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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 cancer 1 , 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. The authors find that stromal methyltransferase nicotinamide N -methyltransferase (NNMT) regulates the transition of normal fibroblasts to cancer-associated fibroblasts through histone methylation and promotes ovarian cancer growth and metastasis.

Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis. Intra-abdominal tumors, such as ovarian cancer 1 , 2 , have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte–ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid–binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

The bulk-boundary correspondence, which links a bulk topological property of a material to the existence of robust boundary states, is a hallmark of topological insulators. However, in crystalline topological materials the presence of boundary states in the insulating gap is not always necessary since they can be hidden in the bulk energy bands, obscured by boundary artifacts of non-topological origin, or, in the case of higher-order topology, they can be gapped altogether. Recently, exotic defects of translation symmetry called partial dislocations have been proposed to trap gapless topological modes in some materials. Here we present experimental observations of partial-dislocation-induced topological modes in 2D and 3D insulators. We particularly focus on multipole higher-order topological insulators built from circuit-based resonator arrays, since crucially they are not sensitive to full dislocation defects, and they have a sublattice structure allowing for stacking faults and partial dislocations. The development of higher-order topological insulators enables robust localization of energy at lower-dimensional boundaries. Here the authors demonstrate that partial dislocation in higher order topological insulators can be intuitively understood as a defect-induced topological phase boundary which supports 0D bound states.

Low-grade serous carcinoma of the ovary is chemoresistant but mutations in the MAPK pathway could be targeted to control tumour growth. We therefore assessed the safety and activity of selumetinib, an inhibitor of MEK1/2, for patients with this cancer. In this open-label, single-arm phase 2 study, women (aged ≥18 years) with recurrent low-grade serous ovarian or peritoneal carcinoma were given selumetinib (50 mg twice daily, orally) until progression. The primary endpoint was the proportion of patients who had an objective tumour response according to RECIST version 1.1, assessed for all the treated patients. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551070. 52 patients were enrolled between Dec 17, 2007, and Nov 23, 2009. All were eligible for analyses. Eight (15%) patients had an objective response to treatment—one patient had a complete response and seven had partial responses. 34 (65%) patients had stable disease. There were no treatment-related deaths. Grade 4 toxicities were cardiac (one), pain (one), and pulmonary events (one). Grade 3 toxicities that occurred in more than one patient were gastrointestinal (13), dermatological (nine), metabolic (seven), fatigue (six), anaemia (four), pain (four), constitutional (three), and cardiac events (two). Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum. The findings suggest that inhibitors of the MAPK pathway warrant further investigation in these patients. National Cancer Institute.

Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be \"bystanders\" to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis.

SummaryRoot 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.IntroductionNo 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.MethodsRisk 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.ResultsWe 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.ConclusionsTooth 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.

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.

BackgroundCytoreductive 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.MethodsThis 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.ResultsA 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.ConclusionThere 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.

Background:Knee joint dysfunction remarkably decreases mobility of the elderly, reconstruction of knee joint function is important to maintain their healthy and independent life. And nowadays, the number of total knee arthroplasty (TKA) is increasing worldwide for that purpose. Successful results of the surgery seem to depend on several preoperative factors including age, muscle strength of lower limbs, frail status, range of motion of the knees.Objectives:We assessed physical function by 3 different methods physical frailty, sarcopenia, and locomotive syndrome in patients with knee disorder just before arthroplasty and investigated the relationship between impairment of mobility and preoperative factors.Methods:All patients scheduled to undergo TKA at our hospital from July 2020 to September 2022 were assessed for basic attributes, clinical assessment, radiography, whole-body mode DXA, knee muscle strength with written informed consent. And frailty by Japanese Cardiovascular Health Study criteria, sarcopenia by Asian Working Group for Sarcopenia 2019 criteria, and locomotive syndrome (LS) by Japanese Orthopedic Association were evaluated.Results:Characteristics of the patients included in this study were shown in Table 1. Among 204 patients (213 knees),172 women, mean age 75.0 years, the overall distribution in frailty was no: 14.6%, pre-frailty: 58.5%, and frailty: 26.8%. That in sarcopenia was no: 93.3%, yes: 3.7%, and severe: 3.7% and in LS Stage 0: 0%, Stage 1: 3.3%, Stage 2: 11.4%, and stage 3: 85.3%. The most prevalent group comprised patients with LS stage 3 without sarcopenia but classified as pre-frail (n=94). The next most common group included patients with LS stage 3 without sarcopenia but classified as frailty (n=43). Eighty-seven percent of the patients with frailty and 92% with LS stage 3 did not suffer from sarcopenia (Table 2). Statistically significant relationships were observed between sarcopenia and frailty (p=0.003; Fisher’s exact test), while no relationship between LS and frailty (p=0.442; Fisher’s exact test) or LS and sarcopenia (p=0.889; Fisher’s exact test). Multivariate analysis of related factors with severity level for frailty and locomotive syndrome revealed correlations for frailty with gait speed (p=0.02) and sarcopenia (p=0.04), whereas statistically significant correlation for LS with KSS (p=0.00) and muscle strength (p=0.01).Conclusion:In the patients with end stage knee OA immediately before arthroplasty, there were a small number of patients with coexisting sarcopenia in physical frailty or LS Stage 3. Therefore, the skeletal muscles of such patients did not deteriorate, although their morbidity was impaired. Locomotive syndrome status was considered appropriate for the assessment of mobility function in such patients rather than physical frailty.Table 1.Characteristics of the patients who were scheduled to undergo knee arthroplastyFactorsn=204 (213 knees)Female (n, (%))172 (80.8%)age (mean, (SD))75 years old(7.7)body mass index (kg/m2) (mean, (SD))26.3 kg/m2 (4.6)symptomatic period (median [min-max])5.0 years [0-38]smoking: never, ever, current (n (%))144 (74.2%), 33 (17.0%), 17 (8.8%)Knee Society Score (mean, (SD))76.2 (27.6)JOA Score (mean, (SD))50.7 (6.7)Pain VAS (mean, (SD))43.2 (29.8)Femoro-Tibial angle on X-ray (mean, (SD))182.2 (8.6)ROM (degree)Extension (mean, (SD))-10.2 (6.8)Flexion (mean, (SD))118.6 (13.6)Muscle strength (N)5.0 years [0-38]Extension (mean, (SD))142.3 (59.0)Flexion (mean, (SD))94.7 (42.6)Grip power (kg) (mean, (SD))19.5 (6.4)Gait speed (m/sec) (mean, (SD))0.90 (0.32)ASMI (kg/m2) (mean, (SD))6.83 (1.10)JOA: Japanese Orthopedic Association, VAS: Visual Analogue Scale, ROM: range of motion, ASMI: appendicular skeletal muscle mass index,Table 2.Frequency of complications of the three diseasesFrailty StatusNon-Frailty(29, 14.6%)PreFrailty(118, 58.5%)Frailty(55, 26.8%)Locomotive Syndrome stageStage 0(0, 0 %)non-Sarcopenia000Sarcopenia000Stage 1(7, 3.3%)non-Sarcopenia061Sarcopenia000Stage-2(22, 11.4%)non-Sarcopenia5124Sarcopenia010Stage 3(173, 85.3%)non-Sarcopenia239443Sarcopenia157REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.