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Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

Se realizó una investigación cualitativa para comprobar la utilidad del cine como apoyo a la docencia en la asignatura de Psiquiatría del quinto año de la carrera de Medicina en tres subgrupos de estudiantes de la Universidad de Ciencias Médicas “Carlos J. Finlay” de Camagüey. La muestra ascendió a 43 estudiantes de ambos sexos y diferentes nacionalidades, a quienes se les realizaron entrevistas individuales grabadas en audio, explorando criterios personales tras haber presenciado un grupo de películas previamente escogidas por abordar el tema del trastorno mental con profundidad. Las mismas se exhibieron una vez por semana, coincidiendo su tema con los objetivos propuestos según los contenidos, siempre después de la conferencia introductoria y clase taller, y antes del seminario correspondiente. Entre los resultados obtenidos se destaca que la totalidad expresó opiniones positivas respecto a la actividad, y propuso se mantuviera en el resto de las rotaciones de Psiquiatría. La totalidad consideró que la misma representó un enriquecimiento de su cultura general. La mayoría expresó que les fue fácil la identificación de síntomas, síndromes y situaciones causales en las películas utilizadas, y manifestó que existe una estrecha relación entre los contenidos semanales y las películas elegidas. Se recogieron además algunas sugerencias respecto a la actividad. Teniendo en cuenta los resultados obtenidos, se puede considerar como muy positiva la utilización del cine como apoyo a la actividad docente en Psiquiatría en el grupo estudiado.

Se realizó una investigación cualitativa para comprobar la utilidad del cine como apoyo a la docencia en la asignatura de Psiquiatría del quinto año de la carrera de Medicina en tres subgrupos de estudiantes de la Universidad de Ciencias Médicas "Carlos J. Finlay" de Camagüey. La muestra ascendió a 43 estudiantes de ambos sexos y diferentes nacionalidades, a quienes se les realizaron entrevistas individuales grabadas en audio, explorando criterios personales tras haber presenciado un grupo de películas previamente escogidas por abordar el tema del trastorno mental con profundidad. Las mismas se exhibieron una vez por semana, coincidiendo su tema con los objetivos propuestos según los contenidos, siempre después de la conferencia introductoria y clase taller, y antes del seminario correspondiente. Entre los resultados obtenidos se destaca que la totalidad expresó opiniones positivas respecto a la actividad, y propuso se mantuviera en el resto de las rotaciones de Psiquiatría. La totalidad consideró que la misma representó un enriquecimiento de su cultura general. La mayoría expresó que les fue fácil la identificación de síntomas, síndromes y situaciones causales en las películas utilizadas, y manifestó que existe una estrecha relación entre los contenidos semanales y las películas elegidas. Se recogieron además algunas sugerencias respecto a la actividad. Teniendo en cuenta los resultados obtenidos, se puede considerar como muy positiva la utilización del cine como apoyo a la actividad docente en Psiquiatría en el grupo estudiado.A qualitative research was carried out in three sub-groups of medical students at Carlos J. Finlay University in order to test the usefulness of films as a teaching aid for the 5th year subject of Psychiatry. The sample was composed of 43 students, both male and female, from different nationalities whose individual interviews were recorded in order to analyze personal criteria after watching a series of movies previously chosen since the plot deals with serious mental disorders. These were screened once a week. Their subject matter coincided with the objectives set according to the class content, always after the introductory lecture and workshop class, and before the corresponding seminar. The most outstanding results show that all students expressed positive views with regard to the activity, and suggested to maintain this initiative in the rest of Psychiatry rotations. All of them considered that this activity allowed them to enrich their general culture. Most expressed that it was easy for them to identify symptoms, syndromes and causal situations used in films and that there is a close relationship between the weekly contents and selected films. In addition some suggestions regarding the activity were collected. Taking into account the obtained results, the use of cinema as a teaching aid in Psychiatry can be considered as very positive in the studied group.

BackgroundEndometriosis, impacting roughly 10% of reproductive-age women and girls globally, presents diagnostic challenges that can cause significant delays between symptom onset and medical confirmation. The aim of the current study was to explore the experience of women with endometriosis as well as that of their partners, from pre-diagnosis to diagnosis to post-diagnosis.MethodsIn-depth semi-structured interviews were conducted with 10 couples coping with endometriosis. Each partner was interviewed separately, and each interview was analyzed both individually and as part of a dyad, using the dyadic interview analysis method.ResultsThree main themes emerged: (i) “Relationship in the shadow of uncertainty”: Coping with health symptoms prior to the formal endometriosis diagnosis; (ii) Coping together or alone when receiving the endometriosis diagnosis; and (iii) “The day after the diagnosis”: Moving between adversity and growth.ConclusionsThe study's findings emphasize the importance of viewing the diagnosis from a dyadic perspective and comprehensively – that is, from pre-diagnosis to accepting the formal diagnosis to post-diagnosis. This journey can have a profound impact on both couple members, affecting their day-to-day functioning, communication, emotional and physical intimacy, and fertility.

Abstract Background MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome. Methods The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers. Results More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients. Conclusions Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.

Background and purpose: Effective communication of radiologic findings is crucial in the acute evaluation of stroke. Conventional methods (CM) of communication can present challenges leading to delays in reporting, ultimately impacting patient outcomes. The goal of this retrospective study was to assess the utility of a HIPAA-compliant messaging system (MS) for expediting communication of CT findings by radiologists to members of the stroke team. Materials and methods: Multimodal stroke protocol CT examinations performed at a high-volume stroke center between January and December 2019 were identified as part of this IRB-approved retrospective study. Read-back times were determined based on templated documentation within individual radiologic reports. The time interval between identification of findings and notification was calculated for each report, and usage of CM versus MS was documented. In addition, an online voluntary survey was disseminated to staff to assess user satisfaction with the MS. Results and conclusions: In total, 442 CTs were included, and 126 (29%) documented use of the MS. The MS was associated with significant reductions in median read-back times, both for all reported findings (1.5 versus 16 minutes, p

Overlapping coding regions balance selective forces between multiple genes. One possible division of nucleotide sequence is that the predominant selective force on a particular nucleotide can be attributed to just one gene. While this arrangement has been observed in regions in which one gene is structured and the other is disordered, we sought to explore how overlapping genes balance constraints when both protein products are structured over the same sequence. We use a combination of sequence analysis, functional assays, and selection experiments to examine an overlapped region in HIV-1 that encodes helical regions in both Env and Rev. We find that functional segregation occurs even in this overlap, with each protein spacing its functional residues in a manner that allows a mutable non-binding face of one helix to encode important functional residues on a charged face in the other helix. Additionally, our experiments reveal novel and critical functional residues in Env and have implications for the therapeutic targeting of HIV-1.

Background: The level of radiation exposure received by operators performing transcatheter aortic valve replacement (TAVR) is not well investigated. The aim of this study is to measure the amount of radiation received by operators performing transfemoral TAVR and to identify various patient and procedural characteristics associated with increased radiation exposure. Methods: Primary (operator 1) and secondary (operator 2) operators' equivalent radiation doses in micro Sieverts (µSv) were calculated prospectively using real-time radiation dosimeters for a total of 140 consecutive transfemoral TAVRs. Corresponding eye and thorax radiation exposures between the operators were compared. Associations between various patient and procedural characteristics and the radiation exposure were tested using the t-test and Wilcoxon Mann-Whitney rank-sum test with Monte Carlo estimation. Multivariable regression analysis was also conducted. Results: Operator 1 had significantly higher cumulative equivalent radiation exposure than operator 2 (86 µSv vs 38 µSv, p-value:

Abstract We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)‐modified FOLFIRINOX (mFOLF) vs nanoparticle albumin–bound paclitaxel plus gemcitabine (nab‐P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan‐Meier method and log‐rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy‐two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab‐P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab‐P/G patients (all P

Abstract Background Atypical multinucleated stromal giant cells (MSGCs) are occasionally encountered in the esophagogastric mucosa. This study aims to investigate the origin and clinical association of MSGCs in the upper gastrointestinal tract. Methods Three hundred sixty-one contiguous biopsies and 1 resection specimen from the stomach and gastroesophageal junction (GEJ) were identified from archives for morphologic and immunohistochemical studies. Results MSGCs were identified in 22 cases (6%: 7 gastric, 15 GEJ). Patients’ average age was 53 years. There was no sex predilection. 77% cases had only 1 or 2 MSGCs per 10 high power fields. MSGCs were located in the lamina propria of the gastric or GEJ mucosa, with an accentuation in the subepithelial zone. The median number of nuclei in a MSGC was 5 (ranging from 3 to 16). The nuclei were touching/overlapping, often arranged into “wreath”, “caterpillar”, or “morula” configurations. MSGCs expressed smooth muscle actin, desmin, while negative for cytokeratin AE1/3, CD68, S100, chromogranin, and CD117. The most common clinical history was epigastric pain, gastroesophageal reflux, and Barrett esophagus. The most common associated pathologic diagnoses included reactive (chemical) gastropathy (71% gastric biopsies) and gastroesophageal reflux (73% GEJ specimens). Conclusions MSGCs in the esophagogastric mucosa show smooth muscle/myofibroblast differentiation by immunohistochemistry and likely represent a reactive/reparative stromal reaction associated with gastroesophageal reflux and reactive (chemical) gastropathy.

Abstract Background ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

The newly emerging variants of SARS-CoV-2 from South Africa (B.1.351/501Y.V2) and Brazil (P.1/501Y.V3) have led to a higher infection rate and reinfection of COVID-19 patients. We found that the mutations K417N, E484K, and N501Y within the receptor-binding domains (RBDs) of the virus could confer ~2-fold higher binding affinity to the human receptor, angiotensin converting enzyme 2 (ACE2), compared to the wildtype RBD. The mutated version of RBD also completely abolishes the binding of bamlanivimab, a therapeutic antibody, in vitro. Detailed analysis shows that the ~10-fold gain of binding affinity between ACE2 and Y501-RBD, which also exits in the high contagious variant B.1.1.7/501Y.V1 from the United Kingdom, is compromised by additional introduction of the K417/N/T mutation. Mutation of E484K leads to the loss of bamlanivimab binding to RBD, although this mutation does not affect the binding between RBD and ACE2.

Abstract Background Simulation-based training improves residents’ skills for end-of-life (EOL) care. In the field, staff providers play a significant role in handling those situations and in shaping practice by role modeling. We initiated an educational intervention to train healthcare providers for improved communication skills at EOL using simulation of sensitive encounters with patients and families. Methods Hospital physicians and nurses (n = 1324) attended simulation-based workshops (n = 100) in a national project to improve EOL care. We analyzed perceptions emerging from group discussions following simulations, from questionnaires before and after each workshop, and from video-recorded simulations using a validated coding system. We used the simulation setting as a novel tool for action research. We used a participatory inquiry paradigm, with repetitive cycles of exploring barriers and challenges with participants in an iterative pattern of observation, discussion and reflection – including a description of our own responses and evolution of thought as well as system effects. Results The themes transpiring included lack of training, knowledge and time, technology overuse, uncertainty in decision-making, poor skills for communication and teamwork. Specific scenarios demonstrated lack of experience at eliciting preferences for EOL care and at handling conflicts or dilemmas. Content analysis of simulations showed predominance of cognitive utterances - by an order of magnitude more prevalent than emotional expressions. Providers talked more than actors did and episodes of silence were rare. Workshop participants acknowledged needs to improve listening skills, attention to affect and teamwork. They felt that the simulation-based workshop is likely to ameliorate future handling of EOL situations. We observed unanticipated consequences from our project manifested as a field study of preparedness to EOL in nursing homes, followed by a national survey on quality of care, leading to expansion of palliative care services and demand for EOL care education in various frameworks and professional areas. Conclusions Reflective simulation exercises show barriers and paths to improvement among staff providers. When facing EOL situations, physicians and nurses use cognitive language far more often than emotions related expressions, active listening, or presence in silence. Training a critical mass of staff providers may be valuable to induce a cultural shift in EOL care.

Abstract Background Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined. Methods In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33–40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. Discussion This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. Trial registration ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

Background Emergent informed consent for clinical trials in acute myocardial infarction (AMI) and stroke is challenging. The role and value of consent are controversial, and insufficient data exist regarding patients’ and surrogates’ experiences. Methods and Results We conducted structured interviews with patients (or surrogates) enrolled in AMI or acute stroke trials at 6 sites between 2011 and 2016. Primary domains included trial recall, consent experiences, and preferences regarding involvement. Descriptive and test statistics were used to characterize responses and explore relationships between key domains and characteristics. Multivariable logistic regression was used to examine associations between key covariates and consent preferences. There were 176 (84 stroke, 92 AMI) completed interviews. Most stroke respondents (82%) were surrogates; all AMI respondents were patients. Average time from trial enrollment to interview was 1.9 years (stroke) and 2.8 years (AMI); 89% of stroke and 62% of AMI respondents remembered being in the trial, and among these respondents, 80% (stroke) and 44% (AMI) remembered reading some of the consent form. Over 90% reported not feeling pressure to enroll, being treated in a caring way, and being treated with dignity. A minority (16% stroke and 26% AMI) reported they would have preferred not to be asked for consent. Just over half (61% stroke and 53% AMI) recalled a postenrollment conversation about the study. Conclusions Most respondents felt they were treated respectfully and were glad they had been asked for consent. Trial recall was relatively low, and many respondents recalled little postenrollment discussion. Further development of context‐sensitive approaches to consent is important.

How should banks be regulated to avoid their failure? Banks must control the risks they take with depositors' money. If depositors lose their trust in their banks, and demand their money, the banks will fail. This article describes three legal bank regulatory systems: Contract with depositors (U.S.); a mix of contract and trust law, but going towards trust (Japan) and a full trust-fiduciary law regulating banks (Israel). The article concludes that bank regulation, which limits the banks' risks and conflicts of interest, helps create trustworthy banks that serve their country best.

Background Obesity and obstructive sleep apnea (OSA) are associated with atrial fibrillation (AF), yet these conditions remain inadequately treated. We report on the feasibility and efficacy of a nurse‐led risk factor modification program utilizing a pragmatic approach to address obesity and OSA in AF patients. Methods and Results AF patients with obesity (body mass index ≥30 kg/m2) and/or the need for OSA management (high risk per Berlin Questionnaire or untreated OSA) were voluntarily enrolled for risk factor modification, which comprised patient education, lifestyle modification, coordination with specialists, and longitudinal management. Weight loss and OSA treatment were monitored by monthly follow‐up calls and/or continuous positive airway pressure (CPAP) unit downloads. Quality of life and arrhythmia symptoms were assessed with the SF‐36 and AF Severity Scale at baseline and at 6 months. From November 1, 2016 to October 31, 2017, 252 patients (age 63±11 years; 71% male; 57% paroxysmal AF) were enrolled, 189 for obesity and 93 for OSA. Obese patients who enrolled lost significantly greater percent body weight than those who declined (3% versus 0.3%; P

Variabilidad de los microsatélites de la cigüeña americana Mycteria americana (Aves, Ciconiidae) en Cuba: implicaciones para su conservación Mycteria americana (Aves, Ciconiidae) es la única especie de cigüeña distribuida en el Caribe. En Cuba se considera residente permanente, pero rara, y solo se conocen dos colonias reproductivamente activas. En este trabajo se emplearon cinco loci de microsatélites para caracterizar genéticamente a 37 individuos de esas colonias, localizadas en dos de los más importantes humedales de Cuba: la ciénaga de Zapata y el archipiélago Sabana–Camagüey. Se observó una baja variabilidad en los índices de variabilidad genética, cuyos valores fueron similares a los referidos para las poblaciones de la especie en Norteamérica y Suramérica, y poca diferenciación genética entre las colonias que, sin embargo, era significativa. Nuestros resultados destacan la necesidad de mejorar la planificación del manejo y la conservación de la especie en Cuba debido a que la combinación de la baja variación genética, el pequeño tamaño de las colonias, la influencia humana y los factores climáticos podrían amenazar su persistencia.

The HIV-1 Tat protein hijacks P-TEFb kinase to activate paused RNA polymerase II (RNAP II) at the viral promoter. Tat binds additional host factors, but it is unclear how they regulate RNAP II elongation. Here, we identify the cytoplasmic ubiquitin ligase UBE2O as critical for Tat transcriptional activity. Tat hijacks UBE2O to ubiquitinate the P-TEFb kinase inhibitor HEXIM1 of the 7SK snRNP, a fraction of which also resides in the cytoplasm bound to P-TEFb. HEXIM1 ubiquitination sequesters it in the cytoplasm and releases P-TEFb from the inhibitory 7SK complex. Free P-TEFb then becomes enriched in chromatin, a process that is also stimulated by treating cells with a CDK9 inhibitor. Finally, we demonstrate that UBE2O is critical for P-TEFb recruitment to the HIV-1 promoter. Together, the data support a unique model of elongation control where non-degradative ubiquitination of nuclear and cytoplasmic 7SK snRNP pools increases P-TEFb levels for transcriptional activation.

In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML.

Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

Conducted by royal commissions, select committees and the newly established inspectorates, early Victorian social investigations elaborated formats and procedures of public inquiry that left an enduring impact on modern, liberal public spheres in the English speaking world and beyond. This article revisits a few features of 19th Century official investigations, highlighting the rather diverse and contradictory effects these fact-seeking ventures had on British democratic culture. I argue that even as government inquiries confirmed and strengthen social gradations as well as hierarchies of knowledge and expertise, they nevertheless allowed the British lower classes to participate in official discourse as knowers, not just sufferers, and opened new possibilities for dissent and contestations. I highlight the manner in which the investigation itself rather than any consequent legislation or policy touched upon the administration of justice either by emulating court procedures or in terms of its epistemic labor. Las investigaciones sociales de principio de la época victoriana dirigidas por comisiones reales, comités selectos y las inspecciones que se estaban creando entonces, elaboraron formatos y procedimientos de investigación pública que dejaron un impacto duradero en las esferas públicas modernas y liberales tanto en el mundo angloparlante como fuera de él. Este artículo revisa algunas características de las investigaciones oficiales del siglo XIX, resaltando los efectos diversos y contradictorios que estas iniciativas de búsqueda de hechos tuvieron en la cultura democrática británica. Se defiende que, a pesar de que las investigaciones gubernamentales confirmaron y reforzaron las escalas sociales y las jerarquías de conocimiento y experiencia, permitieron que las clases bajas británicas participaran en el discurso oficial como conocedores y no sólo víctimas, y abrieron nuevas posibilidades de disensión y lucha. Se destaca la forma en la que las propias investigaciones, más que cualquier legislación o política consiguiente, mencionaron de pasada la administración de justicia, emulando procedimientos judiciales o en su trabajo epistémico. DOWNLOAD THIS PAPER FROM SSRN: https://ssrn.com/abstract=2958131

Anthropogenic activities have resulted in the intensified use of water resources. For example, open pit bitumen extraction by Canada's oil sands operations uses an estimated volume of three barrels of water for every barrel of oil produced. The waste tailings-oil sands process water (OSPW)-are stored in holding ponds, and present an environmental concern as they are comprised of residual hydrocarbons and metals. Following the hypothesis that endogenous OSPW microbial communities have an enhanced tolerance to heavy metals, we tested the capacity of planktonic and biofilm populations from OSPW to withstand metal ion challenges, using Cupriavidus metallidurans, a known metal-resistant organism, for comparison. The toxicity of the metals toward biofilm and planktonic bacterial populations was determined by measuring the minimum biofilm inhibitory concentrations (MBICs) and planktonic minimum inhibitory concentrations (MICs) using the MBEC ™ assay. We observed that the OSPW community and C. metallidurans had similar tolerances to 22 different metals. While thiophillic elements (Te, Ag, Cd, Ni) were found to be most toxic, the OSPW consortia demonstrated higher tolerance to metals reported in tailings ponds (Al, Fe, Mo, Pb). Metal toxicity correlated with a number of physicochemical characteristics of the metals. Parameters reflecting metal-ligand affinities showed fewer and weaker correlations for the community compared to C. metallidurans, suggesting that the OSPW consortia may have developed tolerance mechanisms toward metals present in their environment.

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or metastatic cancers. In this context, the identification of new biomarkers is essential to improve the differential diagnosis between cancer subtypes, to select the most appropriate therapy, and to establish prognostic correlations. Nuclear abnormalities are hallmarks of carcinoma cells and are used as cytological diagnostic criteria of malignancy. Lamins (divided into A- and B-types) are localized in the nuclear matrix comprising nuclear lamina, where they act as scaffolding protein, involved in many nuclear functions, with regulatory effects on the cell cycle and differentiation, senescence and apoptosis. Previous studies have suggested that lamins are involved in tumor development and progression with opposite results concerning their prognostic role. This review provides an overview of lamins expression in lung cancer and the relevance of these findings for disease diagnosis and prognosis. Furthermore, we discuss the link between A-type lamins expression in lung carcinoma cells and nuclear deformability, epithelial to mesenchymal transition, and metastatic potential, and which mechanisms could regulate A-type lamins expression in lung cancer, such as the microRNA miR-9.

This study offers an in-depth examination of the experiences of early childhood educators, focusing on their work with Ethiopian immigrant children and their families. We aim to describe and analyze the teachers’ insider views vis-à-vis the challenges faced by these children and their parents in the Israeli preschool system. Using narrative methodology, the analysis of findings is based upon 20 stories written by 10 early childhood educators. It reveals that for these teachers, the chief struggle is their relationship with the parents of their Ethiopian pupils, one characterized by difficulties, frustrations, and burdens. The engagement with parents of Ethiopian children exhibited a range of possibilities: from the expression of patronizing, hierarchical viewpoints, to a search for ad hoc ways of coping with a persistent cultural gap, to the attainment of genuine, successful partnerships. Lack of sufficient knowledge and understanding of the unique cultural attributes of the Ethiopian community appears to be the basis for the teachers’ view of the parents as lacking faith in them and in the educational system as a whole. In addition, suggestions are made about implications for educational practice and for policies that might assist teachers in ameliorating these challenges via the development of, and professional training in, skills which help coping with the problems and dilemmas unique to the multicultural classroom.

The childhood epileptic encephalopathies (EE's) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1Ftfl or "fitful" mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE's. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1Ftfl mouse model of DNM1 EE. Observations of Dnm1Ftfl/flox mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE.

The HIV-1 protein Rev controls a critical step in viral replication by mediating the nuclear export of unspliced and singly-spliced viral mRNAs. Multiple Rev subunits assemble on the Rev Response Element (RRE), a structured region present in these RNAs, and direct their export through the Crm1 pathway. Rev-RRE assembly occurs via several Rev oligomerization and RNA-binding steps, but how these steps are coordinated to form an export–competent complex is unclear. Here, we report the first crystal structure of a Rev dimer-RRE complex, revealing a dramatic rearrangement of the Rev-dimer upon RRE binding through re-packing of its hydrophobic protein–protein interface. Rev-RNA recognition relies on sequence-specific contacts at the well-characterized IIB site and local RNA architecture at the second site. The structure supports a model in which the RRE utilizes the inherent plasticity of Rev subunit interfaces to guide the formation of a functional complex.

The HIV Rev protein routes viral RNAs containing the Rev Response Element (RRE) through the Crm1 nuclear export pathway to the cytoplasm where viral proteins are expressed and genomic RNA is delivered to assembling virions. The RRE assembles a Rev oligomer that displays nuclear export sequences (NESs) for recognition by the Crm1-RanGTP nuclear receptor complex. Here we provide the first view of an assembled HIV-host nuclear export complex using single-particle electron microscopy. Unexpectedly, Crm1 forms a dimer with an extensive interface that enhances association with Rev-RRE and poises NES binding sites to interact with a Rev oligomer. The interface between Crm1 monomers explains differences between Crm1 orthologs that alter nuclear export and determine cellular tropism for viral replication. The arrangement of the export complex identifies a novel binding surface to possibly target an HIV inhibitor and may point to a broader role for Crm1 dimerization in regulating host gene expression.

Bacterial chemotaxis systems are as diverse as the environments that bacteria inhabit, but how much environmental variation can cells tolerate with a single system? Diversification of a single chemotaxis system could serve as an alternative, or even evolutionary stepping-stone, to switching between multiple systems. We hypothesized that mutations in gene regulation could lead to heritable control of chemotactic diversity. By simulating foraging and colonization of E. coli using a single-cell chemotaxis model, we found that different environments selected for different behaviors. The resulting trade-offs show that populations facing diverse environments would ideally diversify behaviors when time for navigation is limited. We show that advantageous diversity can arise from changes in the distribution of protein levels among individuals, which could occur through mutations in gene regulation. We propose experiments to test our prediction that chemotactic diversity in a clonal population could be a selectable trait that enables adaptation to environmental variability.

Abstract Background MicroRNAs (miRNAs) are well recognized as gene regulators and have been implicated in the regulation of development as well as human diseases. miR-143 is located at a fragile site on chromosome 5 frequently deleted in cancer, and has been reported to be down-regulated in several cancers including colon cancer. Methods To gain insight into the role of miR-143 in colon cancer, we used a microarray-based approach in combination with seed site enrichment analysis to identify miR-143 targets. Results As expected, transcripts down-regulated upon miR-143 overexpression had a significant enrichment of miR-143 seed sites in their 3'UTRs. Here we report the identification of Hexokinase 2 (HK2) as a direct target of miR-143. We show that re-introduction of miR-143 in the colon cancer cell line DLD-1 results in a decreased lactate secretion. Conclusion We have identified and validated HK2 as a miR-143 target. Furthermore, our results indicate that miR-143 mediated down-regulation of HK2 affects glucose metabolism in colon cancer cells. We hypothesize that loss of miR-143-mediated repression of HK2 can promote glucose metabolism in cancer cells, contributing to the shift towards aerobic glycolysis observed in many tumors.

Abstract Background Gestational Diabetes Mellitus (GDM) presents a significant health concern during pregnancy, predisposing individuals to future diabetes. Despite established postpartum diabetes screening guidelines, adherence to follow-up remains inadequate. Aims This study aimed to assess the predictive value of the 50-gram glucose challenge test (GCT) for post-pregnancy diabetes development. Materials and methods A population-based retrospective cohort study was conducted on pregnant women aged 18–45 who underwent GCT screening between November 2007 and July 2017 in a large Israeli community medical organization. Baseline characteristics, GCT results, and diabetes development during follow-up were analyzed using univariate and multivariate Cox regression analyses. Results Among 8,675 women included, 2.4% developed diabetes over a median follow-up of 73.23 months. Elevated GCT results correlated with a higher risk of future diabetes, with a 4% rise in risk per 1 mg/dL increase in glucose above 140 mg/dL. Multivariate analysis revealed a 60-fold rise in the risk of future diabetes in women with GCT results ≥ 200 mg/dL compared to those with GCT

In this study, we identified differences in characteristics and circumstances, main presenting problems, and types of referrals received among young people who were in crisis, at imminent risk of homelessness, or currently homeless. This study draws on data from 11,566 young people who contacted the National Runaway Safeline (NRS) through the National Communication System (NCS), a federal program for young people at risk or experiencing homelessness in the U.S. and those who care for them. Frontline staff collect information directly from young people during crisis intervention engagement through the NRS. We used multinomial logistic regression analyses to predict membership in each of the homelessness risk categories and logistic regression analyses to predict the type of service referrals young people received. Results revealed that young people’s circumstances and presenting problems were associated with homelessness risk category membership, which in turn was linked with the types of service referrals young people received. This study illuminates valuable opportunities for targeting prevention opportunities to the specific needs of young people with varying levels of homelessness risk.

Abstract Background Electronic health records (EHRs) can accelerate documentation and may enhance details of notes, or complicate documentation and introduce errors. Comprehensive assessment of documentation quality requires comparing documentation to what transpires during the clinical encounter itself. We assessed outpatient primary care notes and corresponding recorded encounters to determine accuracy, thoroughness, and several additional key measures of documentation quality. Methods Patients and primary care clinicians across five midwestern primary care clinics of the US Department of Veterans Affairs were recruited into a prospective observational study. Clinical encounters were video-recorded and transcribed verbatim. Using the Physician Documentation Quality Instrument (PDQI-9) added to other measures, reviewers scored quality of the documentation by comparing transcripts to corresponding encounter notes. PDQI-9 items were scored from 1 to 5, with higher scores indicating higher quality. Results Encounters (N = 49) among 11 clinicians were analyzed. Most issues that patients initiated in discussion were omitted from notes, and nearly half of notes referred to information or observations that could not be verified. Four notes lacked concluding assessments and plans; nine lacked information about when patients should return. Except for thoroughness, PDQI-9 items that were assessed achieved quality scores exceeding 4 of 5 points. Conclusions Among outpatient primary care electronic records examined, most issues that patients initiated in discussion were absent from notes, and nearly half of notes referred to information or observations absent from transcripts. EHRs may contribute to certain kinds of errors. Approaches to improving documentation should consider the roles of the EHR, patient, and clinician together.

Abstract The contribution of chronic kidney disease (CKD) towards the risk of developing cardiovascular disease (CVD) is magnified with co-existing type 1 or type 2 diabetes. Lipids are a modifiable risk factor and good lipid management offers improved outcomes for people with diabetic kidney disease (DKD). The primary purpose of this guideline, written by the Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) working group, is to provide practical recommendations on lipid management for members of the multidisciplinary team involved in the care of adults with DKD.

Abstract Background Aortic stenosis (AS) is the most common degenerative valve disease in high income countries. While hemodynamic metrics are commonly used to assess severity of stenosis, they are impacted by loading conditions and stroke volume and are often discordant. Anatomic valve assessments such as aortic valve calcification (AVC) and valve motion (VM) during transthoracic echocardiography (TTE) can offer clues to disease severity. The reliability of these semi-quantitatively assessed anatomic imaging parameters is unknown. Methods This is a retrospective study of semi-quantitative assessment of AVC and valve VM on TTE. TTEs representing a range of AS severities were identified. The degree of calcification of the aortic valve and the degree of restricted VM were assessed in standard fashion. AVC scores and valve motion were assessed by readers with varied training levels blinded to the severity of AS. Correlation and inter-reader reliability between readers were assessed. Results 420 assessments (210 each for AVC and VM) were collected for 35 TTEs. Correlation of AVC for imaging trainees (fellows and students, respectively), ranged from 0.49 (95% CI 0.18–0.70) to 0.62 (95% CI 0.36–0.79) and 0.58 (95% CI 0.30–0.76) to 0.54 (95% CI 0.25–0.74) for VM. Correlation of anatomic assessments between echocardiographer-assigned AVC grades was r = 0.76 (95% CI 0.57–0.87)). The correlation between echocardiographer-assigned assessment of VM was r = 0.73 (95% CI 0.53–0.86), p

We describe a case of a 46-year-old man in Missouri, USA, with newly diagnosed advanced HIV and PCR-confirmed mpox keratitis. The keratitis initially resolved after intravenous tecovirimat and penicillin for suspected ocular syphilis coinfection. Despite a confirmatory negative PCR, he developed relapsed, ipsilateral PCR-positive keratitis and severe ocular mpox requiring corneal transplant.

Chronic disease progression models are available for several highly prevalent conditions. For chronic kidney disease (CKD), the scope of existing progression models is limited to the risk of kidney failure and major cardiovascular (CV) events. The aim of this project was to develop a comprehensive CKD progression model (CKD-PM) that simulates the risk of CKD progression and a broad range of complications in patients with CKD. A series of literature reviews informed the selection of risk factors and identified existing risk equations/algorithms for kidney replacement therapy (KRT), CV events, other CKD-related complications, and mortality. Risk equations and transition probabilities were primarily sourced from publications produced by large US and international CKD registries. A patient-level, state-transition model was developed with health states defined by the Kidney Disease Improving Global Outcomes categories. Model validation was performed by comparing predicted outcomes with observed outcomes in the source cohorts used in model development (internal validation) and other cohorts (external validation). The CKD-PM demonstrated satisfactory modeling properties. Accurate prediction of all-cause and CV mortality was achieved without calibration, while prediction of CV events through CKD-specific equations required implementation of a calibration factor to balance time-dependent versus baseline risk. Predicted annual changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio were acceptable in comparison to external values. A flexible eGFR threshold for KRT equations enabled accurate prediction of these events. This CKD-PM demonstrated reliable modeling properties. Both internal and external validation revealed robust outcomes.

Abstract Background In a previously reported Phase I trial, we observed therapy‐associated declines in circulating myeloid‐derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs. Methods We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879). Results In murine models, WBM treatment significantly suppressed tumour growth with a reduction in both the number and function of MDSCs, which in turn promoted antitumour immune responses mediated by T cells and natural killer (NK) cells. In patients, after consumption of WBM tablets for 3 months, we observed a decline in circulating polymorphonuclear MDSCs (PMN‐MDSCs), along with an increase in cytotoxic CD8+ T and NK cells. Furthermore, single immune cell profiling of peripheral blood from WBM‐treated patients showed suppressed STAT3/IRF1 and TGFβ signalling in circulating PMN‐MDSCs. Subclusters of PMN‐MDSCs presented transcriptional profiles associated with responsiveness to fungi, neutrophil chemotaxis, leukocyte aggregation, and regulation of inflammatory response. Finally, in mouse models of PCa, we found that WBM consumption enhanced the anticancer activity of anti‐PD‐1 antibodies, indicating that WBM may be used as an adjuvant therapy with immune checkpoint inhibitors. Conclusion Our results from PCa murine models and patients provide mechanistic insights into the immunomodulatory effects of WBM and provide a scientific foundation for WBM as a nutraceutical intervention to delay or prevent PCa progression. Highlights White button mushroom (WBM) treatment resulted in a reduction in pro‐tumoural MDSCs, notably polymorphonuclear MDSCs (PMN‐MDSCs), along with activation of anti‐tumoural T and NK cells. Human single immune cell gene expression profiling shed light on the molecular alterations induced by WBM, specifically on PMN‐MDSCs. A proof‐of‐concept study combining WBM with PD‐1 blockade in murine models revealed an additive effect on tumour regression and survival outcomes, highlighting the clinical relevance of WBM in cancer management.

More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.

Abstract The corrosion performance of 6xxx series Al alloys has been found to depend on small changes in composition and microstructure. The corrosion behaviors of three aluminum alloys, AA6111, AA6451, and AA6016, were investigated. AA6111, containing primarily α (Al15 (Fe,Mn)3Si2) intermetallic particles (IMPs), and AA6016, containing primarily β (Al8Fe2Si) IMPs, exhibited the best and the worst overall corrosion performances, respectively, as indicated by the extent of corrosion in exposure tests. However, this ranking was not predicted by the standard interpretation of potentiodynamic polarization curves measured on the alloys. The corrosion susceptibilities of the three alloys were further investigated by evaluating the electrochemical behavior of the component phases separately. Bulk analogs of the component phases were fabricated using standard alloy casting techniques. The fabricated bulk analogs of α and β IMPs, as well as the three alloy matrix phases, were tested using either macrocell or microcell testing. An explanation for the alloy performances was developed by combining the behavior of the component phases.

Introduction The prevalence of non-diabetic hyperglycemia (NDH) and type 2 diabetes mellitus (T2DM) is increasing. While T2DM is recognised to be associated with multimorbidity and early mortality, people with NDH are frequently thought to be devoid of such complications, potentially exposing individuals with NDH to suboptimal care. We therefore used the Discover London Secure Data Environment (SDE) dataset to appreciate the relationship of NDH/T2DM with multimorbidity, healthcare usage, and clinical outcomes.Research design and methods The dataset was retrospectively analysed between January 1, 2015 and December 31, 2020 to understand the relationship between NDH/T2DM and multimorbidity primary/secondary healthcare usage and clinical outcomes. This was compared with a cohort of individuals with thyroid disease but no NDH/T2DM.Results The dataset identified 152,384 and 124,190 adults with NDH and T2DM compared with 11,626 individuals with thyroid disease (control group). Individuals with NDH and individuals with T2DM had a high burden of disease, with only 13.1% of individuals with either NDH or T2DM not found to be suffering from at least one of the disease states of interest. The three most common comorbidities experienced by individuals with NDH were hypertension (41.4%), hypercholesterolemia (37.5%), and obesity (29.8%) compared with retinopathy (68.7%), hypertension (59.4%), and obesity (45.8%) in individuals with T2DM. Comparatively, the most common comorbidities in the control group were depression (30.8%), hypercholesterolemia (24.4%), and hypertension (17.1%). 28 (control group), 12 (NDH), and 16 (T2DM) primary care contacts per individual per year were identified, with 27,881, 282,371, and 314,880 inpatient admissions for the control, NDH, and T2DM cohorts, respectively. Prescription of drugs used to treat T2DM in individuals with NDH and T2DM was 27,772 (18.2%) and 109,361 (88.1%), respectively, accounting for approximately one in five individuals with NDH developing T2DM.Conclusion Both NDH and T2DM were associated with significant multimorbidity alongside primary and secondary care utilisation. Given the morbidity highlighted with NDH, we highlight the need for earlier detection of NDH, recognition of multimorbidity associated with both NDH and T2DM, as well as the need for the further implementation of interventions to prevent progression to T2DM/multimorbidity.

IntroductionLow grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases.MethodsNCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings.ResultsFour patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%.ConclusionPIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.