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PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2). CONCLUSIONS: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Abstract Background Maternal and newborn mortality and morbidity in conflict-affected northeastern areas of Nigeria, such as Yobe State, are disproportionately higher than those in the rest of the country. There is limited evidence on the factors that influence maternal and newborn health (MNH) policymaking and implementation in this region, particularly with respect to the impact of conflict and context-specific issues. This study explores the political, economic and health system factors that drive the prioritization of MNH policies in Yobe State. The aim of this study was to elucidate the conflict-related factors influencing MNH outcomes, which could inform targeted interventions to improve MNH. Methods The study is a descriptive case study that relies on multiple data sources and is guided by the Health Policy Analysis Triangle. We reviewed national and subnational research, technical reports and policies related to reproductive health and the MNH in Nigeria since 2010. Following stakeholder mapping, we identified and invited prospective participants in the MNH policymaking space. Nineteen stakeholders from the government, civil society and nongovernmental organizations, donor agencies, and public and private sector health providers in Yobe State participated in the semistructured in-depth interviews. Data were collected from November 2022 through January 2023 and were thematically analysed via Dedoose software. Findings MNH services in Yobe State have received considerable attention through initiatives such as the National Midwifery Service Scheme, free MNH services, training of midwives with deployment to rural areas, and health facility renovations. The effective implementation of MNH services and policies faces challenges due to insufficient funding, and sustainability is hampered by changes in governance and political transitions. The Boko Haram insurgency exacerbated the humanitarian crisis in Yobe State and disrupted MNH services due to the displacement of populations and the decline in the number of health workers. Additionally, sociocultural and religious beliefs hinder timely access to and utilization of MNH services. Although policies and guidelines for MNH services exist in the state, they are inadequately disseminated to health providers, which affects their effective implementation across facilities. Collaboration and intersectoral coordination platforms exist, but competition and rivalries among unions, political entities, and implementing agencies sometimes impede progress. Conclusion Enhancing MNH services in Yobe state requires increased commitment for funding through the Northeast Development Commission rehabilitation fund; strengthening the health workforce, safety and retention plan; promoting gender inclusivity within the health sector; and addressing sociocultural barriers to women’s health-seeking behaviors. Concrete, time-bound plans for policy dissemination are necessary to ensure effective service implementation.

Abstract Background To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non‐small cell lung cancer (NSCLC) in real‐world settings. Methods We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first‐line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow‐up data were obtained using medical records from diagnosis to March 1, 2018. Results Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3‐year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3‐year progression‐free survival (PFS) and disease‐free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29–0.81]), PFS (0.62 [0.39–0.96]), and DFS (0.62 [0.39–0.97]) versus surgery alone. Conclusions Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.

Time-lapse microscopy is the only method that can directly capture the dynamics and heterogeneity of fundamental cellular processes at the single-cell level with high temporal resolution. Successful application of single-cell time-lapse microscopy requires automated segmentation and tracking of hundreds of individual cells over several time points. However, segmentation and tracking of single cells remain challenging for the analysis of time-lapse microscopy images, in particular for widely available and non-toxic imaging modalities such as phase-contrast imaging. This work presents a versatile and trainable deep-learning model, termed DeepSea, that allows for both segmentation and tracking of single cells in sequences of phase-contrast live microscopy images with higher precision than existing models. We showcase the application of DeepSea by analyzing cell size regulation in embryonic stem cells.

Abstract Background Maternal and neonatal mortality remains a major concern in the Democratic Republic of Congo (DRC), and the country’s protracted crisis context exacerbates the problem. This political economy analysis examines the maternal and newborn health (MNH) prioritization in the DRC, focussing specifically on the conflict-affected regions of North and South Kivu. The aim is to understand the factors that facilitate or hinder the prioritization of MNH policy development and implementation by the Congolese government and other key actors at national level and in the provinces of North and South Kivu. Methods Using a health policy triangle framework, data collection consisted of in-depth interviews with key actors at different levels of the health system, combined with a desk review. Qualitative data were analysed using inductive and then deductive approaches, exploring the content, process, actor dynamics, contextual factors and gender-related factors influencing MNH policy development and implementation. Results The study highlighted the challenges of prioritizing policies in the face of competing health and security emergencies, limited resources and governance issues. The universal health coverage policy seems to offer hope for improving access to MNH services. Results also revealed the importance of international partnerships and global financial mechanisms in the development of MNH strategies. They reveal huge gender disparities in the MNH sector at all levels, and the need to consider cultural factors that can positively or negatively impact the success of MNH policies in crisis zones. Conclusions MNH is a high priority in DRC, yet implementation faces hurdles due to financial constraints, political influences, conflicts and gender disparities. Addressing these challenges requires tailored community-based strategies, political engagement, support for health personnel and empowerment of women in crisis areas for better MNH outcomes.

BackgroundMaternal and newborn mortality rates are disproportionately high in crisis and conflict-affected countries. This study aims to understand factors influencing how MNH in humanitarian and fragile settings (HFS) is prioritized on the global health agenda during the Sustainable Development Goal (SDG) era. This includes examining the policies and processes driving agenda setting and decision-making, as well as the perceptions of global actors. It further reflects on the role of global milestones, reports, convenings, and high-level champions, based on the premise that global prioritization leads to increased attention and resource allocation, ultimately contributing to improved outcomes for mothers and newborns in crisis-affected areas.MethodsA qualitative study conducted from April 2022 to June 2023, employing a desk review and 23 semi-structured key informant interviews with global actors from donor agencies, implementing organizations, research institutes, United Nations agencies, professional associations, and coalitions, predominantly based in the Global North. Data were analyzed using inductive thematic analysis and the research was guided by the Walt and Gibson Health Policy Triangle framework.ResultsParticipants believe that global agenda-setting and investment decisions for MNH are primarily driven by UN agencies, donors, and implementing organizations at the global level. Although the Millennium Development Goal era successfully prioritized MNH, this focus has diminished during the SDGs, especially for HFS. Identified barriers include the complexity of reducing mortality rates in these contexts, limited political will, MNH investment fatigue, and a preference for quick wins. Fragmentation between humanitarian and development sectors and unclear mandates in protracted crises also hinder progress. Without enhanced global advocacy, accountability, and targeted investments in HFS, respondents deem global MNH targets unattainable.ConclusionsWhile waning donor interest and the siloing of HFS in global MNH decision-making pose challenges, targeted actions to address these barriers may include designating quotas for humanitarian actors in global MNH convenings, developing shared messages that convey common interests, and adopting an equity lens. Prioritizing MNH in HFS on the global agenda demands sustained commitment to ensure these settings are not an afterthought through dedicated advocacy and accountability, high-level political engagements, global milestones, and by leveraging opportunities to capture mainstream interest. Failing to shift global priorities will result in continued stagnation and worsening MNH outcomes across HFS.

Background and purpose: Spread-through air space (STAS) is an unfavorable factor in patients with lung cancer treated with surgery. However, the relationship between the treatment outcomes of stereotactic body radiation therapy (SBRT) for lung cancer and STAS has not been adequately investigated. This study aimed to evaluate the impact of tumor cells in the air space (TCIAS), which show a STAS burden, on treatment outcomes in patients with early-stage lung cancer treated with SBRT. Materials and methods: Data of patients who underwent SBRT for early-stage lung cancer treated with SBRT were retrospectively reviewed. The influence of the TCIAS status on local progression-free (LPF), regional failure-free (RFF), distant failure-free (DFF), progression-free survival (PFS), and overall survival (OS) rates was assessed using univariate and multivariate analyses. Results: Overall, 68 patients were included. The median follow-up time was 24.3 months. For patients positive/negative for TCIAS, the 2-year LPF, RFF, DFF, PFS, and OS rates were 81.4 %/91.1 %, 73.7 %/96.2 %, 55.9 %/75.3 %, 55.0 %/84.6 %, and 67.8 %/92.2 %, respectively. In the multivariate analysis, TCIAS-positive was a significant unfavorable factor for RFF (hazard ratio [HR]: 4.10; 95 % confidence interval [CI]: 1.04–16.16, p = 0.04), DFF (HR: 2.61, 95 % CI: 1.03–6.57, p = 0.04), and PFS (HR: 2.36; 95 % CI: 1.05–5.30, p = 0.04). By contrast, TCIAS-positive was not a significant risk factor for LPF and OS. Conclusion: TCIAS-positive is an unfavorable factor for regional and distant failure after SBRT. TCIAS status may be useful in predicting the treatment outcome of SBRT for early-stage lung cancer.

Summary:. Autoimmune syndrome induced by adjuvants (ASIA) is an uncommon clinical condition reported by Shoenfeld et al. Although this syndrome is not scientifically validated, numerous reports on it have been published, and the manifestations are postulated to be diverse, including generalized symptoms such as chronic fatigue, myalgia, arthralgia, or dry mouth, induced by exogenous substances, specifically adjuvants, which can encompass vaccines, organisms, and silicone. Concurrently, adult-onset Still disease (AOSD) is also an infrequent ailment, characterized by spiking fever, arthritis, skin rash, lymphadenopathy, and serositis. Although the precise pathogenesis remains incompletely understood, some case reports suggest that ASIA may be at the root of AOSD development with the same instigator. In this context, we present three cases of patients diagnosed with AOSD, which possibly could be considered an association with ASIA, years after undergoing breast reconstruction with silicone breast implants. In one case, the patient solely received medical treatment due to her refusal to have the implant removed, resulting in multiple flares and severe complications related to glucocorticoid therapy. Conversely, in the other two cases, a combination of immunosuppressive therapy and silicone breast implant explantation led to the complete resolution of clinical symptoms. To the best of our knowledge, there are only 10 documented case reports of AOSD associated with silicone breast implants insertion. We believe this report serves as a complementary addition to prior research and offers further insights into the ongoing debate about whether explantation should be carried out early in the clinical course or not.

Abstract The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)−8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.

Abstract Background This study aimed to devise a simple assessment system for bone metastases (BMs) from lung cancer (LC). Methods A total of 368 LC patients with BMs who underwent radiotherapy (RT) were retrospectively reviewed. Prognostic factors were evaluated using multivariate analysis, and a scoring system based on regression coefficients was devised. Results The median follow‐up time for survival was 4.3 months, and the 0.5‐year overall survival (OS) rate was 44.7%. In the multivariate analysis, the significant prognostic factors were performance status (PS), metastases to internal organs, and post‐RT molecular‐targeting therapies (MTs) (tyrosine kinase inhibitors, and/or immune checkpoint inhibitors). A scoring system aggregating points assigned to each risk factor was created (2 points; non‐administration of post‐RT MTs, 1 point; PS ≥3 and metastases to internal organs). The median OSs were 25.0 months, 12.8 months, and 2.5 months in patients with a total score of 0 (n = 22), 1–2 (n = 124), and 3–4 (n = 221), respectively (p

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8–5.3), 13.3 months (95% CI: 9.6–16.5), and 27.3% (95% CI: 18.3–37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Abstract Background The role of catheter-based imaging in peripheral interventions for lower extremity artery disease (LEAD) has increased with percutaneous interventions. To clarify the relation between intravascular ultrasound (IVUS) information and procedure selection strategy for endovascular treatment therapy (EVT) of the femoropopliteal artery in the real-world clinical settings wherein new endovascular technologies (NETs), including drug-coated balloon (DCB), drug-eluting stent (DES), and covered stent-graft (CS). Our retrospective multicenter analysis examined symptomatic 970 patients treated by EVT for de novo femoropopliteal lesions with IVUS guidance. The decision tree analysis was performed retrospectively to determine the association of IVUS and angiography parameters with the strategy selection of endovascular procedures. We divided the study population according to the developed tree, and identified the most popular strategy selection in each subgroup. We finally examined whether the restenosis risk would be different among respective subgroups of the tree. Results During the study periods, plain old balloon angioplasty, DCB, and bare nitinol stent were most frequently selected (25.3%, 23.9%, and 23.8%, respectively). The drug-eluting stent (DES), covered stent (CS), and spot stent strategies were used in 7.3%, 11.5%, and 8.1%. NETs had the lowest restenosis risk in the overall population. The decision tree had a depth of six branches and divided the patients into 11 subgroups by IVUS and angiography parameters. The restenosis rate was similarly low among these 11 subgroups when the most popular NET in each subgroup was selected (P = 0.94). Conclusions The use of IVUS data along with angiography data would standardize the selection of endovascular procedures and can improve patency outcomes if NETs are used properly.

Electrophotography is a digital, on-demand, dry, and page printing technique that operates based on toner particles of electronic materials using an electrostatic force and generates an electrical circuit via distribution of the toner particles. We developed a 10 μm linewidth resolution with various electronic materials, including conductors, semiconductors, and insulators, without any chemical pretreatments on the substrate films, while a 5 μm resolution was also possible for limited materials. The electrical resistivity of the printed Ag–Ni after an intense pulse light sintering was comparable to that of commercial indium tin oxide transparent films.