PRDM16 regulates a temporal transcriptional program to promote progression of cortical neural progenitors.

Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanisms that drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here, we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phase of neurogenesis in the mouse neocortex. Loss of Prdm16 delays the timely progression of RG, leading to defective cortical laminar organization. Our genomic analyses demonstrate that PRDM16 regulates a subset of genes that are dynamically expressed between early and late neurogenesis. We show that PRDM16 suppresses target gene expression through limiting chromatin accessibility of permissive enhancers. We further confirm that crucial target genes regulated by PRDM16 are neuronal specification genes, cell cycle regulators and molecules required for neuronal migration. These findings provide evidence to support the finding that neural progenitors temporally shift the gene expression program to achieve neural cell diversity.

Patient-reported Quality of Life After Breast-conserving Surgery With Radiotherapy Versus Mastectomy and Reconstruction.

OBJECTIVE: To compare long-term quality of life (QOL) outcomes in breast cancer survivors who received breast-conserving surgery with radiotherapy (BCS+RT) with those who received a mastectomy and reconstructive surgery (Mast+Recon) without radiotherapy and identify other important factors. BACKGROUND: The long-term differences in patient-reported QOL outcomes following BCS+RT and Mast+Recon are not well understood. METHODS: We identified patients from the Texas Cancer Registry with stage 0-II breast cancer diagnosed in 2009-2014 after BCS+RT or Mast+Recon without radiotherapy. Sampling was stratified by age and race and ethnicity. A paper survey was sent to 4800 patients which included validated BREAST-Q and PROMIS modules. Multivariable linear regression models were implemented for each outcome. Minimal clinically important difference for BREAST-Q and PROMIS modules, respectively, was 4 points and 2 points. RESULTS: Of 1215 respondents (25.3% response rate), 631 received BCS+RT and 584 received Mast+Recon. The median interval from diagnosis to survey completion was 9 years. In adjusted analysis, Mast+Recon was associated with worse BREAST-Q psychosocial well-being (effect size: -3.80, P =0.04) and sexual well-being (effect size: -5.41, P =0.02), but better PROMIS physical function (effect size: 0.54, P =0.03) and similar BREAST-Q satisfaction with breasts, physical well-being, and PROMIS upper extremity function ( P >0.05) compared with BCS+RT. Only the difference in sexual well-being reached clinical significance. Older (≥65) patients receiving BCS+RT and younger (<50) patients receiving autologous Mast+Recon typically reported higher QOL scores. Receipt of chemotherapy was associated with detriments to multiple QOL domains. CONCLUSIONS: Patients who underwent Mast+Recon reported worse long-term sexual well-being compared with BCS+RT. Older patients derived a greater benefit from BCS+RT, while younger patients derived a greater benefit from Mast+Recon. These data inform preference-sensitive decision-making for women with early-stage breast cancer.

Temporal trends of healthcare system use between symptomatic presentation and ovarian cancer diagnosis in the United States.

OBJECTIVE: To describe trends in healthcare system use over time between onset of classic ovarian cancer symptoms and ovarian cancer diagnosis in the United States. METHODS: A population-based study of the Surveillance, Epidemiology, and End Results-Medicare database was conducted on patients aged ≥66 years with stage II-IV epithelial ovarian cancer between 1992 and 2015 with at least one of the following diagnosis codes: abdominal pain, bloating, difficulty eating, and/or urinary symptoms. The outcomes were frequency of visit type, frequency of diagnostic modality, and Medicare reimbursement between first symptomatic claim and cancer diagnosis. Jonckheere-Terpstra and Cochran-Armitage tests were used to evaluate trends over time. RESULTS: Among 13 872 women, 13 541 (97.6%) had outpatient, 6466 (46.6%) had inpatient, and 4906 (35.4%) had emergency room visits. The frequency of outpatient (p<0.001) and emergency room visits (p<0.001) increased while the frequency of inpatient visits (p<0.001) decreased between 1992 and 2015. The median number of outpatient visits (p<0.001) and physician specialties seen (p<0.001) increased over time. The median hospital length of stay decreased from 10 days in 1992 to 5 days in 2015 (p<0.001). Between 1992 and 2015, the frequency of ultrasound decreased (p<0.001) while the frequency of computed tomography, magnetic resonance imaging, positron emission tomography imaging, and cancer antigen 125 tumor immunoassay increased (p<0.001). Median monthly total (p<0.001), inpatient (p<0.001), and outpatient (p=0.006) reimbursements decreased while emergency room reimbursements increased (p<0.001) over time. CONCLUSION: Healthcare reimbursement between symptomatic presentation and ovarian cancer diagnosis has decreased over time and may reflect the trends in fewer and shorter hospitalizations and increased use of emergency and outpatient management during the evaluation of symptoms of women with ovarian cancer.

Icariin improves testicular dysfunction via enhancing proliferation and inhibiting mitochondria-dependent apoptosis pathway in high-fat diet and streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes mellitus (DM), a chronic metabolic disease, severely impairs male reproductive function. However, the underpinning mechanisms are still incompletely defined, and there are no effective strategies or medicines for these reproductive lesions. Icariin (ICA), the main active component extracted from Herba epimedii, is a flavonoid traditionally used to treat testicular dysfunction. Whether ICA can improve male reproductive dysfunction caused by DM and its underlying mechanisms are still unclear. In this study, by employing metformin as a comparative group, we evaluated the protective effects of ICA on male reproductive damages caused by DM and explored the possible mechanisms. METHODS: Rats were fed with a high fat diet (HFD) and then intraperitoneally injected with streptozotocin (STZ) to induce diabetes. Diabetic rats were randomly divided into T2DM + saline group, T2DM + metformin group and T2DM + ICA group. Rats without the treatment of HFD and STZ were used as control group. The morphology of testicular tissues was examined by histological staining. The mRNA expression levels were determined by quantitative real-time PCR. Immunostaining detected the protein levels of proliferating cell nuclear antigen (PCNA), hypoxia-inducible factor 1-alpha (HIF-1α) and sirtuin 1 (SIRT1) in testicular tissues. TUNEL assay was performed to determine cell apoptosis in the testicular tissues. The protein expression levels of HIF-1α and SIRT1 in the testicular tissues were determined by western blot assay. RESULTS: ICA effectively improved male reproductive dysfunction of diabetic rats. ICA administration significantly decreased fasting blood glucose (FBG) and insulin resistance index (IRI). In addition, ICA increased testis weight, epididymis weight, sperm number, sperm motility and the cross-sectional area of seminiferous tubule. ICA recovered the number of spermatogonia, primary spermatocytes and Sertoli cells. Furthermore, ICA upregulated the expression of PCNA, activated SRIT1-HIF-1α signaling pathway, and inhibited intrinsic mitochondria dependent apoptosis pathway by upregulating the expression of Bcl-2 and downregulating the expression of Bax and caspase 3. CONCLUSION: These results suggest that ICA could attenuate male reproductive dysfunction of diabetic rats possibly via increasing cell proliferation and decreasing cell apoptosis of testis. ICA potentially represents a novel therapeutic strategy against DM-induced testicular damages.

Prolonged Opioid Use After Surgery for Early-Stage Breast Cancer.

INTRODUCTION: This study examined the patterns of prolonged opioid use and the factors associated with higher risk of prolonged opioid use among opioid-naïve working-age patients with early-stage breast cancer. METHODS: Using MarketScan data, the study identified 23,440 opioid-naïve patients who received surgery for breast cancer between January 2000 and December 2014 and filled at least one opioid prescription attributable to surgery. Prolonged opioid use was defined as one or more prescriptions for opioids within 90 to 180 days after surgery and defined extra-prolonged opioid use as one or more opioid prescriptions between 181 and 365 days after surgery. Multivariable logistic regressions were performed to ascertain factors associated with prolonged and extra-prolonged use of opioids. FINDINGS: Of the 23,440 patients, 4,233 (18%) had prolonged opioid use, and 2,052 (9%) had extra-prolonged opioid use. Patients who received mastectomy plus reconstruction had the highest rate of prolonged opioid use (38%) followed by mastectomy alone (15%). A multivariable logistic regression confirmed that patients with mastectomy and reconstruction had the highest odds ratio of prolonged opioid use compared to lumpectomy and whole breast irradiation (adjusted odds ratio, 5.6; 95% confidence interval, 5.1-6.1). Mean daily opioid dose was consistently high without any obvious dosage reduction among patients with opioid use. INTERPRETATION: This large observational study showed a high rate of prolonged opioid use among patients who received surgery for early-stage breast cancer and found significant difference in prolonged opioid use by treatment type. IMPLICATIONS FOR PRACTICE: This large observational study found a high rate of prolonged opioid use among working-age patients with early-stage breast cancer who received curative surgery, especially among patients who received mastectomy. Among patients with opioid use, the mean daily opioid dose was consistently high without any obvious dosage tapering. This study highlights the need to emphasize appropriate opioid therapy and potential dosage reduction or discontinuation among patients with early-stage breast cancer who received surgical interventions.

National trends in bowel and upper abdominal procedures in ovarian cancer surgery.

OBJECTIVES: In the United States, trends in the initial treatment approach for ovarian cancer reflect a shift in paradigm toward the increased use of neoadjuvant chemotherapy and interval cytoreductive surgery. The aim of this study was to evaluate the trends in surgical cytoreductive procedures in ovarian cancer patients who underwent either primary or interval cytoreductive surgery. METHODS: This retrospective, population-based study examined patients with stage III/IV ovarian cancer diagnosed between January 2000 and December 2013 identified using SEER-Medicare. Small or large bowel resection, ostomy creation, and upper abdominal procedures were identified using relevant billing codes and compared over time. A 1:1 primary and interval cytoreductive propensity matched cohort was created using demographic and clinical variables. 30-day complications and the use of acute care services were compared. RESULTS: A total of 5417 women were identified. 34% underwent bowel resections, 16% ostomy creation, and 8% upper abdominal procedures. There was an increase in bowel resections and upper abdominal procedures from 2000 to 2013 in patients who underwent primary cytoreductive surgery. Compared with patients who received primary cytoreduction, patients who underwent interval cytoreductive surgery were less likely to undergo bowel resection (OR=0.50; 95% CI [0.41, 0.61]) or ostomy creation (OR=0.48; 95% CI [0.42, 0.56]). Upper abdominal procedures did not differ between groups. For patients who underwent primary cytoreductive surgery, these procedures were associated with intensive care unit stay (4.6% vs <2%, P<0.01). In both primary and interval cytoreductive surgery patients, the receipt of bowel and upper abdominal procedures was associated with multiple 30-day postoperative complications and higher rates of readmission and emergency room visits. CONCLUSIONS: The performance of upper abdominal procedures in ovarian cancer patients increased from 2000 to 2013. Interval cytoreductive surgery was associated with decreased likelihood of bowel surgery. In matched primary and interval cytoreductive surgery cohorts, the receipt of these procedures were associated with the increased likelihood of postoperative complications and use of acute care services.

Centers for Medicare and Medicaid Services' Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores and gynecologic oncology surgical outcomes.

OBJECTIVE: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) is a national survey of inpatient experience. This study evaluated the association between HCAHPS survey results and outcomes in gynecologic cancer surgery. METHODS: This observational study used HCAHPS survey data from 2009 to 2011 to assign hospitals into score terciles. The Nationwide Inpatient Sample (NIS) database was used to identify admissions during the same time period for gynecologic cancer-specific surgeries. Data sources were linked at the hospital level. Postoperative complications, mortality, and prolonged length of stay were compared between higher and lower scoring hospitals. Complications were grouped as 'surgical', 'medical', or 'care team'. Mixed effects models were used to evaluate the associations between hospitals' HCAHPS scores and outcomes after adjustment for patient and hospital-level variables. RESULTS: 17,509 linked encounters in 651 hospitals across the U.S. were identified, with 51% uterine, 40% ovarian, and 9% cervical cancer surgical admissions. In-hospital mortality was lower in hospitals in the top HCAHPS score terciles compared to bottom HCAHPS score tercile (odds ratio (OR) 0.54, 95% CI: 0.31-0.94). Surgery in higher scoring HCAHPS hospitals was associated with less 'surgical' complications (OR 0.82, 95% CI 0.69-0.98). No association was found between 'medical', 'care team', overall complications, or prolonged hospitalization (p > 0.05) and HCAHPS scores. CONCLUSIONS: Gynecologic oncology surgeries performed in top HCAHPS tercile hospitals were associated with lower in-hospital mortality and surgical complications compared to surgeries performed in bottom tercile hospitals. Associations between HCAHPS scores and other adverse events were not seen.

National trends, outcomes, and costs of radiation therapy in the management of low- and high-intermediate risk endometrial cancer.

OBJECTIVE: To assess treatment patterns, outcomes, and costs for women with low-(LIR) and high-intermediate risk endometrial cancer (HIR) who are treated with and without adjuvant radiotherapy. METHODS: All patients with stage I endometrioid endometrial cancer who underwent surgery from 2000 to 2011 were identified from the SEER-Medicare database. LIR was defined as G1-2 tumors with <50% myometrial invasion or G3 with no invasion. HIR was defined as G1-2 tumors with ≥50% or G3 with <50% invasion. Patients were categorized according to whether they received adjuvant radiotherapy (vaginal brachytherapy [VBT], external beam radiotherapy [EBRT], or both) or no radiotherapy. Outcomes were analyzed and compared (primary outcome was overall survival). RESULTS: 10,842 patients met inclusion criteria. In the LIR group (n = 7609), there was no difference in 10-year overall survival between patients who received radiotherapy and those who did not (67% vs 65%, adjusted HR 0.95, 95% CI 0.81-1.11). In the HIR group (n = 3233), patients who underwent radiotherapy had a significant increase in survival (60% vs 47%, aHR 0.75, 95% CI 0.67-0.85). Radiotherapy was associated with increased costs compared to surgery alone ($26,585 vs $16,712, p < .001). Costs for patients receiving VBT, EBRT, and concurrent VBT/EBRT were $24,044, $27,512, and $31,564, respectively (p < .001). Radiotherapy was associated with an increased risk of gastrointestinal (7 vs 4%), genitourinary (2 vs 1%), and hematologic (16 vs 12%) complications (p < .001). CONCLUSIONS: Radiotherapy was associated with improved survival in women with HIR, but not in LIR. It also had increased costs and a higher morbidity risk. Consideration of observation without radiotherapy in LIR may be reasonable.

Total and out-of-pocket costs of different primary management strategies in ovarian cancer.

BACKGROUND: Communicating healthcare costs to patients is an important component of delivering high-quality value-based care, yet cost data are lacking. This is especially relevant for ovarian cancer, where no clinical consensus on optimal first-line treatment exists. OBJECTIVE: The objective of this study was to generate cost estimates of different primary management strategies in ovarian cancer. STUDY DESIGN: All women who underwent treatment for ovarian cancer from 2006-2015 were identified from the MarketScan database (n=12,761) in this observational cohort study. Total and out-of-pocket costs were calculated with the use of all claims within 8 months from initial treatment and normalized to 2017 US dollars. The generalized linear model method was used to assess cost by strategy. RESULTS: Among patients who underwent neoadjuvant chemotherapy and those who underwent primary debulking, mean adjusted total costs were $113,660 and $107,153 (P<.001) and mean out-of-pocket costs were $2519 and $2977 (P<.001), respectively. Total costs for patients who had intravenous standard, intravenous dose-dense, and intraperitoneal/intravenous chemotherapy were $105,047, $115,099, and $121,761 (P<.001); and out-of-pocket costs were $2838, $3405, and $2888 (P<.001), respectively. Total costs for regimens that included bevacizumab were higher than those without it ($171,468 vs $104,482; P<.001); out-of-pocket costs were $3127 vs $2898 (P<.001). Among patients who did not receive bevacizumab, 25% paid ≥$3875, and 10% paid ≥$6265. For patients who received bevacizumab, 25% paid ≥$4480, and 10% paid ≥$6635. Among patients enrolled in high-deductible health plans, median out-of-pocket costs were $4196, with 25% paying ≥$6680 and 10% paying ≥$9751. CONCLUSION: Costs vary across different treatment strategies, and patients bear a significant out-of-pocket burden, especially those enrolled in high-deductible health plans.

National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia.

BACKGROUND: Although it is uncommon, the incidence of endometrial cancer and atypical hyperplasia among reproductive-aged women is increasing. The fertility outcomes in this population are not well described. OBJECTIVE: We aim to describe the patterns of care and fertility outcomes of reproductive-aged women with endometrial cancer or atypical hyperplasia. MATERIALS AND METHODS: A cohort of women aged ≤45 years with endometrial cancer or atypical hyperplasia diagnosed in 2000 to 2014 were identified in Truven Marketscan, an insurance claims database of commercially insured patients in the United States. Treatment information, including use of progestin therapy, hysterectomy, and assisted fertility services, was identified and collected using a combination of Common Procedural Terminology codes, International Statistical Classification of Diseases and Related Health Problems codes, and National Drug Codes. Pregnancy events were identified from claims data using a similar technique. Patients were categorized as receiving progestin therapy alone, progestin therapy followed by hysterectomy, or standard surgical management with hysterectomy alone. Multivariable logistic regression was performed to assess factors associated with receiving fertility-sparing treatment. RESULTS: A total of 4007 reproductive-aged patients diagnosed with endometrial cancer or atypical hyperplasia were identified. The majority of these patients (n = 3189; 79.6%) received standard surgical management. Of the 818 patients treated initially with progestins, 397 (48.5%) subsequently underwent hysterectomy, whereas 421 (51.5%) did not. Patients treated with progestin therapy had a lower median age than those who received standard surgical management (median age, 36 vs 41 years; P < .001). The proportion of patients receiving progestin therapy increased significantly over the observation period, with 24.9% treated at least initially with progestin therapy in 2014 (P < .001). Multivariable analysis shows that younger age, a diagnosis of atypical hyperplasia diagnosis rather than endometrial cancer, and diagnosis later in the study period were all associated with a greater likelihood of receiving progestin therapy (P < .0001). Among the 421 patients who received progestin therapy alone, 92 patients (21.8%; 92/421) had 131 pregnancies, including 49 live births for a live birth rate of 11.6%. Among the 397 patients treated with progestin therapy followed by hysterectomy, 25 patients (6.3%; 25/397) had 34 pregnancies with 13 live births. The median age of patients who experienced a live birth following diagnosis during the study period was 36 years (interquartile range, 33-38). The use of some form of assisted fertility services was observed in 15.5% patients who were treated with progestin therapy. Among patients who experienced any pregnancy event following diagnosis, 54% of patients used some form of fertility treatment. For patients who experienced a live birth following diagnosis, 50% of patients received fertility treatment. Median time to live birth following diagnosis was 756 days (interquartile range, 525-1077). Patients treated with progestin therapy were more likely to experience a live birth if they had used assisted fertility services (odds ratio, 5.9; 95% confidence interval, 3.4-10.1; P < .0001). CONCLUSION: The number of patients who received fertility-sparing treatment for endometrial cancer or atypical hyperplasia increased over time. However, the proportion of women who experience a live birth following these diagnoses is relatively small.

Adherence to treatment guidelines and survival for older patients with stage II or III colon cancer in Texas from 2001 through 2011.

BACKGROUND: Treatment guidelines for colon cancer recommend colectomy with lymphadenectomy of at least 12 lymph nodes for patients with stage I to stage III disease as surgery adherence (SA) and adjuvant chemotherapy for individuals with stage III disease. Herein, the authors evaluated adherence to these guidelines among older patients in Texas with colon cancer and the associated survival outcomes. METHODS: Using Texas Cancer Registry data linked with Medicare data, the authors included patients with AJCC stage II and III colon cancer who were aged ≥66 years and diagnosed between 2001 and 2011. SA and adjuvant chemotherapy adherence rates to treatment guidelines were estimated. The chi-square test, general linear regression, survival probability, and Cox regression were used to identify factors associated with adherence and survival. RESULTS: The rate of SA increased from 47.2% to 84% among 6029 patients with stage II or stage III disease from 2001 to 2011, and the rate of adjuvant chemotherapy increased from 48.9% to 53.1% for patients with stage III disease during the same time period. SA was associated with marital status, tumor size, surgeon specialty, and year of diagnosis. Patient age, sex, marital status, Medicare state buy-in status, comorbidity status, and year of diagnosis were found to be associated with adjuvant chemotherapy. The 5-year survival probability for patients receiving guideline-concordant treatment was the highest at 87% for patients with stage II disease and was 73% for those with stage III disease. After adjusting for demographic and tumor characteristics, improved cancer cause-specific survival was associated with the receipt of stage-specific, guideline-concordant treatment for patients with stage II or stage III disease. CONCLUSIONS: The adherence to guideline-concordant treatment among older patients with colon cancer residing in Texas improved over time, and was associated with better survival outcomes. Future studies should be focused on identifying interventions to improve guideline-concordant treatment adherence. Cancer 2018;124:679-87. © 2017 American Cancer Society.

Neoadjuvant chemotherapy in elderly women with ovarian cancer: Rates of use and effectiveness.

BACKGROUND: Neoadjuvant chemotherapy (NACT) may reduce perioperative morbidity in women undergoing primary treatment for ovarian cancer. We evaluated patterns of use and outcomes in a population-based cohort of elderly women with ovarian cancer (OC). METHODS: A cohort of patients ≥66 years old diagnosed between 2000 and 2013 with stage III-IV epithelial OC who received surgery and platinum/taxane chemotherapy for primary treatment was identified from the SEER-Medicare database. Propensity-score matching methods were used to examine differences in outcomes. Kaplan-Meier analysis was performed to compare overall survival (OS) in the matched cohort. RESULTS: From 2000 to 2013, 22.5% of older women received NACT. The use of NACT increased over time from 16% in 2000 to 35.4% in 2013 (p < .0001). Among women who received PCS, the rate of ostomy creation was higher compared with NACT (23.3% vs. 10.8%, p < .0001). Infectious and other surgical complications were higher among those who had PCS, regardless of stage. Median OS of women III ovarian cancer who underwent PCS was longer compared with NACT (38.8 vs. 28 months, p ≤ .0001). There were no survival differences between NACT and PCS in women with stage IV disease (29.4 vs. 29.8 months, p = .61) or for women aged >80. CONCLUSION: Careful consideration should be given to older patients prior to undergoing PCS. Survival outcomes were similar for patients with stage IV disease, although NACT was associated with decreased perioperative morbidity compared with PCS. Among women with stage III disease, PCS was associated with improved overall survival, but higher rates of perioperative morbidity and acute care.

Disparities in treatment and survival among elderly ovarian cancer patients.

OBJECTIVE: To determine correlation between race and receipt of optimal treatment for ovarian cancer and the impact of this on overall survival. METHODS: Using SEER-linked Medicare database, women 66 and older diagnosed with advanced ovarian cancer between 2002 and 2011 were identified. Patients with unclear histology, diagnosed on autopsy and without Medicare Parts A and B were excluded. We used Chi-square test for categorical variables, F test for continuous variables, and multivariable logistic regression to identify characteristics associated with receipt of surgery and chemotherapy. Kaplan-Meier analysis was used to compare overall survival rates. Cox Proportional Hazards regression was performed to identify factors associated with 5-year survival. RESULTS: 9016 ovarian cancer patients were included. 2638 had primary chemotherapy, 4854 had primary surgery, and 1524 had no treatment. 7653 (84.9%) were white, 572 (6.3%) black, 479 (5.3%) Hispanic, and 312 (3.5%) were of other race/ethnicity. More white patients (57.2%) received both chemotherapy and surgery compared to black (39.9%), Hispanic (48.9%), or other (54.2%) (p < .001). Receipt of either only surgery or chemotherapy, or receipt of neither, resulted in higher risk of death when compared to receipt of both. On multivariable analysis, black (OR 0.58 [0.46-0.73]) and Hispanic (0.69 [0.54-0.88]) patients were less likely to receive both chemotherapy and surgery. Being of black race was significantly correlated with worse overall survival [HR 1.13 (1.03-1.23); p = .02]. CONCLUSIONS: Non-white women are less likely to receive the standard of care treatment for ovarian cancer and more likely to die from their disease than white women.

Impact of body mass index and operative approach on surgical morbidity and costs in women with endometrial carcinoma and hyperplasia.

OBJECTIVE: To assess the impact of body mass index (BMI) and operative approach on surgical morbidity and costs in patients with endometrial carcinoma (EC) and hyperplasia (EH). METHODS: All women with BMI data who underwent surgery for EC or EH from 2008 to 2014 were identified from MarketScan, a healthcare claims database. Differences in 30-day complications and costs were compared between BMI groups and stratified by surgical modality. RESULTS: Of 1112 patients, 35%, 36%, and 29% had a BMI of ≤29, 30-39, and ≥40kg/m2, respectively. Compared to patients with a BMI of 30-39 and ≤29, women with a BMI ≥40 had higher rates of venous thromboembolism (3% vs 0.2% vs 0.3%, p<0.01) and wound infection (7% vs 3% vs 3%, p=0.02). This increase was driven by the subset of patients who had laparotomy and was not seen in those undergoing minimally invasive surgery (MIS). Median total costs for women with a BMI ≥40, 30-39, and ≤29 were U.S. $17.3k, $16.8k, and $16.6k respectively (p=0.53). Costs were higher for patients who had laparotomy than those who had MIS across all BMI groups, with the cost difference being highest in morbidly obese women (≥40: $21.6k vs $14.9k, p<0.01; 30-39: $18.9k vs $16.1k, p=0.01; ≤29: $19.3k vs $15k, p<0.01). Patients who had complications had higher costs compared to those who did not, with a higher cost difference in the laparotomy group ($27.7k vs $16.4k, p<0.01) compared to the MIS group ($19.9k vs $15k, p<0.01). CONCLUSIONS: MIS may increase the value of care by minimizing complications and decreasing costs. This may be most pronounced in morbidly obese women.

Treatment Patterns, Outcomes, and Costs for Bowel Obstruction in Ovarian Cancer.

OBJECTIVE: The aim of this study was to assess treatment patterns, outcomes, and costs for bowel obstruction in ovarian cancer. METHODS/MATERIALS: All patients with stage II to IV ovarian cancer who were admitted for bowel obstruction greater than or equal to 6 months after cancer diagnosis from 2000 to 2011 were identified from the Surveillance, Epidemiology, and End Results registry-Medicare database. Management strategies and outcomes of bowel obstruction were compared. RESULTS: Among 1397 women with bowel obstruction, 562 (40%) underwent surgery, and 154 (11%) had a gastrostomy or jejunostomy (G/J) tube placed. Thirty-four percent of patients who underwent surgery subsequently received chemotherapy, compared with 8% of those managed with a G/J tube (odds ratio, 4.8; 95% confidence interval [CI], 2.7-8.8). Thirty-day complications were higher for patients in the surgery group compared with those in the tube group (69% vs 46%; odds ratio, 2.5; 95% CI, 1.8-3.7), as were mean adjusted 30-day total costs ($28,872 vs $18,528, P < 0.001). Median survival was greater for women who underwent surgery compared with those who had a G/J tube (5.3 vs 1.2 months; adjusted hazard ratio, 0.31; 95% CI, 0.25-0.38). The median survival of patients in whom surgical correction failed and required G/J tube placement during the same inpatient admission was 2.6 months. Women who received postintervention chemotherapy had improved survival compared with those who did not in both the surgery (17.0 vs 2.8 months, P < 0.001) and G/J tube (5.7 vs 1.0 months, P < 0.001) groups. CONCLUSIONS: In women with ovarian cancer who develop bowel obstruction, surgery may benefit a subset of patients, likely related to the ability to receive subsequent chemotherapy. Efforts to identify those who derive no benefit may reduce unnecessary laparotomy, along with its associated complications and costs. Given this population's limited survival, patient preferences should be evaluated in future studies assessing the management of bowel obstruction.

Racial and Ethnic Differences in Long-Term Adverse Radiation Therapy Effects Among Breast Cancer Survivors.

PURPOSE: Breast and skin changes are underrecognized side effects of radiation therapy for breast cancer, which may have long-term implications for quality of life (QOL). Racial and ethnic disparities in breast cancer outcomes, including long-term QOL differences after breast radiation therapy, are poorly understood. METHODS AND MATERIALS: We conducted a cross-sectional survey study of patients from the Texas Cancer Registry who received diagnoses of stage 0-II breast cancer from 2009 to 2014 and treated with lumpectomy and radiation therapy; 2770 patients were sampled and 631 responded (23%). The BREAST-Q Adverse Effects of Radiation overall score and subindices measured the effect of radiation therapy on breast tissue. Multivariable logistic regression evaluated associations of demographic and treatment characteristics with outcomes. RESULTS: The median age was 57 years (IQR, 48-65), median time from diagnosis to survey response 9 years (IQR, 7-10), and the cohort included 62 Asian American or Pacific Islander (9.8%), 11 American Indian or Alaskan Native (AIAN) (1.7%), 161 Black (25.5%), 144 Hispanic (22.8%), and 253 White (40.1%) patients. Mean BREAST-Q Adverse Effects of Radiation score was worse for AIAN patients (-22.2; 95% CI, -39.9 to -4.6; P = .01), Black patients (-10.8; 95% CI, -16.1 to -5.5; P < .001), and Hispanic patients (-7.8; 95% CI, -13.0 to -2.5; P = .004) compared with White patients, age <50 compared with ≥65 (effect size -8.6; 95% CI, -14.0 to -3.2; P = .002), less than a college education (-5.8; 95% CI, -10.0 to -1.6; P = .01), bra cup size of D/E versus A/B (-5.3; 95% CI, -9.9 to -0.65; P = .03), and current smokers (-11.3; 95% CI, -18.3 to -4.2; P = .002). AIAN, Black, and Hispanic patients reported worse changes in skin pigmentation, telangiectasias, dryness, soreness, and/or irritation compared with White patients. CONCLUSIONS: AIAN, Black, and Hispanic patients reported substantially worse long-term breast and skin QOL outcomes after radiation therapy. Additional work is needed to understand these differences and how to alleviate them.

The formation of diploid and triploid hybrids of female grass carp × male blunt snout bream and their 5S rDNA analysis.

BACKGROUND: Hybridization is a useful strategy to alter the genotypes and phenotypes of the offspring. It could transfer the genome of one species to another through combing the different genome of parents in the hybrid offspring. And the offspring may exhibit advantages in growth rate, disease resistance, survival rate and appearance, which resulting from the combination of the beneficial traits from both parents. RESULTS: Diploid and triploid hybrids of female grass carp (Ctenopharyngodon idellus, GC, Cyprininae, 2n = 48) × male blunt snout bream (Megalobrama amblycephala, BSB, Cultrinae, 2n = 48) were successfully obtained by distant hybridization. Diploid hybrids had 48 chromosomes, with one set from GC and one set from BSB. Triploid hybrids possessed 72 chromosomes, with two sets from GC and one set from BSB.The morphological traits, growth rates, and feeding ecology of the parents and hybrid offspring were compared and analyzed. The two kinds of hybrid offspring exhibited significantly phenotypic divergence from GC and BSB. 2nGB hybrids showed similar growth rate compared to that of GC, and 3nGB hybrids significantly higher results. Furthermore, the feeding ecology of hybrid progeny was omnivorous.The 5S rDNA of GC, BSB and their hybrid offspring were also cloned and sequenced. There was only one type of 5S rDNA (designated type I: 180 bp) in GC and one type of 5S rDNA (designated type II: 188 bp) in BSB. However, in the hybrid progeny, diploid and triploid hybrids both inherited type I and type II from their parents, respectively. In addition, a chimera of type I and type II was observed in the genome of diploid and triploid hybrids, excepting a 10 bp of polyA insertion in type II sequence of the chimera of the diploid hybrids. CONCLUSIONS: This is the first report of diploid and triploid hybrids being produced by crossing GC and BSB, which have the same chromosome number. The obtainment of two new hybrid offspring has significance in fish genetic breeding. The results illustrate the effect of hybridization and polyploidization on the organization and variation of 5S rDNA in hybrid offspring.

The Key Roles of Makorin RING Finger Protein 3 (MKRN3) During the Development of Pubertal Initiation and Central Precocious Puberty (CPP).

Puberty is initiated from the continuous and growing pulsatile secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus and then the activation of the hypothalamic-pituitary-gonadal (HPG) axis. Numerous factors involve pubertal initiation, whose abnormality may come from the dysfunction of these regulators. Makorin RING finger protein 3 (MKRN3) inhibits the secretion of GnRH and plays indispensable roles during the development of pubertal onset, and mutations of MKRN3 showed the commonest genetic cause of central precocious puberty (CPP). Recently, growing studies have revealed the functional mechanisms of MKRN3 in the pubertal initiation and the occurrence of CPP. In this review, we mainly summarized the research advances on the roles of MKRN3 in the development of pubertal onset and their underpinning mechanisms, contributing to a better understanding of the precise mechanisms of pubertal initiation and the pathogenesis of CPP.

Ferroptosis and Cancer Immunotherapy.

Traditional treatment strategies for cancer are unsatisfactory. As a nonapoptotic cell death process and owning to the characteristics of iron-dependent lipid peroxide accumulation, ferroptosis has become a new target of tumor treatment. Numerous studies have proved that ferroptosis could enhance the immunogenicity of cancer and interact with immune cells. Cancer antigens, exposed to cancer cells that underwent ferroptosis, effectively improve the immunogenicity of the tumor microenvironment and promote the activation and maturation of immune cells. Meantime, immune cells release immunostimulatory cytokines including TNF-α and IFN-γ to downregulate the expression of SLC7A11 and SLC3A2, and reduce the absorption of cysteine, leading to lipid peroxidation and iron deposition in cancer cells. Consequently, induction of ferroptosis via iron deposition-based combination strategies could stimulate and activate natural and adaptive immune responses which release immune-stimulating factors to induce iron deposition in cancer cells. In this review, we provided a critical analysis of the correlation between ferroptosis and the immune responses, providing a novel way to effectively induce ferroptosis in cancer, which may be one of the focuses in future to improve the development of new therapeutic strategies of cancer.

Long-term Patient-Reported Outcomes in a Population-Based Cohort Following Radiotherapy vs Surgery for Oropharyngeal Cancer.

Importance: Oncologic outcomes are similar for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with primary surgery or radiotherapy. However, comparative differences in long-term patient-reported outcomes (PROs) between modalities are less well established. Objective: To determine the association between primary surgery or radiotherapy and long-term PROs. Design, Setting, and Participants: This cross-sectional study used the Texas Cancer Registry to identify survivors of OPSCC treated definitively with primary radiotherapy or surgery between January 1, 2006, and December 31, 2016. Patients were surveyed in October 2020 and April 2021. Exposures: Primary radiotherapy and surgery for OPSCC. Main Outcomes and Measures: Patients completed a questionnaire that included demographic and treatment information, the MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) module, the Neck Dissection Impairment Index (NDII), and the Effectiveness of Auditory Rehabilitation (EAR) scale. Multivariable linear regression models were performed to evaluate the association of treatment (surgery vs radiotherapy) with PROs while controlling for additional variables. Results: Questionnaires were mailed to 1600 survivors of OPSCC identified from the Texas Cancer Registry, with 400 responding (25% response rate), of whom 183 (46.2%) were 8 to 15 years from their initial diagnosis. The final analysis included 396 patients (aged ≤57 years, 190 [48.0%]; aged >57 years, 206 [52.0%]; female, 72 [18.2%]; male, 324 [81.8%]). After multivariable adjustment, no significant differences were found between surgery and radiotherapy outcomes as measured by the MDASI-HN (ß, -0.1; 95% CI, -0.7 to 0.6), NDII (ß, -1.7; 95% CI, -6.7 to 3.4), and EAR (ß, -0.9; 95% CI -7.7 to 5.8). In contrast, less education, lower household income, and feeding tube use were associated with significantly worse MDASI-HN, NDII, and EAR scores, while concurrent chemotherapy with radiotherapy was associated with worse MDASI-HN and EAR scores. Conclusions and Relevance: This population-based cohort study found no associations between long-term PROs and primary radiotherapy or surgery for OPSCC. Lower socioeconomic status, feeding tube use, and concurrent chemotherapy were associated with worse long-term PROs. Further efforts should focus on the mechanism, prevention, and rehabilitation of these long-term treatment toxicities. The long-term outcomes of concurrent chemotherapy should be validated and may inform treatment decision making.