Therapeutics

Plant extracts are increasingly becoming an answer to expensive, high-dose, synthesized chemotherapy, with milder side effects and easier accessibility. Many botanical plants contain active ingredients, such as terpenoids and alkaloids, which may combat cancer; however, studies need to be performed to test whether they are solely effective enough and whether the extracted compounds are selective for the tumor itself. Many chemotherapy drugs were initially of botanical origin, such as vincristine from Catharanthus roseus and paclitaxel from the Taxus baccata tree. The objective of this review is to assess the mechanisms of herbal therapeutics in their role against malignancy. Ajwa, curcumin, ginseng, lycopene, and ursolic acid were all respectively evaluated in the paper for their prevalent properties, their method of extraction, notable usage in medicine, which pathways they activate, and whether the transductions can disrupt cancer formation or proliferation. The findings from the review demonstrated that all the therapeutics exhibited pro-apoptotic behavior, Ajwa and curcumin exerted cell cycle arrest upon neoplasms, and Ajwa, curcumin, and lycopene showed anti-metastatic behavior. Most extracts were tested on colorectal cancer, and the pathways most commonly applied were through BAX/Bcl2 and endoproteases, such as caspase-3 and caspase-9, indicating predominantly mitochondrial apoptosis. In addition, cell cycle arrest was noted to occur during the G2/M phase via Wnt/β-catenin in both curcumin and ginseng, independently of the Wnt/β-catenin pathway in Ajwa constituents, reducing cell viability. All of these studies were demonstrated in vitro within varieties of single cell cultures, which did not take into account bioavailability nor properly demonstrate the tumor microenvironment, which may not yield the same results in vivo. Clinical trials need to be undergone to appropriately test effective dosages, as if a compound is strongly pro-apoptotic, it may not be selective just to tumor cells but also to healthy cells, which may impair their functions. Full article

Background: Handgrip strength (HGS) is strongly recommended for use in clinical settings because it is a convenient assessment of muscle strength and a robust prognostic indicator of health. However, it may lack use in clinical settings, and may not be well understood by healthcare providers and patients. We sought to determine the healthcare provider and patient perceptions of HGS in an internal medicine resident clinic. Methods: Healthcare providers were presented with didactic sessions for HGS and engaged in routine follow-up meetings. HGS was measured on eligible older adult patients during an approximately 9-month phased study period. Both healthcare providers and patients were asked to complete a questionnaire with 10-point Likert scale response items regarding their experiences with HGS. Results were presented as descriptive. Results: Overall, patients had a positive perception of HGS, as they understood HGS instructions (score: 9.8 ± 0.7), their results (score: 9.5 ± 1.3), and found value in HGS for their health (score: 8.4 ± 2.3). However, healthcare providers were generally neutral about HGS, such that at study end HGS was viewed as moderately valuable for their practice (score: 6.0 ± 2.1) and patients (score: 6.0 ± 2.1). Conclusions: Overall, patients had a positive perception of HGS, but healthcare providers were neutral. Our findings should be used to guide HGS for possible implementation and quality management in appropriate healthcare settings. Full article

Background/Objectives: This scoping review aims to identify the diverse existing tools applicable for the measurement of SUD outcomes, examining and comparing their item characteristics, benefits, limitations, cost effectiveness, and overall utility. This study provides recommendations on the next steps toward the design and dissemination of a unified version of a standard SUD outcome measurement tool. Methods: Using PRISMA-ScR guidelines, the databases PubMed and Embase, as well as the grey literature, were searched for existing SUD outcome measurement tools. Additionally, references and information on tools were found via the Addictions Drug and Alcohol Institute Library at the University of Washington. Tools were examined based on their characteristics, benefits, limitations, and overall utility. Results: Thirteen tools met the analysis requirements and were analyzed, revealing great variance. The domains covered by each tool is categorized for comparison among other tools, showing strong focus over some domains more than others. Additionally, great variance in characteristics such as the number of questions, question structure, time required for completion, and scoring were seen. Sources for each of these tools’ development were seen to reveal the unique origination of each, as well as their intended utility. Conclusions: Our analysis highlights the importance of considering certain characteristics when selecting measurement instruments, emphasizing the need for clear and concise questions to enhance levels of adherence and interpretation. The current lack of standardization among SUD measurement tools in assessing new and existing SUD treatment modalities has hindered progress in the field, compromising the quality of care delivered. Full article

Background: Plasma cell myeloma is an incurable malignancy of clonal plasma cells. Recent success in immunotherapeutic strategies has altered the landscape of myeloma treatment. Daratumumab is an anti-CD38 IgG kappa monoclonal antibody that has shown great efficacy in the treatment of myeloma. However, Daratumumab brought with it new challenges in post-therapeutic laboratory assessment, including therapeutic antibody interference with serum protein electrophoresis and serum immunofixation electrophoresis assays. In this study, we highlight the interference identified in post-therapeutic flow cytometry analysis related to bound Daratumumab on normal hematopoietic cells. We also highlight the methods of detection of residual plasma cell neoplasm, post-Daratumumab therapy.: A total of 28 patients with refractory plasma cell myeloma who received Daratumumab (2016–2018) were included in this study. Flow cytometry was performed using 4- or 10-color antibody panels (BD FASC Canto) and analyzed by cluster analysis (Cytopaint Classic software) using four tube panels including VS38c for measurable residual disease (MRD) testing. Pretreatment and post-Daratumumab follow-up bone marrow flow cytometry samples were analyzed. In addition, 10 multiple myeloma patient samples were reflexed to multi-epitope CD38 analysis by flow cytometric analysis of post-Daratumumab residual disease. When discussing CD38 expression, we will refer to CD38 as being detected by conventional reagents. Results: All post-Daratumumab-treated cases (100%) showed negative staining for CD38 using conventional reagents on all plasma cells in the specimens. MRD testing successfully identified small clonal plasma cell populations using VS38C and multi-epitope CD38 (meCD38) antibodies, despite the absence of demonstrable CD38 expression. Additionally, all cases exhibited weak kappa light chain staining on hematogones, attributed to the binding of Daratumumab kappa monoclonal antibody. This interaction can create the appearance of a CD10+ monotypic B-cell population. We also noted diminished CD38 staining on myeloblasts, resulting in an atypical CD34/CD38 staining pattern. This alteration could potentially be misinterpreted as indicative of a myelodysplastic neoplasm (MDS). Furthermore, decreased staining of CD38 was noted on T cells, natural killer (NK) cells, basophils, monocytes, and plasmacytoid dendritic cells. Conclusions: With the emergence of successfully targeted immunotherapies, such as anti-CD38 antibodies, it is important to understand and correctly interpret variations in flow cytometry that may arise from the therapy. Hematogones exhibit high-intensity levels of CD38 expression; thus, Daratumumab binds to them, creating the appearance of kappa expression on all hematogones. Stage I/early stage II hematogones normally lack surface immunoglobulin light chain expression, but in the presence of Daratumumab, they appear to be a CD10(+) monotypic population of B cells. The misinterpretation of these normal cells as a CD10(+) B-cell clone can lead to inaccurate assessment, unnecessary bone marrow immunohistochemical evaluation, and unwarranted anxiety. Additionally, artefacts on various other hematopoietic cells can result in inaccurate assessments of immunophenotypic aberrancy due to binding of the drug. This may lead to the false interpretation of a secondary/therapy-related myeloid neoplasm. This study highlights in detail the interferences that must be considered when assessing residual disease in the era of targeted drug therapies. Full article

Background: Past studies have found mixed benefits to treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in heart failure (HF) patients. Here we evaluate the effect of OSA treatment in symptomatic HF patients who received an inpatient sleep study. Methods: We performed a retrospective observational review of 6-month outcomes in 109 hospitalized HF patients with newly diagnosed OSA who followed up to initiate PAP therapy (N = 48) or never started PAP (N = 61). Primary outcomes were cardiovascular readmissions and all-cause mortality. Results: Patients who started PAP overall had worse apnea–hypopnea index (AHI) compared to those who did not (AHI 49.4 vs. 31.3). There were significantly fewer deaths in the “PAP” group versus the “non-PAP” group: 2% versus 15% (p = 0.04). We then sub-analyzed our population based on strict CPAP adherence, defined as ≥4 PAP hours per night and at least ≥70% of nights used. Twenty-eight out of 48 PAP patients met adherence criteria. The “Adherent” group (N = 28) had notable PAP use of 6.3 h per night (interquartile range 5–7.7 h/night). In comparison to the “Non-Adherent or Never Started PAP” group (N = 81), the Adherent group had no observed deaths and significantly fewer first-time readmissions: 11% versus 33% (p = 0.026). Conclusions: Despite worse baseline OSA in our PAP population, we found an association between PAP compliance and improved cardiovascular outcomes. Future research should investigate dose–response relationships between PAP use and HF outcomes. There are important limitations to our study. Full article

Bacterial vectors for biomolecule delivery to targeted organelles, facilitating temporary or continuous protein production, have emerged as a promising approach for treating acquired and inherited diseases. This method offers a selective cancer eradication and targeting strategy with minimal side effects. Bacterial vectors provide an alternative to viral gene delivery, given their capacity to deliver large genetic materials while inducing minimal immunogenicity and cytotoxicity. Bacteria such as Bifidobacterium, Salmonella, Clostridium, and Streptococcus have demonstrated potential for tumor-targeted biomolecule delivery or serve as oncolytic bacteria. These vectors have also been used to transfer and amplify genes encoding biomolecules such as pro-drug-converting enzymes, toxins, angiogenesis inhibitors, and cytokines. The microenvironment of necrotic tumors offers a unique opportunity for targeted therapy with the non-pathogenic anaerobic bacterium. For example, Clostridium sporogenes can germinate selectively in the necrotic regions upon injection as endospores, which helps to enhance the specificity of Clostridium sporogenes, resulting in tumor-specific colonization. Also, E. coli and Salmonella sp. can be capacitated with a hypoxic sensing promotor gene for specificity delivery into the core region of solid tumors. The uniqueness of the tumor microenvironment, including hypoxia, immunosuppression, metabolite deficiency or enrichment, and necrosis, selectively enables bacteria in the tumor. Combining traditional cancer therapy with bacterial therapy will significantly complement and cover the limitations of other treatments. This review provides an overview of the use of the bacteria vector in cancer therapy, discussing strategies to maximize delivery efficiency and address potential challenges. In this review, we discuss the potential of bacteria vectors as anti-cancer therapeutics while focusing on therapeutic delivery strategies. We highlight the complementary use of bacteria therapy with other cancer therapies and the mechanism of bacteria cancer immunotherapy with limitations and perspectives for future use. Full article

Background: Schwannomas, predominantly benign nerve sheath tumors, are typically found within the intradural extramedullary space of the spinal cord with potential extradural expansion. Other typical localizations are the upper limbs and neck area. Pure epaxial paraspinal schwannomas are very rare, often asymptomatic, and predominantly occur in the thoracic region, with only a handful of cases reported globally. The range of differential diagnoses for paraspinal lesions is extensive, emphasizing the importance of accurate diagnosis to ensure optimal therapy and avoid unnecessary treatments. Method: We conducted a systematic literature review searching for published recommendations for paraspinal lesion management in addition to examining the case of a 49-year-old male patient who presented with a history of persistent back pain. A thorough medical history and physical examination were followed by ultrasound and MRI, revealing a well-defined paravertebral mass spanning from T7 to T9. A secure ultrasound-guided biopsy was performed, leading to a preliminary diagnosis of paraspinal schwannoma. Subsequently, complete surgical resection was performed. Results: pathological reports confirmed the initial diagnosis of paraspinal schwannoma. Further investigation using FMI and RNA sequencing did not detect any specific genetic anomalies aside from an NF2 gene mutation. A follow-up MRI conducted six months later showed no signs of recurrence. Conclusions: The broad spectrum of differential diagnoses for paraspinal lesions necessitates a multidisciplinary approach to ensure accurate diagnosis and tailored treatment. This approach involves meticulous imaging interpretation followed by a secure biopsy procedure to obtain preliminary pathology results, ultimately leading to the implementation of the most suitable surgical treatment. Full article

Background/Objectives: Mantle cell lymphoma (MCL) represents a rare B-cell lymphoma subtype with rather high relapse rates. Somatic mutations in the PPM1D gene were shown to be associated with adverse outcomes in patients with diffuse large B-cell lymphoma (DLBCL) who received CD19 CAR-T-cell therapy with tisa-cel, which may also apply to mantle cell lymphoma receiving brexu-cel CAR-T-cells. Methods: In this study, we determined the prevalence of PPM1D mutations in peripheral blood cells of MCL patients before CAR-T-cell infusion and analyzed the impact of low-frequency PPM1D mutations on efficacy and safety aspects of brexu-cel CAR-T-cell treatment in the first 16 r/r MCL patients enrolled at Inselspital Bern. Results: The prevalence of low-frequency PPM1D gene mutations was 25%, with variant allele frequencies (VAF) of 0.011 to 0.099. Clinical response was analyzed in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild-type (PPM1Dwt) groups with median progression-free survival of 1 versus 32 months (p = 0.07) and median overall survival of 1.5 vs. 27 months (p = 0.001). Conclusions: Our data suggest that low-frequency PPM1D gene mutations in peripheral blood cells may predict inferior outcomes in patients with mantle cell lymphoma treated with CAR-T-cell therapy. Full article

Background/Objectives: Directed acyclic graphs (DAGs) inform the epidemiologic statistical modeling confounders to determine close to true causal relationships in a study context. They inform the inclusion of the predictive model variables that affect the causal relationship. Non-small cell lung cancer (NSCLC) is frequently diagnosed, aggressive, and the second leading cause of cancer deaths in the United States. Determining factors affecting both the guideline-concordant treatment receipt and survival outcomes for early-stage lung cancer will help inform future statistical models aiming to achieve a close to true causal relationship. Methods: Peer-reviewed original research published during 2002–2023 was identified through PubMed, Embase, Web of Sciences, Clinical trials registry, and the gray literature. DAGitty version 3.1, an online software program, developed implied DAGs and integrated DAG graphics. The evidence synthesis for constructing directed acyclic graphs (ESC-DAGs) protocol was utilized to guide DAG development. The conceptual models utilized were Andersen and Aday for factors affecting treatment receipt and Shi and Steven for survival outcome factors. Results: A total of 36 studies were included in the DAG synthesis out of 9421 retrieved across databases. Eight studies served in the synthesis of treatment receipt DAG, while 28 studies were used for the survival outcomes DAG. There were 10 causal paths and 13 covariates for treatment receipt and 2 causal pathways and 32 covariates for survival outcomes. Conclusions: There are very few studies reporting on factors affecting early-stage NSCLC guideline-concordant care receipt compared to factors affecting its survival outcomes in the past two decades of original research. Future investigations can utilize data extracted in the current study to develop a meta-analysis informing effect size. Full article

Objective(s): The objective of this study was to report our experience with a series of patients with temporal bone fractures from 2019 to 2023 and to evaluate the dilemmas in diagnosing the extent of their ontological injuries through a narrative review of the literature focusing on the classifications of temporal bone fractures. Methods: Data were collected retrospectively from the electronic medical records of patients who presented to the emergency department and were diagnosed with temporal bone fractures using computed tomograms of the head and temporal bone between September 2019 and March 2023. A total of 117 patients were included in the study. Demographic data, fracture classification, mechanism of injury, and presence and/or repair of cerebrospinal fluid (CSF) leak, facial nerve injury (both immediate and delayed), and hearing loss (both immediate and delayed) were also recorded. Results: In total, 49.5% of our cohort were between the ages of 19 and 39, and the majority (66%) were males. The primary cause of the trauma was falls in 41% of patients, followed by motor vehicle accidents (29%), and 70% had a Glasgow Coma Score (GCS) between 13 and 15 at presentation. In total, 92.3% of temporal bone fractures did not involve the otic capsule, and 79.3% were longitudinal fractures. In total, 89% of the CSF leaks were seen in patients with longitudinal fractures. Similarly, 70% of facial nerve deficits were seen in patients with longitudinal and otic capsule-sparing fractures. Conclusion: Diagnosis of facial asymmetry and hearing loss in patients with TBFs can be challenging in acute care settings but was less challenging in our cohort due to patients presenting with good GCSs. Dilemmas in clinical evaluation in the acute care setting are due to poor GCSs, heterogeneity of documentation of injuries, and classification of TBFs. Implementation of universal protocols with homogeneity in the documentation and classification of temporal bone fractures may help improve patient care and prediction of outcomes. Full article

Atrial fibrillation (AF) in the setting of heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent comorbidity and is enabled by adverse left atrial (LA) remodeling, dilation, and scar tissue formation. These changes are facilitated by poor left ventricular compliance. A growing body of clinical evidence and medical guidelines suggest that managing atrial tachyrhythms with catheter ablation (CA) is paramount to treating concomitant HF. This recommendation is complicated in that thermal CA modalities, namely radiofrequency ablation and cryoablation, are both therapeutic via inducing additional scar tissue. AF treatment with thermal CA may compound the atrial scar burden for patients who already have extensive scars secondary to HFpEF. Therefore, thermal CA could act as “gasoline” to the slowly burning “fire” within the LA, increasing the rate of AF recurrence. Pulsed-field ablation (PFA), which utilizes high-voltage irreversible electroporation, is a non-thermal CA technique that is capable of disrupting reentrant microcircuits and arrhythmogenic foci without inducing significant scar burden. PFA has the potential to mitigate the strong fibrosis response to thermal CA that predisposes to AF by serving as “water” rather than “gasoline”. Thus, PFA may increase the efficacy and durability of CA for AF in HFpEF, and subsequently, may decrease the risk of procedural complications from repeat CAs. In this article, we provide a summary of the clinical concepts underlying HFpEF and AF and then summarize the data to date on the potential of PFA being a superior CA technique for AF in the setting of comorbid HFpEF. Full article

Background: Complement-mediated hemolytic uremic syndrome (CM-HUS), formerly known as atypical HUS, is a rare but potentially fatal thrombotic microangiopathy (TMA) characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and acute kidney injury. It is primarily caused by complement dysregulation. The condition can progress to end-stage renal disease (ESRD), often necessitating kidney transplant. In rare instances, it can develop in post-renal-transplant patients. Methods: Here, we present the cases of two patients with ESRD status post kidney transplant who presented with thrombocytopenia, anemia, and acute kidney injury. In both cases, work-up was suggestive of CM-HUS, and stabilization was achieved with eculizumab. Discussion: The pathogenesis of CM-HUS involves dysregulation of the complement system, and complement inhibitors such as eculizumab can be used for initial management and relapse. The relapse rate following eculizumab treatment can range from 20 to 67%. Patients with a history of kidney transplant are more prone to relapse than those with native kidneys. Re-treatment with complement inhibitors has proven effective in managing relapses, and long-term continuation of complement inhibitor medications is recommended to prevent recurrence. Conclusions: CM-HUS is rare, especially in post-transplant patients, and can be potentially fatal. It is crucial for clinicians to recognize and treat this condition promptly. Management often involves complement inhibitors. The risk of relapse is particularly high in patients with a history of kidney transplant, but long-term continuation of these medications can prevent relapse. Full article

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is preferred for biliary drainage in malignant distal biliary obstruction (MDBO). Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is considered a rescue therapy for failed ERCP. This study aims to evaluate the safety and efficacy of this technique as the primary modality for MDBO biliary drainage. Methods: An electronic database search was conducted following PRISMA guidelines to identify studies on EUS-CDS for primary biliary drainage in MDBO. A meta-analysis was performed using random and fixed effects models. Results: We extracted data from 10 eligible studies comprising 519 patients. The mean age for the study was 70 years ± SD 2.66. The pooled technical success rate was 92.36% (95% CI = 88.39–95.56), and the clinical success rate was 88.91% (95% CI = 85.22–92.13). The pooled stent dysfunction rate was 13.66% (95% CI = 7.47–21.35), and the reintervention rate was 15.91% (95% CI = 11.00–21.54) of patients. The mean stent patency duration was 229.20 days ± SD 113.9. The total pooled adverse events rate was 17.50% (95% CI = 12.90–22.64), and 9.03% (95% CI = 4.43–15.05) was considered moderate to severe. Procedure-related pancreatitis had a pooled rate of 0%. The pooled adverse event rate of acute cholangitis was 6.84% (95% CI = 3.69–10.88), and for acute cholecystitis it was 2.61% (95% CI = 1.06–4.83). Conclusions: EUS-CDS demonstrates favorable outcomes when used as a primary approach in MDBO. With a long stent patency duration and no procedure-related acute pancreatitis, it may be considered the primary technique when expertise is available. Full article

Background/Objectives: Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitate the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA ¹⁷⁷Lu-octreotide with the ALK inhibitor lorlatinib. Methods: Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, ¹⁷⁷Lu-octreotide, and a combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Results: Combination treatment with ¹⁷⁷Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. An increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with ¹⁷⁷Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both ¹⁷⁷Lu-octreotide and lorlatinib, with BID down-regulated and HRK up-regulated on days 2 and 7, respectively. Conclusions: The data suggest that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with ¹⁷⁷Lu-octreotide and could improve treatment outcomes in patients with HR-NB. Full article