Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer.

Most high-grade serous ovarian cancer (HGSOC) patients develop resistance to platinum-based chemotherapy and recur, but 15% remain disease free over a decade. To discover drivers of long-term survival, we quantitatively analyzed the proteomes of platinum-resistant and -sensitive HGSOC patients from minute amounts of formalin-fixed, paraffin-embedded tumors. This revealed cancer/testis antigen 45 (CT45) as an independent prognostic factor associated with a doubling of disease-free survival in advanced-stage HGSOC. Phospho- and interaction proteomics tied CT45 to DNA damage pathways through direct interaction with the PP4 phosphatase complex. In vitro, CT45 regulated PP4 activity, and its high expression led to increased DNA damage and platinum sensitivity. CT45-derived HLA class I peptides, identified by immunopeptidomics, activate patient-derived cytotoxic T cells and promote tumor cell killing. This study highlights the power of clinical cancer proteomics to identify targets for chemo- and immunotherapy and illuminate their biological roles.

Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.

High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.

Accuracy of artificial intelligence-assisted growth prediction in skeletal Class I preadolescent patients using serial lateral cephalograms for a 2-year growth interval.

OBJECTIVE: To investigate the accuracy of artificial intelligence-assisted growth prediction using a convolutional neural network (CNN) algorithm and longitudinal lateral cephalograms (Lat-cephs). MATERIALS AND METHODS: A total of 198 Japanese preadolescent children, who had skeletal Class I malocclusion and whose Lat-cephs were available at age 8 years (T0) and 10 years (T1), were allocated into the training, validation, and test phases (n = 161, n = 17, n = 20). Orthodontists and the CNN model identified 28 hard-tissue landmarks (HTL) and 19 soft-tissue landmarks (STL). The mean prediction error values were defined as 'excellent,' 'very good,' 'good,' 'acceptable,' and 'unsatisfactory' (criteria: 0.5 mm, 1.0 mm, 1.5 mm, and 2.0 mm, respectively). The degree of accurate prediction percentage (APP) was defined as 'very high,' 'high,' 'medium,' and 'low' (criteria: 90%, 70%, and 50%, respectively) according to the percentage of subjects that showed the error range within 1.5 mm. RESULTS: All HTLs showed acceptable-to-excellent mean PE values, while the STLs Pog', Gn', and Me' showed unsatisfactory values, and the rest showed good-to-acceptable values. Regarding the degree of APP, HTLs Ba, ramus posterior, Pm, Pog, B-point, Me, and mandibular first molar root apex exhibited low APPs. The STLs labrale superius, lower embrasure, lower lip, point of lower profile, B', Pog,' Gn' and Me' also exhibited low APPs. The remainder of HTLs and STLs showed medium-to-very high APPs. CONCLUSION: Despite the possibility of using the CNN model to predict growth, further studies are needed to improve the prediction accuracy in HTLs and STLs of the chin area.

Proof-of-Principle Experiment for Testing Strong-Field Quantum Electrodynamics with Exotic Atoms: High Precision X-Ray Spectroscopy of Muonic Neon.

To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and 5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.

Clinical outcomes in patients with COVID-19 and gynecologic cancer: A society of gynecologic oncology COVID-19 and gynecologic cancer registry study.

OBJECTIVES: Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS: The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS: Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS: Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

Gaps in patient-physician communication at the time of malignant bowel obstruction from recurrent gynecologic cancer: a qualitative study.

PURPOSE: We sought to investigate the patient and physician approaches to malignant bowel obstruction (MBO) due to recurrent gynecologic cancer by (1) comparing patient and physician expectations and priorities during a new MBO diagnosis, and (2) highlighting factors that facilitate patient-doctor communication. METHODS: Patients were interviewed about their experience during an admission for MBO, and physicians were interviewed about their general approach towards MBO. Interviews were analyzed for themes using QDAMiner qualitative analysis software. The analysis utilized the framework analysis and used both predetermined themes and those that emerged from the data. RESULTS: We interviewed 14 patients admitted with MBO from recurrent gynecologic cancer and 15 gynecologic oncologists. We found differences between patients and physicians regarding plans for next chemotherapy treatments, foremost priorities, communication styles, and need for end-of-life discussions. Both patients and physicians felt that patient-physician communication was improved in situations of trust, understanding patient preferences, corroboration of information, and increased time spent with patients during and before the MBO. CONCLUSION: Gaps in patient-physician communication could be targeted to improve the patient experience and physician counseling during a difficult diagnosis. Our findings emphasize a need for patient-physician discussions to focus on expectations for future cancer-directed treatments, support for patients at home with home health or hospice level support in line with their wishes, and acknowledgement of uncertainty while providing direct information about the MBO diagnosis.

Changes of synovial fluid biomarker levels after opening wedge high tibial osteotomy in patients with knee osteoarthritis.

OBJECTIVE: The purpose of this study was to evaluate the effects of high tibial osteotomy (HTO) on the biological status of knee osteoarthritis (OA) using joint markers in synovial fluid (SF). METHODS: Fifty patients with medial compartmental OA of the knee who underwent opening wedge HTO were enrolled. Paired SF samples from the affected knee and arthroscopic evaluation of articular cartilage were collected at the time of HTO surgery and the time of plate removal (postoperative 17 ± 4 months). The concentrations of the following SF biomarkers were measured: interleukin (IL)-1ß, IL-6, IL-8, IL-10, tumour necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, MMP-13, vascular endothelial growth factor (VEGF), and cartilage oligomeric matrix protein (COMP). The Knee Society Score (KSS) and hip-knee-ankle (HKA) angle were assessed before and 2 years after HTO. RESULTS: The KSS knee and function scores were significantly improved after HTO (mean changes of 36.4 and 23.7, respectively). The mean HKA angle was altered from mechanical varus (-8.6°) to valgus (5.2°). Concentrations of IL-6, IL-8, MMP-2, MMP-3, MMP-13, VEGF, and COMP in SF were significantly decreased after HTO (mean changes of -49.1%, -30.2%, -31.1%, -26.3%, -30.8%, -42.5%, and -13.7% from preoperative baseline, respectively). The cartilage status was improved in 19 cases (38%) after HTO. However, changes of all biomarkers were not significantly different between subjects with and without an improved cartilage status. CONCLUSIONS: SF levels of biochemical markers for cartilage degradation and synovial inflammation were altered after HTO, suggesting an improvement in the OA disease state.

Differences in Sociodemographic Disparities Between Patients Undergoing Surgery for Advanced Colorectal or Ovarian Cancer.

BACKGROUND: Cytoreductive surgery (CRS) for ovarian cancer with peritoneal metastases (OPM) is an established treatment, yet access-related racial and socioeconomic disparities are well documented. CRS for colorectal cancer with peritoneal metastases (CRPM) is garnering more widespread acceptance, and it is unknown what disparities exist with regards to access. METHODS: This retrospective cross-sectional multicenter study analyzed medical records from the National Cancer Database from 2010 to 2015. Patients diagnosed with CRPM or ORP only and either no or confirmed resection were included. Patient- and facility-level characteristics were analyzed using uni- and multivariable logistic regressions to identify associations with receipt of CRS. RESULTS: A total of 6634 patients diagnosed with CRPM and 14,474 diagnosed with OPM were included in this study. Among patients with CRPM, 18.1% underwent CRS. On multivariable analysis, female gender (odds ratio [95% CI] 2.04 [1.77-2.35]; P < 0.001) and treatment at an academic or research facility (OR 1.55 [1.17-2.05]; P = 0.002) were associated with CRS. Among patients with OPM, 87.1% underwent CRS. On multivariable analysis, treatment at facilities with higher-income patient populations was positively associated with CRS, while age (OR 0.97 [0.96-0.98]; P < .0001), use of nonprivate insurance (OR 0.69 [0.56-0.85]; P = 0.001), and listed as Black (OR 0.62 [0.45-0.86]; P = 0.004) were negatively associated with CRS. CONCLUSION: There were more systemic barriers to CRS for patients with OPM than for patients with CRPM. As CRS becomes more widely practiced for CRPM, it is likely that more socioeconomic and demographic barriers will be elucidated.

Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

Chemotherapy response score as a prognostic tool in patients with advanced stage endometrial carcinoma treated with neoadjuvant chemotherapy.

BACKGROUND: Chemotherapy response score (CRS) applied to interval debulking specimens quantifies histopathologic response to neoadjuvant chemotherapy in patients with advanced ovarian carcinoma and correlates with progression-free and overall survival. OBJECTIVE: To investigate whether the chemotherapy response score could be applied to interval debulking specimens in patients with advanced endometrial carcinoma and be a prognostic indicator. METHODS: The study included patients with clinical stage III-IV endometrial carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery. Chemotherapy response scores were assigned to omental and adnexal metastases, and categorized as no/minimal (CRS1), partial (CRS2), and complete/near-complete (CRS3) response to neoadjuvant chemotherapy. Descriptive statistics were used to evaluate baseline characteristics and feasibility of chemotherapy response score assessment. Univariate analyses were used to evaluate associations between the chemotherapy response score, complete cytoreduction, and survival. RESULTS: This study included 40 patients. The median age was 63.5 years, and 31 patients (78%) had stage IV disease. Thirty patients had an omentectomy, 22 patients (73%) had an omental chemotherapy response score assigned. Thirty-nine patients had a bilateral salpingo-oophorectomy, 28 patients (72%) had an adnexal chemotherapy response score assigned. Omental CRS2 and CRS3 were associated with improved progression-free survival (CRS2: HR=0.18, p<0.01; CRS3: HR=0.11, p<0.01) and overall survival (CRS2: HR=0.10, p<0.01; CRS3: HR=0.16, p=0.04). Adnexal CRS2 and CRS3 were associated with improved progression-free survival (CRS2: HR=0.23, p<0.01; CRS3: HR=0.20, p=0.03). Chemotherapy response scores were also associated with an increased likelihood of having a complete cytoreduction. CONCLUSION: Chemotherapy response score can be applied to omental and adnexal metastases in patients with advanced endometrial carcinoma and was associated with survival and complete cytoreduction. The score may be a prognostic indicator and help to guide first-line treatment of patients with endometrial carcinoma.

Simultaneous assessment of coronary flow reserve and left ventricular function during vasodilator stress evaluated by 13N-ammonia hybrid PET/MRI.

AIM: To explore changes in left ventricular (LV) function and the relationship of these changes with myocardial blood flow (MBF) evaluated by 13N-ammonia hybrid positron-emission tomography (PET)/magnetic resonance imaging (MRI) during vasodilator stress in patients with suspected coronary artery disease (CAD). MATERIALS AND METHODS: Fifty-two consecutive patients with suspected CAD, who underwent 13N-ammonia PET/MRI, were enrolled. Vasodilator stress was induced by intravenous injection of adenosine. MBF and coronary flow reserve (CFR) were calculated from dynamic acquisition of 13N-ammonia PET. LV function was evaluated by MRI both at rest and during vasodilator stress. An abnormal perfusion on myocardial images was defined as a summed difference score of ≥4. RESULTS: MRI showed that the LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction (LVEF) remained unchanged during vasodilator stress in all patients (n=52) as well as in the patients with CFR of <2 (n=27), stress MBF of <1.3 ml/g/min (n=28), abnormal myocardial perfusion (n=30), and more than one diseased vessel (n=46). In only four patients, the LVEF measured by MRI decreased by >5% during vasodilator stress. In these four patients, CFR was lower (1.57 ± 0.12 versus 2.18 ± 0.86, p<0.01) and the number of diseased vessels was higher (2.75 ± 0.50 versus 1.48 ± 0.92, p<0.01) than in patients without post-stress LV dysfunction. CONCLUSION: The LV volume and systolic function evaluated by cardiac MRI remained unchanged during vasodilator stress; however, LV dysfunction during vasodilator stress may occur in patients with severe CAD.

Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS: The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS: The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION: Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.

ANTECEDENTES: La quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales. MÉTODOS: Se evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global. RESULTADOS: Las dosis recomendadas de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2 , respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0-22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes. CONCLUSIÓN: Agregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878).

When to Operate, Hesitate and Reintegrate: Society of Gynecologic Oncology Surgical Considerations during the COVID-19 Pandemic.

The COVID-19 pandemic has challenged our ability to provide timely surgical care for our patients. In response, the U.S. Surgeon General, the American College of Srugeons, and other surgical professional societies recommended postponing elective surgical procedures and proceeding cautiously with cancer procedures that may require significant hospital resources and expose vulnerable patients to the virus. These challenges have particularly distressing for women with a gynecologic cancer diagnosis and their providers. Currently, circumstances vary greatly by region and by hospital, depending on COVID-19 prevalence, case mix, hospital type, and available resources. Therefore, COVID-19-related modifications to surgical practice guidelines must be individualized. Special consideration is necessary to evaluate the appropriateness of procedural interventions, recognizing the significant resources and personnel they require. Additionally, the pandemic may occur in waves, with patient demand for surgery ebbing and flowing accordingly. Hospitals, cancer centers and providers must prepare themselves to meet this demand. The purpose of this white paper is to highlight all phases of gynecologic cancer surgical care during the COVID-19 pandemic and to illustrate when it is best to operate, to hestitate, and reintegrate surgery. Triage and prioritization of surgical cases, preoperative COVID-19 testing, peri-operative safety principles, and preparations for the post-COVID-19 peak and surgical reintegration are reviewed.

FDG-PET/MRI with high-resolution DWI characterises the distinct phenotypes of endometrial cancer.

AIM: To evaluate the capability of integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET)/magnetic resonance imaging (MRI) to characterise the distinct phenotypes of endometrial cancer. MATERIALS AND METHODS: Thirty-one patients with endometrial cancer (23 with type I, including 17 G1 and six G2 endometrioid adenocarcinomas, and eight with type II, including three G3 endometrioid adenocarcinomas, two carcinosarcomas, and three serous carcinomas) underwent pretreatment FDG-PET/MRI with simultaneous reduced field-of-view diffusion-weighted imaging (DWI). The standardised uptake value (SUV), apparent diffusion coefficient (ADC), and SUV-to-ADC ratio were compared between low-risk (type I and stage I and negative for lymph-vascular space invasion [LVSI]) and high-risk cancers. The diagnostic accuracy for discriminating the cancer phenotypes was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The SUV was not significantly different between low-risk and high-risk endometrial cancers. High-risk cancers had a significantly lower ADC (756±232×10-6) and a greater SUV-to-ADC ratio (21.7±7.7×109) than low-risk cancers (937±154×10-6, p<0.05 and 13.1±4.1×109, p<0.005, respectively). On comparison of the area under the ROC curves (AUCs), the SUV-to-ADC ratio demonstrated the greatest diagnostic accuracy (ratio 0.83, ADC 0.72, and SUV 0.66). The AUCs for the ratios were significantly higher than those for the SUV values (p<0.05). The optimal SUV-to-ADC cut-off value of 16.9×109 for predicting high-risk cancer revealed a sensitivity of 73%, specificity of 81%, and accuracy of 77%, which was significantly higher than the accuracy for SUV. CONCLUSION: The SUV-to-ADC ratio obtained using integrated FDG-PET/MRI with high-resolution DWI reflects tumour aggressiveness including LVSI, and will be useful for lesion characterisation to decide on an appropriate therapeutic strategy for endometrial cancer.

The Warburg effect and tumour immune microenvironment in extramammary Paget's disease: overexpression of lactate dehydrogenase A correlates with immune resistance.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant skin cancer. One of the hallmarks of cancers, including EMPD, is an enhancement of aerobic glycolysis, which is also known as the Warburg effect. In the last step of glycolysis, the enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactic acid, the accumulation of which contributes to the creation of an acidic tumour microenvironment. This in turn results in immunosuppression in various types of cancers. However, the contribution of these pathways has not been well-studied in EMPD. OBJECTIVE: To investigate the significance of the Warburg effect and its contribution to the tumour immune microenvironment in EMPD. METHODS: The mRNA expression levels of molecules involved in glycolysis and immune-related cytokines were examined by ddPCR. The number of immune cells was assessed by immunohistochemistry (IHC). RESULTS: The levels of two glycolytic enzymes, HK2 and LDHA, in tumour tissues were significantly increased compared to those in paired-normal tissues. IHC analyses revealed increased numbers of PD-L1+ , PD-1+ , CD163+ M2 macrophages, Iba1+ macrophages and Foxp3+ Tregs that were associated with high LDHA levels in EMPD. ddPCR demonstrated that multiple cytokines including IL-4, IL-6, IL-10, TGF-ß and CCL-2 were upregulated and associated with high LDHA levels in EMPD. Statistical analyses showed that IL-6 mRNA expression correlated with the number of CD163+ , Iba-1+ and Foxp3+ cells. CONCLUSION: The Warburg effect contributes to immunomodulation in the tumour microenvironment and further elucidation may lead to better understanding of the pathogenesis of EMPD.

Impaired residual renal function predicts denosumab-induced serum calcium decrement as well as increment of bone mineral density in non-severe renal insufficiency.

Denosumab treatment of osteoporotic patients, except those with severe renal insufficiency, reduced cCa levels. Low baseline cCa, low estimated glomerular filtration rate, and high bone turnover increased the risk of lower cCa, while increasing bone mineral density. Pretreatment with antiresorptive agents was beneficial in reducing the risk of hypocalcemia. INTRODUCTION: Although denosumab-induced hypocalcemia has been frequently observed in patients with chronic kidney disease (CKD) stages 4-5D being treated with denosumab for osteoporosis, few studies have assessed the risk factors for serum-corrected calcium (cCa) reductions in patients with non-severe renal insufficiency. This study assessed the risk factors for reduced cCa concentration following denosumab administration and analyzed factors predictive of changes in bone mineral density (BMD). METHODS: Seventy-seven osteoporotic patients, not including those with CKD stages 4-5D, were treated with 60 mg denosumab once every 6 months. Biochemical parameters and BMD were analyzed from prior to the initial dose until 1 month after the second dose. RESULTS: Following the first administration of denosumab, cCa levels decreased, reaching a minimum on day 7. Multiple linear regression analyses showed that baseline cCa, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone alkaline phosphatase (BAP) or pretreatment with antiresorptive agents were significant factors independently associated with the absolute reduction in cCa from baseline to day 7 (ΔcCa0-7 days). ΔcCa0-7 days after the second dose of denosumab was significantly lower than that after the first dose. After 6 months of denosumab treatment, both LS-BMD and FN-BMD significantly increased from baseline. LS-BMD and FN-BMD correlated significantly with baseline TRACP-5b or BAP and eGFR, respectively. CONCLUSIONS: Both low eGFR and high bone turnover were independent risk factors for denosumab-induced cCa decrement, and for increases in BMD. Pretreatment with antiresorptive agents may reduce the risk of hypocalcemia.

Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Room-Temperature Low-Field Colossal Magnetoresistance in Double-Perovskite Manganite.

We have discovered room-temperature low-field colossal magnetoresistance (CMR) in an A-site ordered NdBaMn_{2}O_{6} crystal. The resistance changes more than 2 orders of magnitude at a magnetic field lower than 2 T near 300 K. When the temperature and magnetic field sweep from an insulating (metallic) phase to a metallic (insulating) phase, the insulating (metallic) conduction changes to the metallic (insulating) conduction within 1 K and 0.5 T, respectively. The CMR is ascribed to the melting of the charge and orbital ordering. The entropy change which is estimated from the B-T phase diagram is smaller than what is expected for the charge and orbital ordering. The suppression of the entropy change is attributable to the loss of the short-range ferromagnetic fluctuation of Mn spin moments, which is an important key of the high temperature and low magnetic field CMR effect.