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INTRODUCTION: Consultation audio recordings improve patient decision-making but are underutilized. Patient-administered recording apps on mobile devices may increase access, but implementation has not been evaluated. METHODS: We conducted a single-arm study delivering education, coaching, and reminders for patients to record their appointment using a mobile recording app. Patients had progressive, advanced prostate cancer and an upcoming appointment where the option of docetaxel would be discussed. We used the RE-AIM framework for evaluation. Reach was the proportion of patients who participated. Effectiveness was change in informed decision-making pre- vs. post-appointment. We used a questionnaire evaluating patient knowledge about docetaxel (0%-100% correct) and the decisional conflict scale-informed subscale (0 = feels extremely uninformed to 100 = extremely informed) to compare means using the paired t-test. Adoption was the proportion of providers agreeing to be recorded. Implementation was coordinator adherence to intervention delivery. We conducted semistructured interviews with patients, caregivers, and providers to assess barriers, facilitators, and suggestions for recording implementation. RESULTS: Of 102 patients approached, 50 (49%) patients participated. Mean age was 75 years, 38 (76%) were Non-Hispanic White, and 43 (86%) had telehealth appointments. Knowledge increased from 44.7% to 49.5% (p = 0.019), particularly about palliative care (42% answering correctly to 60%, p = 0.035). Decisional conflict-informed subscale increased from 48.9 to 70.9 (p

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Benign familial pemphigus (BFP) Gougereau–Haley–Haley is a rare autosomal dominant genodermatosis caused by mutations of the ATP2C1 gene responsible for the function of calcium-dependent ATPases regulating calcium sequestration in the Golgi apparatus. The article provides an overview of modern methods of treatment of various groups of drugs, including drugs for topical treatment (topical glucocorticosteroids, calcipotriol, combined drugs), systemic drugs (glucocorticosteroids, apremilast), injection techniques (intradermal administration of botulinum toxin) currently used. Taking into account the lack of clinical recommendations for the treatment of patients with benign familial pemphigus, to evaluate the effectiveness of treatment methods described in modern publications. The observational study included 4 patients with clinically and histologically verified benign familial pemphigus, and described the results of therapy using techniques using intradermal administration of botulinum toxin A (3 patients) and apremilast (1 patient). The results of observations of patients with BFP and photo documentation are presented. BFP is a rare dermatosis, the description of treatment methods for which is scarce in various publications, large-scale randomized studies are needed to determine the comparative effectiveness and safety of various drugs and physiotherapy techniques for the treatment of this disease. The material presented in the article will help practitioners to offer patients possible methods of BFP therapy and take into account the experience of colleagues.

Introduction Persistent organic pollutants (POPs) are a serious and global threat to human health owing to their persistence, prevalence, and bioaccumulative nature. Exposure to POPs is associated with various health [...], BACKGROUND: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship. OBJECTIVE: This study aimed to explore the association between early life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life. METHODS: This study used metagenomics, nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and MS-based metabolomics. RESULTS: TCDF-exposed mice exhibited lower abundances of A. muciniphila, lower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), as well as lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), findings suggestive of disruption in the gut microbiome community structure and function. Importantly, microbial and metabolic phenotypes associated with early life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, and they were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphila, supporting suppressed activity along the ILA pathway. CONCLUSIONS: These data obtained in a mouse model point to the complex effects of POPs on the host and microbiota, providing strong evidence that early life, short-term, and self-limiting POP exposure can adversely impact the microbiome, with effects persisting into later life with associated health implications. https://doi.org/10.1289/EHP13356

RELEVANCE. Despite the development of modern diagnostic methods, osteosynthesis instruments and rehabilitation, surgical management of distal tibia fractures remains a great problem due to the high complication rate leading to permanent disability, such as problems with soft tissue healing, infectious complications, post-traumatic arthrosis of the ankle joint. These complications are associated with the high incidence of high-energy injuries, soft-tissue envelope features, and the wide range of movements in the ankle joint. At the same time, in the treatment for comminuted intra-articular pilon fractures, there is no clearly defined operation algorithm: choice of access, reduction and fixation techniques. Recently, when planning osteosynthesis, additive technologies have become increasingly widespread, in particular, 3D printing of full-size fracture prototypes. AIM OF STUDY. To analyze preoperative planning methods of osteosynthesis in pilon fractures and evaluate 3D-printing for the improvement of surgical treatment of pilon fractures. MATERIAL AND METHODS. The literature search was carried out in the databases of medical publications: PubMed, eLibrary, Cyberleninka. The search was performed using the following terms: pilon fractures, osteosynthesis, preoperative planning, 3D-printing, 3D-model, and the corresponding terms in Russian. RESULTS. According to various authors, the use of 3D printing in preoperative planning improves the parameters of operative duration, reduction quality, functional outcome, intraoperative blood loss, and reduces the number of complications. CONCLUSIONS. Evaluation of the long-term results of using 3D printing in preoperative planning for osteosynthesis in pilon fractures is ongoing. But even now we can draw conclusions about the prospects of the method and recommend it for widespread use in the routine practice of the orthopedic traumatologist.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a real-world cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent real world studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p

BACKGROUND: In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. METHODS: This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting. FINDINGS: Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65-75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66-76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3-13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2-8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40-0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45-0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42-0·63), and EQ-5D-5L utility score (0·65, 0·54-0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. INTERPRETATION: [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. FUNDING: Advanced Accelerator Applications (Novartis).

A myriad of organ-specific complications have been observed with COVID-19. While racial/ethnic minorities have been disproportionately burdened by this disease, our understanding of the unique risk factors for complications among a diverse population of cancer patients remains limited. This is a multi-institutional, multi-ethnic cohort study evaluating COVID-19 complications among cancer patients. Patients with an invasive cancer diagnosis and confirmed SARS-CoV-2 infection were identified from March to November 2020. Demographic and clinical data were obtained and a multivariate logistic regression was employed to evaluate the impact of demographic and clinical factors on COVID-19 complications. The study endpoints were evaluated independently and included any complication, sepsis, pulmonary complications and cardiac complications. A total of 303 patients were evaluated, of whom 48% were male, 79% had solid tumors, and 42% were Hispanic/Latinx (Hispanic). Malignant hematologic cancers were associated with a higher risk of sepsis (OR 3.93 (95% CI 1.58-9.81)). Male patients had a higher risk of sepsis (OR 4.42 (95% CI 1.63-11.96)) and cardiac complications (OR 2.02 (95% CI 1.05-3.89)). Hispanic patients had a higher odds of any complication (OR 2.31 (95% CI 1.18-4.51)) and other race was associated with a higher odds of cardiac complications (OR 2.41 (95% CI 1.01-5.73)). Clinically, fever, cough, and ≥2 co-morbidities were independently significantly associated with any complication. This analysis evaluated covariates that can significantly predict a myriad of complications among a multi-ethnic cohort of cancer patients. The conclusions drawn from this analysis elucidate a mechanistic understanding of differential illness severity from COVID-19.

e17010 Background: Approximately 12% of patients (pts) with metastatic PCa (mPCa) identified by conventional imaging harbor DDRv. The increased use of PSMA PET has identified a group of pts with extra-prostatic PCa which is not apparent on conventional imaging and for whom the frequency of germline DDRv testing remains unknown. Methods: A single-institution retrospective analysis of patients with PCa detected by PSMA PET who had also undergone germline genetic testing was undertaken. Data collected included PSA level at time of PSMA PET imaging, stage/Gleason score at diagnosis (dx), rationale for germline testing, castration status, and whether the metastatic disease identified on PSMA PET represented de novo or recurrent mPCa. Germline sequencing results were evaluated for 16 DNA damage repair genes: ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, GEN1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, and RAD51D. The frequency of DDRv was evaluated in groups defined by PSMA imaging results: localized (N0M0), Node-Positive (N+M0), metastatic (M+) PCa. Results: Of 795 PCa pts who underwent germline testing and 2101 PCa pts who underwent PSMA PET imaging, 386 had undergone both, and constitute the study cohort. In the study cohort the distribution of PCa extent identified by PSMA PET was: 81/386 (21.0%) N0M0; 76/386 (19.7%) N+M0; 229/386 (59.3%) M+. There were no statistically significant differences in the prevalence of DDRv with regards to age, Gleason score at dx, PSA at time of imaging, castration status at time of imaging, rationale for germline testing, or if metastatic, whether de novo or recurrent. The distribution of DDRv is shown in the table. There were no statistically significant differences between groups. Conclusions: The overall frequency of pathogenic germline DDRv in PCa pts who had undergone PSMA PET imaging was 4.66%, considerably lower than what has been reported in men with mPCa detected with conventional imaging. The presence or absence of extra-prostatic PCa detected by PSMA PET imaging did not appear to affect the frequency of DDRv. Validation of these findings in other cohorts will be important to guide recommendations for germline genetic testing in the growing group of PCa pts undergoing PSMA PET imaging. [Table: see text]

Introduction. The article studies patent activity in the regions of Russia. The relevance of the research in this area is determined by the importance of the innovation component in economic growth, as well as by the established targets in the Concept of Technological Development of the Russian Federation for the period up to 2030. The aim of the study is to identify possible types and directions of patent policy for different groups of Russian regions on the basis of patent activity factors. Materials and Methods. The empirical material for the analysis includes data from the World Intellectual Property Organization (WIPO) and the Federal State Statistics Service (FSSS) for 2012‒2021. We use linear regression to identify the key factors affecting the patent activity of the regions. The method of hierarchical clustering allowed us to identify groups of regions according to their patent activity. Results. The linear regression showed the statistically significant dependence of regional patent activity on I-activity level of organizations, the number of active fixed broadband Internet subscribers per 100 population and the average of internal costs for research and development per 1 organization in the region. The hierarchical clustering distinguished 5 clusters of regions: “The Leader”, “Innovation centers”, “Regions of high manufacturability”, “Old R&D regions” and “Regions-outsiders”. The authors also formulate definitions of the regional patent policy and the national patent policy and present typologies of state patent policy. Discussions and Conclusions. Based on empirical and theoretical analysis, recommendations on further directions for the development of active patent policies were given to groups of regions. The results of the study can be applied in the development and implementation of scientific and technological regional development strategies, and will also be useful to specialists and government officials involved in regulating patent activity in the regions.

The paper reports on the research into the immunotherapeutic properties of a conjugate based on BCG antigens with betulonic acid after experimental infection of guinea pigs with Mycobacterium scrofulaceum culture, belonging to nontuberculosis mycobacteria type II according to the Runyon classification. Fifteen guinea pigs were used for the experimental purposes, divided into 3 groups. Mycobacterium scrofulaceum was subcutaneously injected into animals of Groups 1 and 2 (n = 10) at a dose of 5 mg. Fourteen days later, a conjugate based on BCG antigens with betulonic acid was subcutaneously injected into animals of Group 2 (n = 5) at a dose of 500 µg/mL of protein. Five intact animals were used as controls. During the experiment, neutrophil bactericidal activity was assessed, and histopathological examination of inguinal lymph nodes was done. The experiment showed that the inoculation of Mycobacterium scrofulaceum into guinea pigs activates cationic proteins and neutrophil myeloperoxidase, and on experiment day 42 (preceded by mycobacteria withdrawal from the body) their concentration reduced to the level of the control group. The vaccine administration induced a more active intracellular phagocyte metabolism during the entire observation period, which resulted in the elimination of nontuberculosis mycobacteria in animals as early as day 7 after treatment with the conjugate. The elimination was confirmed by the absence of mycobacterial antigen in blood smears tested in indirect immunofluorescence, as well as by histopathological changes in inguinal lymph nodes demonstrated as a reduction of germinal centers within lymphoid follicles.

ABSTRACT Introduction Consultation audio recordings improve patient decision‐making but are underutilized. Patient‐administered recording apps on mobile devices may increase access, but implementation has not been evaluated. Methods We conducted a single‐arm study delivering education, coaching, and reminders for patients to record their appointment using a mobile recording app. Patients had progressive, advanced prostate cancer and an upcoming appointment where the option of docetaxel would be discussed. We used the RE‐AIM framework for evaluation. Reach was the proportion of patients who participated. Effectiveness was change in informed decision‐making pre‐ vs. post‐appointment. We used a questionnaire evaluating patient knowledge about docetaxel (0%–100% correct) and the decisional conflict scale‐informed subscale (0 = feels extremely uninformed to 100 = extremely informed) to compare means using the paired t‐test. Adoption was the proportion of providers agreeing to be recorded. Implementation was coordinator adherence to intervention delivery. We conducted semistructured interviews with patients, caregivers, and providers to assess barriers, facilitators, and suggestions for recording implementation. Results Of 102 patients approached, 50 (49%) patients participated. Mean age was 75 years, 38 (76%) were Non‐Hispanic White, and 43 (86%) had telehealth appointments. Knowledge increased from 44.7% to 49.5% (p = 0.019), particularly about palliative care (42% answering correctly to 60%, p = 0.035). Decisional conflict‐informed subscale increased from 48.9 to 70.9 (p

This paper presents new records of six species of moths and butterflies from Kunashir Island. We report on the first records of Nymphalis (Kaniska) canace (Linnaeus, 1763), Araschnia levana (Linnaeus, 1758) (Nymphalidae), Archiearis parthenias (Linnaeus, 1761) (Geometridae), Bastilla maturata (Walker, 1858) (Erebidae), Xylena (Lithomoia) solidaginis (Hübner, 1803), and Orthosia aoyamensis (Matsumura, 1926) (Noctuidae) from Kunashir Island.

Increasing wildfire and declining snowpacks in mountain regions threaten water availability. We combine satellite-based fire detections with snow seasonality classifications to examine fire activity in California's seasonal and ephemeral snow zones. We find a nearly tenfold increase in fire activity during 2020–2021 versus 2001–2019. Accumulation season broadband snow albedo declined 25%–71% at two burned sites (2021 and 2022) according to in-situ data relative to un-burned conditions, with greater declines associated with increased burn severity. By enhancing snowpack susceptibility to melt, both decreased snow albedo and canopy drove midwinter melt during a multi-week dry spell in 2022. Despite similar meteorological conditions in December–February 2013 and 2022–linked to persistent high pressure weather regimes–minimal melt occurred in 2013. Post-fire snowpack differences are confirmed with satellite measurements. With growing geographical overlap between wildfire and snow, our findings suggest California's snowpack is increasingly vulnerable to the compounding effects of dry spells and wildfire.

BackgroundLimited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.MethodsThis is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.Results1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.ConclusionsUsing one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.FundingThis study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.Clinical trial numberCCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

BackgroundEnfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking.MethodsWe retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models.ResultsAmong 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics.ConclusionIn this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

BackgroundEarly progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.Patients and methodsWe performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.ResultsWe included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.ConclusionAmong patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.