Therapeutics, Volume 1, Issue 2 (December 2024) – 5 articles

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