Clinical Behavior Research Articles

Triple-Negative Breast Cancer: Molecular Particularities Still a Challenge.

Worldwide, breast cancer (BC) is one of the most common cancers in women and is responsible for the highest number of cancer-related deaths among women, with a special clinical behavior and therapy response. Triple-negative breast cancer (TNBC) is seen as a highly invasive BC, characterized by a short survival, higher mortality, recurrence, and metastasis when it is compared to the other BC subtypes. The molecular subtyping of TNBC based on mRNA expression levels does not accurately reflect protein expression levels, which impacts targeted therapy effectiveness and prognostic predictions. Most TNBC cases exhibit a high frequency of homologous recombination (HR) DNA repair deficiency (HRD) signatures and are associated with a complex genomic profile. Biomarker research in TNBC includes investigating genetic mutations, gene expression patterns, immune system-related markers, and other factors that can provide valuable information for diagnosis, treatment selection, and patient outcomes. Additionally, these biomarkers are often crucial in the development of personalized and precision medicine approaches, where treatments are customized to each patient's unique characteristics. This ongoing research is essential for improving the management and outcomes of TNBC, which is a challenging and heterogeneous form of breast cancer. The findings of this research have practical implications for refining treatment strategies, particularly in selecting appropriate systemic therapies and integrating traditional treatment modalities like surgery and radiotherapy into comprehensive care plans for TNBC patients.

Unraveling the prevalence and clinical behavior or sporadic apparently non-invasive medullary thyroid carcinoma

Unraveling the prevalence and clinical behavior or sporadic apparently non-invasive medullary thyroid carcinoma

Higher microRNA-221 and lower microRNA-451 expression are associated with poor prognosis in patients with thyroid papillary carcinoma.

To analyze the relationship between serum microRNA-221 and microRNA-451 expression and the pathological features and prognosis of patients with thyroid papillary carcinoma. Cross-sectional study that included 120 patients with papillary thyroid cancer treated at the hospital and 120 healthy volunteers selected as the control group who underwent physical examination. The relative expression levels of microRNA-221 and microRNA-451 were compared between the thyroid papillary carcinoma group (prior to treatment) and the control group. Additionally, microRNA-221 and microRNA-451 expression levels were analyzed in patients with papillary thyroid carcinoma across different pathological characteristics. Serum microRNA-221 relative levels were significantly higher (p<0.001) in the papillary carcinoma group compared to the control group, while microRNA-451 levels were higher in the control group (p<0.001). In the papillary carcinoma group, microRNA-221 expression was significantly higher in patients with extracapsular invasion (p<0.001), lymphatic metastasis (p=0.003), and poor prognosis (p<0.001). Conversely, microRNA-451 expression was significantly lower (p<0.001) in patients with extracapsular invasion, lymphatic metastasis and poor prognosis. In the multivariate logistic regression analysis, morphological features suggestive of an aggressive clinical behavior (extracapsular invasion and lymphatic metastasis) were related to high expression of microRNA-221 and low expression of microRNA-451 in patients with thyroid papillary carcinoma (p<0.001). Serum microRNA-221 and microRNA-451 expression levels are significantly higher and lower, respectively, in patients with papillary thyroid carcinoma, particularly in patients with morphological features suggestive of an aggressive clinical behavior (extracapsular invasion and lymphatic metastasis) and, therefore, of a poor prognosis.

Distinctive features associated with differentiation syndrome in acute promyelocytic leukemia in patients treated by all-trans retinoic acid and arsenic trioxide

In acute promyelocytic leukemia (APL), the combination treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) appears to have a synergistic effect. Due to this synergism, differentiation syndrome (DS) in APL assumes a distinct identity separate from the formerly known ATRA syndrome, with distinct temporal patterns, diagnostic parameters, and clinical behavior. We retrospectively evaluated single-center data of years 2013–2022. Patients with newly diagnosed APL were categorized into three groups (16 patients in ATRA/ATO standard-risk group, 3 patients in ATRA/chemotherapy standard-risk group, and 5 patients in ATRA/chemotherapy high-risk group). Our aim was to analyze leukocytosis, signs of DS, and hepatic impairment within the first 25 days of treatment. The incidence of DS in the ATRA/ATO SR group was 43.8 %, with a median of 4 days and 2 days from ATRA and ATO initiation, respectively. This group also exhibited higher peak levels of leukocytosis 34.5 (6.0–113.4) x109/L (p = 0.0809). ALT elevation was more prevalent in the ATRA/ATO SR group (93.75 %), with 68.75 % grade 3–4 elevations (p = 0.0094). Importantly, all patients in this group had ALT levels that returned to normal during the subsequent consolidations. These findings suggest hepatopathy as a potential manifestation of ATRA/ATO induced leukocyte differentiation and/or DS. Diverse differentiation patterns were identified within the ATRA/ATO group, classifying patients into three distinct subgroups based on the concurrent dynamics of leukocytes and ALT levels, illustrating simultaneous, sequential, and divergent elevation patterns. These emphasize the different distribution of differentiation (organs vs. peripheral blood). We introduced real-world data and advocated for reevaluation of the current DS definition and associated diagnostic thresholds. Our study, conducted in a small country with a limited number of APL patients, acknowledges the inherent constraints in sample size. Further investigations with larger patient cohorts are warranted to validate and reinforce the outcomes observed in our study.

Promoter mutation-independent TERT expression is related to the immune-enriched milieu in papillary thyroid cancer.

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors.

Investigation of the relationship between the self-efficacy levels in clinical practice and coping behaviors with stress among international nursing students

BackgroundIn this era of rapid globalization, our knowledge regarding the clinical performance perceptions and stress coping behaviors of international students in nursing education is quite limited. The unexplored nature of this topic has the potential to manifest as future clinical challenges. ObjectiveTo examine the relationship between international nursing students' perceived self-efficacy in clinical applications and their coping behaviors with stress. MethodsOur cross-sectional and correlational study collected data from 117 international nursing students at a state university between June 2022 and July 2023. The data collection tools included the Participant Identification Form, Self-Efficacy in Clinical Performance Scale (SECP), and The Coping Behavior Inventory with Stress Scale for Nursing Students (CBIS-NS). t-test, ANOVA, correlation analysis, and Bonferroni test were used for data analysis. ResultsStudents, predominantly Azerbaijani (15.4 %) and 64.1 % female, engaged in practices, mainly in medical (34.2 %) and surgical units (33.3 %). Clinical self-efficacy was high, stress coping moderate. A significant positive link existed between coping behaviors and clinical self-efficacy (p < 0.05). Those in public health/mental health units (8.12 ± 1.46) had higher self-efficacy than surgical unit peers (6.94 ± 1.71) (p < 0.05). Satisfied students showed better stress coping (t = 2.645; p = 0.009). Weak positive links were found between transfer/avoidance coping behaviors and clinical self-efficacy (p < 0.05). ConclusionThis study demonstrated a statistically significant positive relationship between international nursing students' perceptions of clinical performance and coping behaviors with stress. Given the rapid globalization of education in the global era, especially in diverse educational and clinical environments with students from different ethnic backgrounds, it is recommended to develop new intervention strategies to enhance students' clinical performances and foster positive coping behaviors with stress.

LMP1 enhances aerobic glycolysis in natural killer/T cell lymphoma

Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.

Characteristics, treatment and prognosis of patients with chronic heart failure according to ejection fraction. Results of an Ecuadorian registry.

In Ecuador, there are few data about the clinical behaviour of heart failure (HF). This study aims to analyse the clinical characteristics, treatment and prognosis according to the current classification based on left ventricular ejection fraction (EF). A retrospective observational study was carried out in patients with chronic HF from the 'Los Ceibos' registry during the period January 2017-December 2022. Patients were classified into HF with preserved EF (HFpEF) [EF ≥ 50%], HF with mildly reduced EF (HFmrEF) [EF:41-49%], and HF with reduced (HFrEF) [EF ≤ 40%]. The patients were followed up for a mean time of 2.28 (IQR 1.25-3.49) years. A total of 711 patients were included, 333 (46.8%) with HFrEF, 109 patients (15.3%) with HFmrEF and 269 patients (37.8%) with HFpEF. The average age was 69.8 ± 13.1 years, 31.4% were women. The main comorbidity was arterial hypertension (92.7%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used in 74.5%, beta-blockers in 82.3%, and mineralocorticoid receptor antagonists in 51.3%. 58.3% of patients with HFrEF received three drugs of the so-called foundational quadruple therapy. A lower all-cause (24.5%) and cardiovascular mortality rate (11,2%) was observed in the HFpEF group compared to HFmrEF (47.4% and 25,7%) and HFrEF (45.3% and 25,8%), p < 0.001. In the 'Los Ceibos' registry, a higher prevalence of HFrEF was observed. The main comorbidity was HTN. Half of the patients with HFrEF received three drugs of the foundational therapy. At four years of follow-up, lower all-cause and cardiovascular mortality rate was observed in the HFpEF group.

Using Short-Form Videos to Get Clinical Trial Newcomers to Sign Up: Message-Testing Experiment.

Recruiting participants for clinical trials poses challenges. Major barriers to participation include psychological factors (eg, fear and mistrust) and logistical constraints (eg, transportation, cost, and scheduling). The strategic design of clinical trial messaging can help overcome these barriers. While strategic communication can be done through various channels (eg, recruitment advertisements), health care providers on the internet have been found to be key sources for communicating clinical trial information to US adults in the social media era. This study aims to examine how communication source (ie, medical doctors and peers) and message framing of TikTok videos (ie, psychological and logistical framing) influence clinical trial-related attitudes, perceptions, and sign-up behaviors under the guidance of the integrated behavioral model. This study used a 2 (source: doctor vs peer) × 2 (framing: psychological vs logistical) between-participant factorial design web-based experiment targeting adults in the United States who had never participated in clinical trials (ie, newcomers). A Qualtrics panel was used to recruit and compensate the study respondents (n=561). Participants viewed short-form videos with doctors or peers, using psychological or logistical framing. The main outcome measures included perceived source credibility, self-efficacy, attitude toward clinical trial participation, behavioral intention, and sign-up behavior. Structural equation modeling was used to analyze the direct and indirect effects of message factors on the outcome variables. Source (doctor=1; peer=0) and framing (psychological=1; logistical=0) were dummy-coded. Doctor-featured messages led to greater perceived source credibility (β=.31, P<.001), leading to greater self-efficacy (95% CI 0.13-0.30), which in turn enhanced behavioral intention (95% CI 0.12-0.29) and clinical trial sign-up behavior (95% CI 0.02-0.04). Logistical barrier-framed messages led to greater self-efficacy (β=-.09, P=.02), resulting in higher intention to participate in clinical trials (95% CI -0.38 to -0.03) and improved sign-up behavior (95% CI -0.06 to -0.004). Logistical barrier-framed messages were also directly associated with an increased likelihood of signing up for a clinical trial (β=-.08, P=.03). The model accounted for 21% of the variance in clinical trial sign-up behavior. Attitude did not significantly affect behavioral intention in this study (β=.08, P=.14), and psychological and logistical barrier-framed messages did not significantly differ in attitudes toward clinical trial participation (β=-.04, P=.09). These findings advance our understanding of how people process popular message characteristics in short-form videos and lend practical guidance for communicators. We encourage medical professionals to consider short-form video sites (eg, TikTok and Instagram Reels) as effective tools for discussing clinical trials and participation opportunities. Specifically, featuring doctors discussing efforts to reduce logistical barriers is recommended. Our measuring of actual behavior as an outcome is a rare and noteworthy contribution to this research.

Clinicopathological and genetic characterization of radiotherapy-induced undifferentiated pleomorphic sarcoma following breast cancer: a case series of three tumors and comprehensive literature review

AimsCompared to primary breast sarcoma (BSs), radiotherapy-induced sarcoma (RIS) is a less frequent type of secondary breast sarcoma. Undifferentiated pleomorphic sarcoma (UPS) is an even rarer occurrence within the RIS category. This study aimed to present the clinicopathologic and molecular features of breast radiotherapy-induced UPS.MethodsA retrospective study was conducted at the Third Affiliated Hospital of Soochow University to analyze three patients with radiation-induced undifferentiated pleomorphic sarcoma (UPS) following breast cancer, spanning from 2006 to 2023. The clinical and pathological variables were extracted from the medical records, while immunohistochemistry was employed to analyze the immunophenotypes of these tumors. Genomic characteristics were assessed through DNA and RNA sequencing techniques. Another 15 cases from the literature were also reviewed to better characterize the tumor.ResultsThe affected areas encompass the chest wall and breasts, with an incubation period ranging from 6 to 17 years. The tumor cells exhibit pleomorphism and demonstrate a high degree of pathological mitosis. Notably, two cases displayed an accelerated disease progression, characterized by recurrent tumors and metastases occurring within short intervals of 48 and 7 months respectively subsequent to the initial diagnosis. The two prevailing identified genes were TP53 (2/3, 66.7%) and RB1 (1/3, 33.3%). Through analysis of somatic copy number variation (CNV), it was discovered that two oncogenes, MCL1 (1/3, 33.3%) and MYC (1/3, 33.3%), had experienced gains in CNV. The Tumor Mutational Burden (TMB) values for case 1, case 2, and case 3 were 5.9 mut/Mb, 1.0 mut/Mb, and 3.0 mut/Mb, respectively. Moreover, the analysis of RNA-NGS (next-generation sequencing) revealed the presence of a novel gene fusion, named COL3A1-GULP1, in case 2.ConclusionsBased on our thorough analysis of research findings and previous reports, it is evident that radiotherapy-induced UPS exhibits a highly diverse and frequently severe clinical and biological behavior. Identifying tumor formation using genome sequencing can help understand its biological behavior and determine personalized treatments.

Pediatric atypical teratoid/rhabdoid tumor in the cauda equina with rapid tumor progression: illustrative case.

Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon malignant neoplasm and rarely occurs in the spinal space, especially in the cauda equina. Only 8 cases of pediatric AT/RT of the cauda equina have been reported. Therefore, its clinical behavior and optimal treatment remain unclear. The authors describe the case of a 9-year-old boy who presented with progressive back and left leg pain. Initial magnetic resonance imaging showed an intradural extramedullary lesion at the L3-4 level, which progressed rapidly to the L2-5 level within a month. He underwent partial resection of the tumor with an L2-5 laminectomy. The histopathological diagnosis was AT/RT. He received adjuvant chemotherapy and radiotherapy, and his gait disturbance improved postoperatively. At 6 months' follow-up, disease recurrence was not observed. Although extremely rare, AT/RT should be included in the differential diagnosis for prompt therapeutic intervention. Safe resection with minimal functional impairment, followed by postoperative chemoradiation, can lead to tumor control and improve neurological function. https://thejns.org/doi/10.3171/CASE24219.

The observational EURACAN prospective clinical registry dedicated to epithelioid hemangioendothelioma: The protocol of an international and collaborative effort on an ultra-rare entity.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE. To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.

Co-production of the ‘EPIC’ multidimensional tool-kit to support neurodivergent children and young people at home and school: a feasibility and pilot study

BackgroundInterventions focused on cognitive function in neurodivergent children typically focus on single functions, e.g. working memory training. They are often focused on ‘deficit’ models and lack an emphasis on understanding areas of individual strengths and difficulties as a prerequisite to appropriate support. The multidimensional nature and phenotypic variability of cognitive profiles in these children indicate a need for a multicomponent-tailored intervention programme focused on understanding and supporting an individual child’s cognitive functioning.AimsThe ‘EPIC’ intervention (Edinburgh Psychoeducation Intervention for Children and Young People) is focused on improving cognition, learning and behaviour in neurodivergent children such as those with attention deficit hyperactivity disorder (ADHD) or who are autistic. Building on our previous co-production work, this study aimed to use a participatory methods approach to develop EPIC practices and materials in relation to our key principles which include psychoeducation, multicomponent, individualised approach, strengths and difficulties profiling and pairing of a child’s individual strengths and difficulties with internal and external strategies. We also set out to assess the feasibility and acceptability of EPIC, and pilot this novel tool-kit intervention with neurodivergent children and their parents and teachers.MethodsThe intervention practices, materials and strategies of EPIC were co-produced with neurodivergent children, their parents, teachers and clinicians taking a strengths and difficulties approach. Identification of psychoeducation activities and strategy practices (e.g. mind-maps, chunking), testing of feasibility and collection of pilot data were conducted over a bi-weekly 8-week programme. Eleven neurodivergent children aged 7 to 12 completed the 16-session individualised programme. Acceptability and feasibility were ascertained via qualitative reports elicited within child and teacher interviews and child ratings of enjoyment. Pilot evaluation data was collected pre- and post-intervention participation, and across cognitive assessments (CANTAB, BRIEF), educational attainment (WIAT) and parent and teacher questionnaires measuring clinical symptoms and behaviour (Conners, AQ, SDQ, self-perception). Data was compared with a matched neurodivergent treatment-as-usual control group (N = 9).ResultsThe co-produced EPIC intervention was both feasible to deliver and acceptable to children, parents and their teachers. Pilot data identified that the 8-week intervention improved cognition (short-term and working memory) and literacy (receptive vocabulary, oral word fluency, listening comprehension). Improvements in the intervention group were also found for parent-reported child behavioural difficulties and aggression, and teacher-reported scholastic competence. Effect sizes generated (Cohen’s d) ranged from 0.65 to 2.83. Parents reported continuing to use EPIC strategies when interviewed over a year after participating in the programme.ConclusionThe current study met our objectives fully. ‘EPIC’ (Edinburgh Psychoeducation Intervention for Children and Young People) is feasible in home and school contexts and improves a range of aspects of cognition, learning and behaviour in neurodivergent children. Our findings show EPIC is suitable to be assessed within a full-scale trial.

Clinical features, surgical management and outcome of squamous and basal cell carcinoma in squamates and chelonians.

Squamous cell carcinoma (SCC) is one of the most commonly diagnosed neoplastic disorders in reptiles. Recently, however, it has been demonstrated that basal cell carcinomas (BCCs) are frequently misclassified as SCCs. Several histological SCC and BCC variants have been characterised and their classification may allow the establishment of appropriate prognosis estimation and treatment approaches. To describe the clinical features and surgical outcomes of SCCs and BCCs diagnosed between 2010 and 2022 in reptiles. Thirty-three captive reptiles (21 squamates and 12 chelonians). Detailed clinical history, including staging and surgical outcomes, were performed. Statistical analysis assessed significant factors using Prism (v8.2.1). While SCC was predominantly diagnosed in lizards, BCC was most commonly diagnosed in chelonians, and both neoplasms mainly occurred in adult to aged, male individuals. Although the gross pathological findings were highly comparable between SCC and BCC, considerable variation could be seen according to the primary location (oral, cutaneous or epidermis of the shell). Humane euthanasia or noncurative intent surgeries were performed in a minority of the cases. Curative intent surgeries were successful in 19 of 27 cases during a 1- to 7-year follow-up period, yet recurrence was seen in 8 cases. The results of this study allowed the identification of significant high-risk prognostic factors for SCC and BCC in reptiles. This study contributes to predicting the clinical behaviour and prognosis of distinct SCC and BCC histological variants, and selecting the most appropriate treatment protocol.

Durable benefit and slowdown in tumor growth dynamics with erdafitinib in a FGFR3-TACC3 fusion-positive IDH-wild type glioblastoma.

FGFR3-TACC3 fusion-positive IDH-wild-type (IDH-WT) glioblastoma (GB) is a rare GB subtype occurring in approximately 3% of cases. It is clinical behavior and molecular profile is different from those of fusion-negative IDH-WT GBs. Evidence on the role of FGFR inhibitors in FGFR-altered gliomas is limited. We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months.

An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

Drug-Drug Interactions between COVID-19 and Tuberculosis Medications: A Comprehensive Review of CYP450 and Transporter-Mediated Effects.

Most medications undergo metabolism and elimination via CYP450 enzymes, while uptake and efflux transporters play vital roles in drug elimination from various organs. Interactions often occur when multiple drugs share CYP450-transporter-mediated metabolic pathways, necessitating a unique clinical care strategy to address the diverse types of CYP450 and transporter-mediated drug-drug interactions (DDI). The primary focus of this review is to record relevant mechanisms regarding DDI between COVID-19 and tuberculosis (TB) treatments, specifically through the influence of CYP450 enzymes and transporters on drug absorption, distribution, metabolism, elimination, and pharmacokinetics. This understanding empowers clinicians to prevent subtherapeutic and supratherapeutic drug levels of COVID medications when co-administered with TB drugs, thereby mitigating potential challenges and ensuring optimal treatment outcomes. A comprehensive analysis is presented, encompassing various illustrative instances of TB drugs that may impact COVID-19 clinical behavior, and vice versa. This review aims to provide valuable insights to healthcare providers, facilitating informed decision-making and enhancing patient safety while managing co-infections. Ultimately, this study contributes to the body of knowledge necessary to optimize therapeutic approaches and improve patient outcomes in the face of the growing challenges posed by infectious diseases.

The 4Ms of an age-friendly health system in behavioral health: pilot test of an educational framework

Objectives This pilot test of the 4Ms-Behavioral Health (4Ms-BH) training program was designed to assess knowledge gains, clinical behavior change, and acceptability among mental health clinicians and compile lessons to guide widespread implementation of the framework. The ultimate future goal is to improve care for older adults by expanding the 4Ms framework for behavioral health providers. Method Fifteen mental health clinicians from Community Mental Health Centers in three states completed eight hours of live session training over six months: one three-hour introduction followed by five monthly application sessions. Clinicians completed knowledge and clinical behavior measures before and after training, along with follow-up discussion regarding acceptability and sustainability. Results Although knowledge gains were not significant in the overall 4Ms knowledge assessment, knowledge in the Medication and Mobility domains improved at 17% and 15%, respectively. Participants completing the program demonstrated an increased frequency of clinical behaviors pertinent to older adult care with large effect sizes in each of the 4Ms assessment and action activities from pre-training to post-training (Cohen’s d range = 0.82 − 1.66, p ≤ 0.01). Conclusion The 4Ms-BH framework was well-received by participants, who demonstrated some significant knowledge gains and clinical behavior change. These pilot data suggest that this framework has strong potential to effectively train mental health clinicians with little geriatric training.

Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.