Existing Psychiatric Diagnoses Among Breast Cancer Patients Interact with Outcomes After Autologous and Implant-Based Bilateral Breast Reconstruction: A Propensity Score Matched Analysis.

BACKGROUND: Breast reconstruction is an integral postoncologic procedure that has been associated with improved mental health and psychological outcomes. The possible interaction between existing psychiatric diagnoses hospital courses and postoperative complications warrants further exploration. METHODS: Bilateral breast reconstruction patients were identified from the 2016 to 2018 Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP - NIS). Number and type of psychiatric diagnoses within the cohort were then evaluated using a host of ICD-10 codes. A propensity score analysis was applied to control for confounding variables such as demographics, existing comorbidities, and hospital characteristics. A binary logistic regression model was then used to identify the prediction value of psychiatric diagnosis and its interaction with modality of reconstruction for objective outcomes like length of hospital stay, treatment charge, and postoperative complications. RESULTS: A total of 10,114 patients were identified as the final cohort of breast reconstruction patients. 2621 (25.9%) patients possessed an average of 1.4 ± 0.6 existing psychiatric diagnoses. Presence of at least 1 psychiatric diagnosis was a strong predictor alone for extended length of stay (OR: 1.34, 95% CI: 1.28-1.41, P < .001) and occurrence of postoperative complications (OR: 1.31, 95% CI: 1.21-1.41, P < .001). Psychiatric diagnosis displayed a significant interaction with modality of breast reconstruction and conferred a lower increase in risk of extended length of stay in autologous reconstruction when compared to implant-based reconstruction (OR: 0.80, 95% CI: 0.72-0.89, P < .001). CONCLUSION: Existing psychiatric diagnoses were shown to strongly predict and modulate risk of adverse postoperative outcomes depending on modality of reconstruction.

Corrigendum: miR-31-3p functions as a tumor suppressor by directly targeting GABBR2 in prostate cancer.

[This corrects the article DOI: 10.3389/fonc.2022.945057.].

Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC.

Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.

Global risk of selection and spread of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions.

In the thirteen years since the first report of pfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH or P. falciparum specific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 for P. falciparum detection. For these reasons, the continued spread of pfhrp2/3 deletions represents a growing public health crisis that threatens efforts to control and eliminate P. falciparum malaria. National malaria control programmes, their implementing partners and test developers desperately seek pfhrp2/3 deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed by pfhrp2/3 deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence of pfhrp2/3 deletions and conduct a literature review to estimate model parameters known to impact the selection of pfhrp2/3 deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting for pfhrp2/3 deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route for pfhrp2 deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk for pfhrp2/3 deletions. These results provide a refined and updated prediction model for the emergence of pfhrp2/3 deletions in an effort to help guide pfhrp2/3 policy and prioritise future surveillance efforts and innovation.

Association between sociodemographic factors and diagnosis of lethal prostate cancer in early life.

OBJECTIVE: A subset of patients are diagnosed with lethal prostate cancer (CaP) early in life before prostate-specific antigen (PSA) screening is typically initiated. To identify opportunities for improved detection, we evaluated patient sociodemographic factors associated with advanced vs. localized (CaP) diagnosis across the age spectrum. METHODS: We conducted a retrospective cohort study using the National Cancer Database, identifying patients diagnosed with CaP from 2004 to 2020. We compared characteristics of patients diagnosed at the advanced (cN1 or M1) versus localized (cT1-4N0M0) stage. Using multivariable logistic regression, we evaluated the associations among patient clinical and sociodemographic factors and advanced diagnosis, stratifying patients by age as ≤55 (before screening is recommended for most patients), 56 to 65, 66 to 75, and ≥76 years. RESULTS: We identified 977,722 patients who met the inclusion criteria. The mean age at diagnosis was 65.3 years and 50,663 (5.1%) had advanced disease. Overall, uninsured (OR = 3.20, 95% CI 3.03-3.78) and Medicaid-insured (OR 2.58, 95% CI 2.48-2.69) vs. privately insured status was associated with higher odds of diagnosis with advanced disease and this effect was more pronounced for younger patients. Among patients ≤55 years, uninsured (OR 4.14, 95% CI 3.69-4.65) and Medicaid-insured (OR 3.39, 95% CI 3.10-3.72) vs. privately insured patients were associated with higher odds of advanced cancer at diagnosis. Similarly, residence in the lowest vs. highest income quartile was associated with increased odds of advanced CaP in patients ≤55 years (OR 1.15, 95% CI 1.02-1.30). Black vs. White race was associated with increased odds of advanced CaP at diagnosis later in life (OR 1.17, 95% CI 1.09-1.25); however, race was not significantly associated with advanced stage CaP in those ≤55 years (P = 0.635). CONCLUSIONS: Sociodemographic disparities in diagnosis at advanced stages of CaP were more pronounced in younger patients, particularly with respect to insurance status. These findings may support greater attention to differential use of early CaP screening based on patient health insurance.

Universal Lower Bound on Topological Entanglement Entropy.

Entanglement entropies of two-dimensional gapped ground states are expected to satisfy an area law, with a constant correction term known as the topological entanglement entropy (TEE). In many models, the TEE takes a universal value that characterizes the underlying topological phase. However, the TEE is not truly universal: it can differ even for two states related by constant-depth circuits, which are necessarily in the same phase. The difference between the TEE and the value predicted by the anyon theory is often called the "spurious" topological entanglement entropy. We show that this spurious contribution is always non-negative, thus the value predicted by the anyon theory provides a universal lower bound. This observation also leads to a definition of TEE that is invariant under constant-depth quantum circuits.

Tissue-specific biological aging predicts progression in prostate cancer and acute myeloid leukemia.

Introduction: Chronological aging is a well-recognized diagnostic and prognostic factor in multiple cancer types, yet the role of biological aging in manifesting cancer progression has not been fully explored yet. Methods: Given the central role of chronological aging in prostate cancer and AML incidence, here we investigate a tissue-specific role of biological aging in prostate cancer and AML progression. We have employed Cox proportional hazards modeling to associate biological aging genes with cancer progression for patients from specific chronological aging groups and for patients with differences in initial cancer aggressiveness. Results: Our prostate cancer-specific investigations nominated four biological aging genes (CD44, GADD45B, STAT3, GFAP) significantly associated with time to disease progression in prostate cancer in Taylor et al. patient cohort. Stratified survival analysis on Taylor dataset and validation on an independent TCGA and DKFZ PRAD patient cohorts demonstrated ability of these genes to predict prostate cancer progression, especially for patients with higher Gleason score and for patients younger than 60 years of age. We have further tested the generalizability of our approach and applied it to acute myeloid leukemia (AML). Our analysis nominated three AML-specific biological aging genes (CDC42EP2, CDC42, ALOX15B) significantly associated with time to AML overall survival, especially for patients with favorable cytogenetic risk score and for patients older than 56 years of age. Discussion: Comparison of the identified PC and AML markers to genes selected at random and to known markers of progression demonstrated robustness of our results and nominated the identified biological aging genes as valuable markers of prostate cancer and AML progression, opening new avenues for personalized therapeutic management and potential novel treatment investigations.

Social Determinants of Health in Urban Transgender Patients: A Case Report.

The social determinants of health (SDOH) are a complex web of factors that influence the health of individuals throughout their lifetime. There are many drivers of health inequities within the SDOH, such as socioeconomic status, education, employment, gender, and race/ethnicity. It is possible that mental illness may develop when these factors negatively affect health. However, current research primarily focuses on SDOH in cisgender individuals leaving a scientific gap in transgender individuals who require unique considerations when providing comprehensive medical care. We present the case of a 20-year-old transgender female who was admitted for suicidal attempts during a methamphetamine overdose, and who had been struggling with mental illness and suicidal gestures since she was a young teenager. The significance of our findings is discussed in the context of the substantial lack of current research on SDOH in transgender individuals to underscore the need for clinical awareness and promote future research.

miR-4284 Functions as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting Glutamate Decarboxylase 1.

MicroRNAs (miRNAs) play a crucial role as oncogenic or tumor suppressors in the pathogenesis and progression of tumors. However, few studies have investigated the exact role of miR-4284 in renal cell carcinoma (RCC). We aimed to investigate the role of miR-4284 as a tumor suppressor in renal cancer cell lines. A498 and Caki-1 were transfected with miR-4284. The Cell Counting Kit-8, colony formation, apoptosis assays, and quantitative reverse transcription-polymerase chain reaction were used to evaluate tumor growth-inhibiting functions. The wound-healing, transwell, and sphere-formation assays were conducted to investigate tumorigenic characteristics. The potential target genes of miR-4284 were predicted and experimentally verified. A xenograft experiment was performed to estimate the tumor-growth-suppressive function of miR-4284. miR-4284 overexpression suppressed proliferation, induced apoptosis, and suppressed tumorigenic features of renal cancer cells. Glutamate decarboxylase 1 (GAD1) was directly targeted by miR-4284. A xenograft mouse model injected with Caki-1 cells transfected with miR-4284 showed significantly decreased tumor growth rate and volume. miR-4284 affected tumor growth, metastasis, and apoptosis of renal cancer cells in vitro and in vivo. These findings highlight the potential of miR-4284 as a target for anticancer miRNA therapeutics in RCC.

Extended versus standard pelvic lymph node dissection yields no difference in 3-year biochemical recurrence rates.

Background: extended pelvic lymph node dissection (ePLND) increases the detection rate of lymph node positive prostate cancer compared to a standard pelvic lymph node dissection (sPLND). However, improvement of patient outcomes remains questionable. Here we report and compare 3-year postoperative PSA recurrence rates between patients that underwent sPLND versus ePLND at the time of prostatectomy. Methods: 162 patients received a sPLND (which involvedremoval of periprostatic, external iliac, and obturator lymph nodes bilaterally), and 142 patients received an ePLND (which involved removal of periprostatic, external iliac, obturator, hypogastric, and common iliac nodes bilaterally). Decision to undergo ePLND versus sPLND at our institution was changed in 2016 based on the National Comprehensive Cancer Network guideline. The median follow-up time was 7 and 3 years for sPLND and ePLND patients, respectively. All node-positive patients were offered adjuvant radiotherapy. Kaplan-Meier analysis was carried out to assess the impact of a PLND on early postoperative PSA progression-free survival. Subgroup analyses were done for node-negative and node-positive patients, as well as Gleason score. Results: Gleason score and T stage were not significantly different between patients who received an ePLND and sPLND. The pN1 rate for ePLND and sPLND were 20% (28/142) and 6% (10/162), respectively. There was no difference in the use of adjuvant treatments in the pN0 patients. Significantly, more ePLND pN1 patients received adjuvant androgen deprivation therapy (25/28 vs. 5/10 P = 0.012) and radiation (27/28 vs. 4/10 P = 0.002). Yet, no difference in biochemical recurrence between ePLND and sPLND was observed (P = 0.44). This remained true in subgroup analyses of node-positive (P = 0.26), node-negative (P = 0.78), Gleason Score 6-7 (P = 0.51), and Gleason Score 8-10 (P = 0.77). Conclusions: PLND provided no additional therapeutic benefit, even though ePLND patients were significantly more likely to have node-positive disease and undergo adjuvant treatment, compared to a sPLND.

Local Therapeutics for the Treatment of Oligo Metastatic Prostate Cancer.

PURPOSE OF REVIEW: Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies are increasingly utilized in the early treatment of the disease, particularly in patients with oligometastatic prostate cancer (OMPC). OMPC represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC. RECENT FINDINGS: To date, there are three utilized forms of local therapy for OMPC: cryoablation, radiation therapy, and cytoreductive prostatectomy. Cryoablation can be utilized for the total ablation of the prostate and has shown promising results in patients with OMPC either in combination with ADT or with ADT and systemic chemotherapy. Radiation therapy along with ADT has demonstrated improvement in progression-free survival. The STAMPEDE Arm G, PEACE-1, and the HORRAD clinical trials have investigated radiation therapy for mPCa compared to standard of care versus systemic therapy with varying results. Cytoreductive radical prostatectomy (CRP) in conjunction with ADT has also been proposed in the management of OPMC with promising results from case-control and retrospective studies. Currently there are larger controlled trials investigating CRP for OPMC including the SIMCAP, LoMP, TRoMbone, SWOG 1802, IP2-ATLANTA, g-RAMPP, and FUSCC-OMPCa trials. Given the novel nature of local treatments for OPMC, treatment selection is still controversial and requires long-term follow-up and randomized clinical trials to aid patient and clinician decision making.

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m2 weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n = 4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n = 6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor-infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted. The clinical trial registration is NCT02734290.

Personalizing approaches to the management of metastatic hormone sensitive prostate cancer: role of advanced imaging, genetics and therapeutics.

PURPOSE: To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics. METHODS: Literature review using PUBMED-Medline databases as well as clinicaltrials.gov to include reported or ongoing clinical trials on treatment for mHSPC. We prioritized the findings from phase III randomized clinical trials, systematic reviews, meta-analyses and clinical practice guidelines. RESULTS: There have been significant changes to the diagnosis and staging evaluation of mHSPC with the integration of increasingly accurate positron emission tomography (PET) imaging tracers that exceed the performance of conventional computerized tomography (CT) and bone scan. Germline multigene testing is recommended for the evaluation of patients newly diagnosed with mHSPC given the prevalence of actionable alterations that may create candidacy for specific therapies. Although androgen deprivation therapy (ADT) remains the backbone of treatment for mHSPC, approaches to first-line treatment include the integration of multiple agents including androgen receptor synthesis inhibitors (ARSI; abiraterone) Androgen Receptor antagonists (enzalutamide, darolutamide, apalautamide), and docetaxel chemotherapy. The combination of ADT, ARSI, and docetaxel chemotherapy has recently been evaluated in a randomized trial and was associated with significantly improved overall survival including in patients with a high burden of disease. The role of local treatment to the prostate with radiation has been evaluated in randomized trials with additional studies underway evaluating the role of cytoreductive radical prostatectomy. CONCLUSION: The staging and initial management of patients with mHSPC has undergone significant advances in the last decade with advancements in the diagnosis, treatment and sequencing of therapies.

The efficacy and safety of an indocyanine green-hyaluronic acid mixture (LuminoMark™) for localization in patients with non-palpable breast lesions: A multicenter, randomized, open-label, parallel phase 3 clinical trial.

Purpose: The incidence of early tumor detection is increasing due to popularization of breast cancer screening and the development of imaging techniques. Thus, suitable preoperative localization is required for proper diagnosis and treatment of non-palpable breast lesions. The purpose of this study was to evaluate the efficacy and safety of indocyanine green (ICG)-hyaluronic acid (HA) mixture for lesion localization compared to activated charcoal. Methods: This was a multicenter, randomized, open-label, parallel phase 3 clinical trial performed at four centers in Korea. Female patients scheduled for surgery to remove non-palpable breast lesions were enrolled. One hundred and nine patients were randomly assigned to a control group (activated charcoal: 0.3. - 1 mL) or a study group (ICG-HA mixture, 0.2 mL) for the localization of a breast lesion. The primary endpoint was the accuracy of resection. Secondary endpoints included the technical success rate, histopathological accuracy, skin pigmentation rate, and adverse event rate. Results: A total of 104 patients were eligible for per-protocol analysis (control group, n = 51; study group, n = 53). The accuracy of resection in the study group was not inferior to that of the control group (90.57% vs. 98.04%, 95% confidence interval (CI): -2.31 - 18.91, p = 0.21). There was no statistically significant difference in technical success rate between the two groups (marking on breast skin: p = 0.11, marking on the excised specimen: p = 0.12). However, there were statistically significant differences in histopathological accuracy (0.26 ± 0.13 vs. 0.33 ± 0.17, p = 0.01) and skin pigmentation rate (0.00% vs. 30.77%, p< 0.01). Adverse events were not reported in either group. Conclusions: When localization was performed using ICG-HA, the accuracy of resection was not inferior to that of activated charcoal. However, skin pigmentation rate was significantly lower. In conclusion, ICG-HA is effective and safe for localizing of non-palpable breast lesions.

Management of Pathologic Node-Positive Prostate Cancer following Radical Prostatectomy.

PURPOSE OF REVIEW: Approximately 15% of prostate cancer patients have lymph node metastases at the time of radical prostatectomy (RP). However, there is no universally accepted standard of care for these men. The options for treatment in this subset of patients range from observation to a combination of adjuvant androgen deprivation therapy (aADT) and radiation therapy (RT). RECENT FINDINGS: A recent systematic review showed that there was no clear choice out of the options above to treat these patients. Studies have shown that patients treated with adjuvant radiation therapy have lower all-cause mortality when compared to patients treated with salvage radiation therapy. In this review, we summarize treatment options for pathologic node-positive (pN1) patients and discuss the urgent need for robust clinical trials that includes observation as the control group to help establish a standard of care for treating patients with node-positive prostate cancer after RP.