to chemotherapy was less than $8100, cost of laparoscopy was greater than $13,700, or standardized discounted costs were used. CONCLUSIONS: With current published prices and utilization, OC is more costly but more effective than OTC. OC becomes cost-saving with increased utilization, when cost of OC prior to chemotherapy is markedly low, cost of laparoscopy is high, or standardized discounted oncofertility pricing is assumed. We identify the critical thresholds of OC and OTC that should be met to deliver more cost-effective care for oncofertility patients.

Competency-based education in general surgery: Are Canadian residents ready?

Summary: Competency-based education (CBE) is currently being implemented by the Royal College of Physicians and Surgeons of Canada across all residency programs. This shift away from time-based residency is proposed to be the answer to maximize training opportunity in the era of work hour restrictions and growing concerns regarding accountability in medical education. A Web-based survey was conducted to obtain feedback from Canadian general surgery residents on their experience and perception of competence within core procedures, as well as attitudes toward CBE. A total of 244 residents completed the survey. For most procedures, more than 50% of residents felt they could perform the procedure with no guidance after completing 11-30 cases. Generally, residents were welcoming of CBE; however, medium-sized programs reported some concerns regarding inadequate exposure to cases and risk of training less well-rounded surgeons. This is valuable resident feedback for programs to consider during the implementation process.

Patient preferences for maintenance PARP inhibitor therapy in ovarian cancer treatment.

OBJECTIVE: To measure preferences of women with ovarian cancer regarding risks, side effects, costs and benefits afforded by maintenance therapy (MT) with a poly ADP ribose polymerase (PARP) inhibitor. METHODS: A discrete-choice experiment elicited preferences of women with ovarian cancer regarding 6 attributes (levels in parentheses) relevant to decisions for MT versus treatment break: (1) overall survival (OS; 36, 38, 42 months); (2) progression-free survival (PFS; 15, 17, 21 months); (3) nausea (none, mild, moderate); (4) fatigue (none, mild, moderate); (5) probability of death from myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML; 0% to 10%); (6) monthly out-of-pocket cost ($0 to $1000). Participants chose between 2 variable MT scenarios and a static scenario representing treatment break, with multiple iterations. Random-parameters logit regression was applied to model choices as a function of attribute levels. RESULTS: 95 eligible participants completed the survey; mean age was 62, 48% had recurrence, and 17% were ever-PARP inhibitor users. Participants valued OS (average importance weight 24.5 out of 100) and monthly costs (24.6) most highly, followed by risk of death from MDS/AML (17.9), nausea (14.7), PFS (10.5) and fatigue (7.8). Participants would accept 5% risk of MDS/AML if treatment provided 2.2 months additional OS or 4.8 months PFS. Participants would require gains of 2.6 months PFS to accept mild treatment-related fatigue and 4.4 months to accept mild nausea. CONCLUSIONS: When considering MT, women with ovarian cancer are most motivated by gains in OS. Women expect at least 3-4 months of PFS benefit to bear mild side effects of treatment.

Training interventions to improve adenoma detection rates during colonoscopy: a systematic review and meta-analysis.

BACKGROUND: Colonoscopies are effective means of detecting and removing precancerous adenomatous polyps. The adenoma detection rate (ADR) is a marker of colonoscopy quality and an independent predictor of colorectal cancer incidence. Focused training interventions may improve an endoscopist's ADR, but the supporting research is limited. This systematic review and meta-analysis identified, critically appraised, and meta-analyzed data from randomized trials (RCTs) evaluating the effect of training interventions on ADRs. METHODS: Ovid Medline, EMBASE, CENTRAL, Eric, CINAHL, Scopus, Web of Science, and ClinicalTrials.gov were searched for RCTs investigating the effect of an educational intervention on ADRs. Two reviewers independently screened, identified, and extracted trial-level data. Internal validity was assessed in duplicate using the Risk of Bias tool. Our primary outcome was the ADR. Secondary outcomes were advanced ADR, adenocarcinoma detection rate, polyp detection rate, and withdrawal times. Safety outcomes were post-polypectomy bleeding rate and colonoscopy-related perforation rate. RESULTS: From 2837 screened citations, we identified 3 trials (119 endoscopists) meeting our inclusion criteria. Training interventions were associated with a trend toward increased ADRs (odds ratio 1.16, 95% confidence interval (CI) 1.00-1.34; I2 83%; 3 trials; 119 endoscopists). When limited to screening colonoscopies, the odds ratio for ADRs associated with training interventions was 1.17 (95% CI 1.00-1.36; I2 80%; 3 trials; 119 endoscopists). There was a high level of heterogeneity between the trials' training interventions. Training intervention improved the advanced ADR, adenocarcinoma detection rate, polyp detection rate, and withdrawal times. Safety outcomes were not reported. CONCLUSIONS: A focused training intervention was associated with a strong trend toward increased ADRs among certified endoscopists. While the described training interventions definitely show promise, further efforts around continuing professional developments activities are needed to more consistently improve ADRS among certified endoscopists.

Aberrant Expression of RAD52, Its Prognostic Impact in Rectal Cancer and Association with Poor Survival of Patients.

The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and cancer survival and response to preoperative radiotherapy. RAD52 expression was examined in tumour samples from 179 patients who underwent surgery for rectal cancer, including a sub-cohort of 40 patients who were treated with neoadjuvant therapy. A high score for RAD52 expression in the tumour centre was significantly associated with worse disease-free survival (DFS; p = 0.045). In contrast, reduced RAD52 expression in tumour centre samples from patients treated with neoadjuvant therapy (n = 40) significantly correlated with poor DFS (p = 0.025) and overall survival (OS; p = 0.048). Our results suggested that RAD52 may have clinical value as a prognostic marker of tumour response to neoadjuvant radiation and both disease-free status and overall survival in patients with rectal cancer.

Cost-effectiveness of hyperthermic intraperitoneal chemotherapy (HIPEC) at interval debulking of epithelial ovarian cancer following neoadjuvant chemotherapy.

OBJECTIVES: A recent randomized controlled trial demonstrated an overall survival benefit to the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to neoadjuvant chemotherapy (NACT) for stage III epithelial ovarian cancer (EOC). The objective of the current study was to quantify the cost-effectiveness of HIPEC in this setting. METHODS: A decision analytic cost-effectiveness model was designed from a payer perspective to compare 2 surgical management strategies for EOC: (1) interval cytoreductive surgery (ICS); (2) ICS + HIPEC. Overall survival and ostomy rates with HIPEC were modeled from published studies. We assumed that 25% of each arm would later undergo secondary cytoreductive surgery, with the ICS arm eligible for HIPEC at that time. Costs were obtained from Medicare data, published studies, and the financial department of an academic hospital. Quality of life was not different between the arms; we assigned utilities based on a prior time-trade off study of ovarian cancer treatment. A Monte Carlo probabilistic sensitivity analysis was performed in the base case; primary outcome was the incremental cost-effectiveness ratio (ICER), expressed in 2017 US Dollars/quality-adjusted life years (QALYs). RESULTS: ICS was the least costly strategy at $78,849, compared to ICS + HIPEC at $79,954. ICS + HIPEC was more effective than ICS (2.9 QALYs versus 2.45 QALYs for ICS). ICS + HIPEC was highly cost-effective, with an ICER of $2436/QALY compared to ICS. In one-way sensitivity analyses, probability of ostomy reversal and use of HIPEC at secondary cytoreduction did not substantially impact the cost-effectiveness of ICS + HIPEC. CONCLUSION: ICS + HIPEC constitutes cost-effective management of stage III EOC when NACT is performed.