Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center.

PURPOSE: Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. METHODS: Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. RESULTS: Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). CONCLUSION: An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

The Role of Vasculature and Angiogenic Strategies in Bone Regeneration.

Bone regeneration is a complex process that involves various growth factors, cell types, and extracellular matrix components. A crucial aspect of this process is the formation of a vascular network, which provides essential nutrients and oxygen and promotes osteogenesis by interacting with bone tissue. This review provides a comprehensive discussion of the critical role of vasculature in bone regeneration and the applications of angiogenic strategies, from conventional to cutting-edge methodologies. Recent research has shifted towards innovative bone tissue engineering strategies that integrate vascularized bone complexes, recognizing the significant role of vasculature in bone regeneration. The article begins by examining the role of angiogenesis in bone regeneration. It then introduces various in vitro and in vivo applications that have achieved accelerated bone regeneration through angiogenesis to highlight recent advances in bone tissue engineering. This review also identifies remaining challenges and outlines future directions for research in vascularized bone regeneration.

Human epidermal growth factor receptor-2 (HER2) expression in FIGO3 high-grade endometrial endometrioid carcinoma: Clinicopathologic characteristics and future directions.

OBJECTIVES: To study the expression of HER2 in high-grade FIGO3 endometrial endometroid carcinoma (EEC) and to correlate our findings with the clinicopathologic characteristics of this tumor. METHODS: HER2 expression by immunohistochemistry (IHC) was performed on 10% formalin-fixed paraffin embedded tissue on cases diagnosed as FIGO3 EEC. HER2 expression was interpreted as negative (0), low (1+ and 2+) or positive (3+) using similar criteria as in the breast. HER2 amplification by Fluorescence in situ hybridization (FISH) was performed on cases interpreted as 2+ and 3+ by IHC. RESULTS: One hundred and forty-three FIGO3 EEC were identified. Of these, 70 (49%) cases were HER2 negative (IHC 0), and 73 (51%) cases expressed/amplified HER2 by IHC and/or FISH. Of the 73 cases expressing or amplifying HER2, 59 cases were IHC 1+, 12 cases were IHC 2+, and 2 cases were IHC 3+. FISH testing was performed in 12 cases. Only one of the two HER2 IHC 3+ cases showed HER2 gene amplification by FISH and the other 11 cases were not amplified. The 5-year overall survival (OS) rate for HER2 IHC 1+ cases was 92.20% (95% CI: 83.97-100.00), and the 5-year OS rate for HER2 IHC 2+/3+ cases was 89.50% (95% CI: 56.41-100.00). CONCLUSION: Our findings indicate that about one half of FIGO3 EEC variably expresses HER2 and with the emerging concept of "HER2 low", anti-HER2 agents may be explored as potential therapeutic options in these patients, for possible survival benefits.

Engineering of Cell Derived-Nanovesicle as an Alternative to Exosome Therapy.

BACKGROUND: Exosomes, nano-sized vesicles ranging between 30 and 150 nm secreted by human cells, play a pivotal role in long-range intercellular communication and have attracted significant attention in the field of regenerative medicine. Nevertheless, their limited productivity and cost-effectiveness pose challenges for clinical applications. These issues have recently been addressed by cell-derived nanovesicles (CDNs), which are physically synthesized exosome-mimetic nanovesicles from parent cells, as a promising alternative to exosomes. CDNs exhibit structural, physical, and biological properties similar to exosomes, containing intracellular protein and genetic components encapsulated by the cell plasma membrane. These characteristics allow CDNs to be used as regenerative medicine and therapeutics on their own, or as a drug delivery system. METHODS: The paper reviews diverse methods for CDN synthesis, current analysis techniques, and presents engineering strategies to improve lesion targeting efficiency and/or therapeutic efficacy. RESULTS: CDNs, with their properties similar to those of exosomes, offer a cost-effective and highly productive alternative due to their non-living biomaterial nature, nano-size, and readiness for use, allowing them to overcome several limitations of conventional cell therapy methods. CONCLUSION: Ongoing research and enhancement of CDNs engineering, along with comprehensive safety assessments and stability analysis, exhibit vast potential to advance regenerative medicine by enabling the development of efficient therapeutic interventions.

Nanocrystalline Composite Layer Realized by Simple Sintering Without Surface Treatment, Reducing Hydrophilicity and Increasing Thermal Conductivity.

The surface treatment for a polymer-ceramic composite is additionally performed in advanced material industries. To prepare the composite without a surface treatment, the simplest way to manufacture an advanced ceramic-particle is devised. The method is the formation of a nanocrystalline composite layer through the simple liquid-phase sintering. Using magnesia (MgO) which shows hydrophilicity, a nanocrystalline surface layer is realized by liquid-phase sintering. The amorphous matrix of nanocrystalline composite layer makes MgO hydrophobic and ensures miscibility with polymers, and the nanocrystalline MgO ensures high thermal conductivity. In addition, the liquid phase removes the open pores and makes the surface morphology smooth MgO with smooth surface (MgO-SM). Thermal interface materials (TIM) prepared with MgO-SM and epoxy show a high thermal conductivity of ≈7.5 W m-1 K-1 , which is significantly higher than 4.5 W m-1 K-1 of pure MgO TIM. Consequently, the formation process of a nanocrystalline surface layer utilizing simple liquid-phase sintering is proposed as a fabrication method for a next-generation ceramic-filler. In addition, it is fundamentally identified that the thermal conductivity of MgO depends on the Mg deficiency, and therefore a poly-crystal MgO-SM (produced at a low temperature) has a higher thermal conductivity than a single-crystal MgO (produced at a high temperature).

Piezoelectric and Triboelectric Nanogenerators for Enhanced Wound Healing.

Wound healing is a highly orchestrated biological process characterized by sequential phases involving inflammation, proliferation, and tissue remodeling, and the role of endogenous electrical signals in regulating these phases has been highlighted. Recently, external electrostimulation has been shown to enhance these processes by promoting cell migration, extracellular matrix formation, and growth factor release while suppressing pro-inflammatory signals and reducing the risk of infection. Among the innovative approaches, piezoelectric and triboelectric nanogenerators have emerged as the next generation of flexible and wireless electronics designed for energy harvesting and efficiently converting mechanical energy into electrical power. In this review, we discuss recent advances in the emerging field of nanogenerators for harnessing electrical stimulation to accelerate wound healing. We elucidate the fundamental mechanisms of wound healing and relevant bioelectric physiology, as well as the principles underlying each nanogenerator technology, and review their preclinical applications. In addition, we address the prominent challenges and outline the future prospects for this emerging era of electrical wound-healing devices.

Medullary colonic carcinomas present with early-stage disease and do not express neuroendocrine markers by immunohistochemistry.

Background: Medullary colonic carcinoma (MCC) is a rare and distinct phenotype of colorectal cancers characterized histologically by sheets of malignant cells with vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, exhibiting prominent infiltration by lymphocytes and neutrophilic granulocytes. We present the clinicopathologic and immunohistochemical characteristics of this rare tumor in our patient population. Methods: Eleven cases diagnosed with MCC from 1996-2020 met the diagnostic histologic criteria and had tissue blocks available for further analysis. Immunohistochemistry for mismatch repair deficiency, CDX2, synaptophysin, and chromogranin, and microsatellite instability testing by polymerase chain reaction were performed. Additional clinical information was obtained from the electronic medical records. Results: The median age at diagnosis was 69 years. MCC was more common in women (64%) than men (36%) and all (100%) cases involved the right colon. The median carcinoembryonic antigen level at diagnosis was 2.8 ng/mL. Lymphovascular invasion and perineural invasion occurred in 64% and 9% of cases, respectively. Synaptophysin and chromogranin showed no expression in any of the cases (0%), and CDX2 was only expressed in 18% of cases by immunohistochemistry. Most patients (73%) presented with stage II disease and 7 (64%) cases were microsatellite instability-high. Only lymph node metastasis showed an association with overall survival (OS) (hazard ratio 0.04, 95% confidence interval 0.0003-0.78; P=0.035). During a median follow up of 1.25 years, the median OS was not estimable as the survival curve did not reach the median point of survival, indicating that more than half of the patients were still alive at the end of the study. Conclusion: Based on our experience, neuroendocrine markers, including synaptophysin and chromogranin, are not expressed in MCC, and many patients present with early-stage disease.

Ask questions (ASQ): Implementation of a question prompt list communication intervention in a network of outpatient medical oncology clinics.

OBJECTIVE: This descriptive, single-arm study assessed the implementation and patient perceptions of an evidence-based Question Prompt List (QPL), the ASQ brochure, across a network of oncology clinics in a diverse patient population. METHOD: The QPL was revised in collaboration with stakeholders. Implementation was assessed using the RE-AIM framework. Eligible patients were scheduled for a first appointment with an oncologist at any of eight participating clinics. All participants received the ASQ brochure and completed three surveys: one at baseline, one immediately before, and one following their appointment. Surveys assessed sociodemographic characteristics; communication-related outcomes (perceived knowledge, self-efficacy in interacting with physicians, trust in physicians, distress); and perceptions of the ASQ brochure. Analyses included descriptive statistics and linear mixed-effects models. RESULTS: Reach: Participants (n = 81) represented the diverse population served by the clinic network. EFFICACY: All outcomes improved significantly, with no significant differences by clinic site or patient race. Adoption: All eight invited clinics participated and recruited patients. Patient perceptions of the ASQ brochure were overwhelmingly positive. CONCLUSION: Implementation of the ASQ brochure was successful in this oncology clinic network providing care to a diverse patient population. PRACTICAL IMPLICATIONS: This evidence-based communication intervention can be implemented widely in similar medical contexts and populations.

The Role of Surgery in Stage I Small Cell Lung Cancer: A National VA Database Analysis.

BACKGROUND: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, data regarding the role of surgery in very limited SCLC is lacking. METHODS: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs. lower lobe as delineated by ICD-10 codes C34.1 and C34.3. RESULTS: Four-hundred and forty-six patients received concurrent CRT; while 223 underwent treatment that contained surgery (93 surgery only, 87 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.21-4.48) while median OS for the CRT cohort was 2.45 years (95% CI 2.17-2.74). HR of death for surgery-inclusive treatment when compared to CRT is 0.67 (95% CI 0.55-0.81; P < .001). Subset analysis based on the location of the tumor in both the upper or lower lobes showed improved survival with surgery as compared to CRT regardless of the location. HR for the upper lobe was 0.63 (95% CI 0.50-0.80; P < .001) and lower lobe 0.61 (95% CI 0.42-0.87; P = .006). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.43-0.83; P = .002) favoring surgery. CONCLUSIONS: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study suggests a more expansive role for surgery in stage I SCLC.

Linearly polarized emission from CdSe/CdS core-in-rod nanostructures: Effects of core position.

Semiconductor nanocrystals with an anisotropic morphology exhibit unique properties, most notably their linear polarization. The colloidal growth of semiconductor nanorods with core dots inside, also referred to as dot-in-rod (DIR) structure, has enabled the synthesis of anisotropic nanocrystals with better stability and controllable fluorescence polarization. In this study, we synthesize CdSe/CdS DIR nanocrystals, in which the position of the CdSe core particle can be controlled by using different ligand compositions during the CdS growth. Varying the core position within the DIR structure, e.g., from the center to the end of the DIR particles, results in a change in the degree of linear polarization. When the core is positioned at the center of the nanorod, the linear polarization turns out to be higher compared with tip-core DIRs. Time-resolved photoluminescence analysis reveals that the center-core DIRs have higher electron-hole interaction than tip-core DIRs because of weak uniaxial strain in center-core DIR that arises from lattice dislocations at the interface to relieve accumulated strain.

Advanced In Vitro Three-Dimensional Skin Models of Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most prevalent inflammatory skin diseases that is characterized by eczematous rashes, intense itching, dry skin, and sensitive skin. Although AD significantly impacts the quality of life and the number of patients keeps increasing, its pathological mechanism is still unknown because of its complexity. The importance of developing new in vitro three-dimensional (3D) models has been underlined in order to understand the mechanisms for the development of therapeutics since the limitations of 2D models or animal models have been repeatedly reported. Thus, the new in vitro AD models should not only be created in 3D structure, but also reflect the pathological characteristics of AD, which are known to be associated with Th2-mediated inflammatory responses, epidermal barrier disruption, increased dermal T-cell infiltration, filaggrin down-regulation, or microbial imbalance. In this review, we introduce various types of in vitro skin models including 3D culture methods, skin-on-a-chips, and skin organoids, as well as their applications to AD modeling for drug screening and mechanistic studies.

Phosphatidylethanolamines Are Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Adults and Induce Liver Cell Metabolic Perturbations and Hepatic Stellate Cell Activation.

Pathogenesis roles of phospholipids (PLs) in nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This study investigated the role of PLs in the progression of NAFLD among obese individuals via studying the alterations in serum PL composition throughout the spectrum of disease progression and evaluating the effects of specific phosphatidylethanolamines (PEs) on FLD development in vitro. A total of 203 obese subjects, who were undergoing bariatric surgery, were included in this study. They were histologically classified into 80 controls (C) with normal liver histology, 93 patients with simple hepatic steatosis (SS), 16 with borderline nonalcoholic steatohepatitis (B-NASH) and 14 with progressive NASH (NASH). Serum PLs were profiled by automated electrospray ionization tandem mass spectrometry (ESI-MS/MS). HepG2 (hepatoma cells) and LX2 (immortalized hepatic stellate cells or HSCs) were used to explore the roles of PL in NAFLD/NASH development. Several PLs and their relative ratios were significantly associated with NAFLD progression, especially those involving PE. Incubation of HepG2 cells with two phosphatidylethanolamines (PEs), PE (34:1) and PE (36:2), resulted in significant inhibition of cell proliferation, reduction of mitochondrial mass and membrane potential, induction of lipid accumulation and mitochondrial ROS production. Meanwhile, treatment of LX2 cells with both PEs markedly increased cell activation and migration. These effects were associated with a significant change in the expression levels of genes involved in lipogenesis, lipid oxidation, autophagy, apoptosis, inflammation, and fibrosis. Thus, our study demonstrated that elevated level of PEs increases susceptibility to the disease progression of obesity associated NAFLD, likely through a causal cascade of impacts on the function of different liver cells.

Addressing multilevel barriers to clinical trial participation among Black and White men with prostate cancer through the PACCT study.

BACKGROUND: Cancer clinical trial participation is low and inequitable. Partnering Around Cancer Clinical Trials (PACCT) addressed systemic and interpersonal barriers through an observational study of eligibility and an intervention to improve patient-physician communication and trial invitation rates. METHODS: Physicians at two comprehensive cancer centers and Black and White men with prostate cancer participated. Patients were followed for 2 years to determine whether they became potentially eligible for an available therapeutic trial. Potentially eligible patients were randomized to receive a trials-focused Question Prompt List or usual care. Patient-physician interactions were video-recorded. Outcomes included communication quality and trial invitation rates. Descriptive analyses assessed associations between sociodemographic characteristics and eligibility and effects of the intervention on outcomes. RESULTS: Only 44 (22.1%) of participating patients (n = 199) became potentially eligible for an available clinical trial. Patients with higher incomes were more often eligible (>$80,000 vs. <$40,000, adjusted OR = 6.06 [SD, 1.97]; $40,000-$79,000 vs. <$40,000, adjusted OR = 4.40 [SD, 1.81]). Among eligible patients randomized to the intervention (n = 19) or usual care (n = 25), Black patients randomized to the intervention reported participating more actively than usual care patients, while White intervention patients reported participating less actively (difference, 0.41 vs. -0.34). Intervention patients received more trial invitations than usual care patients (73.7% vs. 60.0%); this effect was greater for Black (80.0% vs. 30.0%) than White patients (80.0% vs. 66.7%). CONCLUSIONS: Findings suggest the greatest enrollment barrier is eligibility for an available trial, but a communication intervention can improve communication quality and trial invitation rates, especially for eligible Black patients.

A comprehensive SEER registry analysis of elderly patients with classical Hodgkin lymphoma based on treatment era and race.

We conducted a Surveillance, Epidemiology, and End Results Program (SEER-18) registry analysis of classical Hodgkin lymphoma (cHL) patients more than 60 years old and compared outcomes of those diagnosed between 2006 and 2010 (cohort 1) to those identified between 2011 and 2015 (cohort 2) based on treatment era and race. Cohort 1 had a median overall survival (OS) of 4 years and cohort 2 had a median OS of 4.75 years [hazard ratio (HR): 0.92 (0.85-1.00); p = 0.052]. Non-Hispanic blacks (NHBs) had a similar 5-year OS compared to non-Hispanic whites (NHWs) of 48.6% vs. 50.2% (HR: 0.95 [0.79-1.15]; p > 0.99); on the contrary, Hispanics had worse 5-year OS of 41.8% vs. 48.6% (HR: 1.24 [1.09-1.41]; p < 0.001). NHW was the only race that had improvement in 5-year OS in 2011-2015 compared to 2006-2010 (51% vs. 46.5%, p = 0.002). In the multivariable analysis, older age, male gender, stage III-IV, unmarried status, Hispanic race, lack of chemotherapy, and diagnosis in 2006-2010 were associated with worse OS. Lymphoma was the most common cause of death in 60% of patients. In conclusion, elderly cHL patients diagnosed after 2010 had improved OS by nine months that was most prevalent in NHWs, and disparity in OS existed between NHWs and Hispanics throughout the study period.

A Direct Patient-Provider Relationship With the Medical Physicist Reduces Anxiety in Patients Receiving Radiation Therapy.

PURPOSE: The complex technological processes involved in radiation therapy can be intimidating to patients, causing increased treatment-related anxiety and reduced satisfaction. An intervention was implemented to provide direct consultations between patients and medical physicists to reduce patient anxiety and improve patient satisfaction. A randomized clinical trial was conducted to test the intervention's effect on anxiety, distress, treatment adherence, technical understanding, and satisfaction in patients receiving radiation therapy. METHODS AND MATERIALS: Eligible patients were recruited into "intervention" and "standard of care" arms within a phase 2 screening randomized trial. Intervention-arm patients met with a medical physicist who provided technical information and addressed patient questions or concerns at the time of treatment simulation and before the first treatment. In addition to baseline information collected before randomization, participants were surveyed (1) before simulation, (2) before the first treatment, and (3) before the completion of treatment to evaluate the study endpoints. Primary endpoints included patient anxiety and distress. Secondary endpoints included patient treatment adherence, overall satisfaction, and technical understanding of treatment. Patients in the intervention arm were surveyed before and after each physicist meeting. RESULTS: Participant anxiety was significantly reduced in the intervention arm (difference, -0.29; 95% confidence interval, -0.57 to -0.02; P = .038). No differences in distress or treatment adherence were observed between groups. Although measures of technical understanding and satisfaction were evaluated as exploratory objectives, participants in the intervention group were more likely to feel that technical aspects of treatment were adequately explained (difference, 0.78; 95% confidence interval, 0.03-1.54), and all measures of technical understanding and satisfaction were considerably higher in the intervention group at the time of the first visit. CONCLUSIONS: The establishment of a direct patient-provider relationship with the medical physicist reduced anxiety in patients receiving radiation therapy. In addition, increases in patient understanding of the technical aspects of care and in satisfaction were observed at the initiation of treatment.

Regulator of Chromosome Condensation (RCC1) a novel therapeutic target in pancreatic ductal adenocarcinoma drives tumor progression via the c-Myc-RCC1-Ran axis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here we for the first time evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC subsistence and drug resistance. RCC1 expression was found to be elevated in PDAC tissues in comparison with normal pancreatic tissues and was linked to poor prognosis. RCC1 silencing in a panel of PDAC cells by RNA interference and CRISPR-Cas9 resulted in reduced cellular proliferation in 2D and 3D cultures. RCC1 KD reduced migratory and clonogenic ability, enhanced apoptosis, and altered cell cycle distribution in human PDAC cells as well as cells isolated from the LSL-Kras G12D/+; LSL-Trp53 R172H/+ ;Pdx1-Cre (KPC) mouse tumors. Subcutaneous cell-derived xenografts show significantly attenuated growth of RCC1 KO tumors. Mechanistically, RCC1 knockdown resulted in disruption of subcellular Ran distribution indicating that stable nuclear Ran localization is critical for PDAC proliferation. Nuclear and cytosolic proteomic analysis revealed altered subcellular proteome in RCC1 KD KPC-tumor-derived cells. Altered cytoplasmic protein pathways include several metabolic pathways and PI3K-Akt signaling pathway. Pathways enriched in altered nuclear proteins include cell cycle, mitosis, and RNA regulation. RNA sequencing of RCC1 KO cells showed widespread transcriptional alterations. Upstream of RCC1, c-Myc activates the RCC1-Ran axis, and RCC1 KO enhances the sensitivity of PDAC cells to c-Myc inhibitors. Finally, RCC1 knockdown resulted in the sensitization of PDAC cells to Gemcitabine. Our results indicate that RCC1 is a potential therapeutic target in PDAC that warrants further clinical investigations.

Comparison of Carboplatin With Cisplatin in Small Cell Lung Cancer in US Veterans.

Importance: The current standard of care for the treatment of small cell lung cancer (SCLC) is concurrent chemoradiation for patients with limited-stage SCLC (LS-SCLC) and chemoimmunotherapy for extensive-stage SCLC (ES-SCLC). The backbone of chemotherapy regimens in both is a platinum-etoposide doublet: cisplatin is traditionally the preferred platinum agent in the curative intent setting, whereas carboplatin is preferred in ES-SCLC because of its favorable toxicity profile. Objective: To determine whether cisplatin is associated with better survival outcomes than carboplatin in treating LS-SCLC and ES-SCLC. Design, Setting, and Participants: In this cohort study, data were compiled from the National Veterans Affairs Central Cancer Registry for patients with SCLC who received platinum-based multiagent chemotherapy between 2000 and 2020 for ES-SCLC and 2000 and 2021 for LS-SCLC. Only patients with pathologically confirmed cases of LS-SCLC who received concurrent chemoradiation and ES-SCLC who received chemotherapy were included. Main Outcomes and Measures: The primary end point was overall survival (OS). The secondary end points included OS by Eastern Cooperative Oncology Group performance status, age, and laterality. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median OS and hazard ratios (HRs), respectively. Survival curves were compared by a Wald test. Results: A total of 4408 SCLC cases were studied. Most patients were White (3589 patients [81.4%]), male (4252 [96.5%]), and non-Hispanic (4142 [94.0%]); 2262 patients (51.3%) were 60 to 69 years old, followed by 1476 patients (33.5%) aged 70 years or older, 631 patients (14.3%) aged 50 to 59 years, and 39 patients (0.9%) aged 30 to 49 years. Among 2652 patients with ES-SCLC, 2032 were treated with carboplatin-based therapy and 660 received cisplatin; the median OS was 8.45 months (95% CI, 7.75-9.20 months) for cisplatin and 8.51 months (95% CI, 8.07-8.97 months) for carboplatin (HR, 1.01; 95% CI, 0.91-1.12; P = .90). Subset analysis showed no survival difference between the 2 agents in different age or performance status groups except for patients aged 70 years and older, for whom the median OS was 6.36 months (95% CI, 5.31-7.56 months) for cisplatin and 8.47 months (95% CI, 7.79-9.19 months) for carboplatin (HR, 0.77; 95% CI, 0.61-0.96; P = .02). Multivariable analysis of performance status and age did not show a significant difference in survival between the 2 groups (HR, 0.96; 95% CI, 0.83-1.10; P = .54). Of 1756 patients with LS-SCLC, 801 received carboplatin, and 1018 received cisplatin. The median OS was 26.92 months (95% CI, 25.03-28.81 months) for cisplatin and 25.58 months (95% CI, 23.64-27.72 months) for carboplatin (HR, 1.04; 95% CI, 0.94-1.16; P = .46). The median OS was not significantly different between 2 agents according to cancer stage (I-III), performance status, and age groups. A multivariable analysis of factors associated with OS accounting for stage (I-III), performance status, and age did not demonstrate a significant difference in survival between carboplatin and cisplatin in patients with LS-SCLC (HR, 0.995; 95% CI, 0.86-1.15; P = .95). Conclusions and Relevance: Cisplatin is not associated with a survival advantage over carboplatin among patients with either ES-SCLC or LS-SCLC, irrespective of performance status and age. The favorable toxicity profile of carboplatin and comparable OS support its use in both LS-SCLC and ES-SCLC in clinical practice and may allow more room for combination with novel treatment strategies in clinical trials.

A clinicopathologic and immunohistochemical study of primary and secondary breast angiosarcoma.

BACKGROUND: We aimed to study the clinicopathologic and immunohistochemical (IHC) (CD117, c-Myc, and p53) characteristics, and overall survival of primary and secondary breast angiosarcoma (BAS). METHODS: This was a retrospective study of BAS cases diagnosed between 1997 and 2020 at our institution. Hematoxylin and eosin-stained slides were reviewed for tumor morphology, margin status, and lymph node metastasis. CD117, p53, D2-40, CD31, and c-Myc IHC stains were performed on 11 viable tissue blocks. Additional clinical information was obtained from the electronic medical records. RESULTS: Seventeen patients with BAS were identified. Of these, five (29%) were primary and 12 (71%) were secondary BAS, respectively. The median age at diagnosis for primary BAS was 36 years. The median age at diagnosis for secondary BAS was 67 years. The median time to secondary BAS development following radiotherapy was 6.5 years (range, 2 to 12 years). There was no significant difference between primary and secondary BAS in several histopathologic parameters examined, including histologic grade, necrosis, mitotic count, lymph node metastasis, and positive tumor margins. There was also no difference in CD117, p53, D2-40, CD31, and c-Myc expression by IHC between primary and secondary BAS. During a median followup of 21 months, primary BAS had two (40%) reported deaths and secondary BAS had three (25%) reported deaths. However, this difference in survival between both groups was not statistically significant (hazard ratio, 0.51; 95% confidence interval, 0.09 to 3.28; p = .450). CONCLUSIONS: BAS is a rare and aggressive disease. No histologic, IHC (CD117, c-Myc, and p53), or survival differences were identified between primary and secondary BAS in this study.

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment.

Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

Estrogen receptor status has no prognostic relevance in metaplastic breast carcinoma.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare histologic variant of breast cancer characterized by the presence of glandular and non-glandular components. The prognostic significance of estrogen receptor (ER) status has been scarcely studied in these tumors. We therefore investigated the prognostic relevance of ER status in MBC within our patient population. DESIGN: We reviewed MBC cases (n = 125) between January 2000 and September 2019. Histologic slides were reviewed for variables including tumor morphology and hormonal status. Additional clinical information was obtained from the electronic medical records. RESULTS: Of the 125 patients, 15 (12%) had ER positive tumors and 110 (88%) had ER negative tumors. Eleven (73%) ER positive tumors had ER positivity > 10% and 4 (27%) had ER positivity ≤ 10%. ER positive tumors had a smaller median tumor size of 2.5 cm, compared with ER negative tumors with median tumor size 3.05 cm, however this difference was not statistically significant (P = 0.82). There were no statistical differences between ER positive and ER negative tumors in terms of histologic grade (P = 0.34), histologic subtype (P = 0.65), clinical stage (P>0.99) or human epidermal growth factor receptor 2 (HER2) expression (P = 0.29). There was also no difference in overall survival (OS) between ER positive and ER negative metaplastic breast cancers (HR = 0.35, 95% CI, 0.003-2.67, P = 0.39). CONCLUSION: Our experience suggests that ER positivity has no prognostic relevance in MBC. Regardless of ER expression status, there were no statistically significant differences in overall survival between ER positive and ER negative MBC.