Endocapillary proliferative glomerulonephritis associated with Q fever endocarditis: A case report.

Acute Coxiella burnetti (Q fever) infection is known to activate the autoimmune inflammatory response. We report a rare case of glomerulonephritis associated with the Coxiella infection. An elderly male first presented with recurrent fevers of unknown origin and was subsequently diagnosed with Q fever infection and treated with doxycycline. He represented 2 months later with an acute kidney injury and active urinary sediment. Renal biopsy demonstrated a mesangiopathic pattern with staining for both C1q and IgM, raising possibilities of infection-related glomerulonephritis, C1q nephropathy and lupus nephritis. This case demonstrates glomerulonephritis as a complication of Q fever infection and the differential diagnosis and workup up that needs to be considered in cases of chronic Q fever.

Clinical review of substitutions or alternatives for critical chemotherapy drug shortages in hematologic malignancies.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Over the past decade, drug shortages have become increasingly more problematic for clinicians, with over 300 drug shortages reported in the first quarter of 2023. Shortages of chemotherapy drugs can have a negative impact on patient care, as omission or delay of treatment can lead to worse outcomes. Although many articles have been published on this topic, currently no review articles discuss strategies for using alternative regimens or substitutions in the event of severe chemotherapy drug shortages. SUMMARY: In this article, we review the literature on antineoplastic agents used to treat hematologic malignancies that experienced a drug shortage from 2010 through 2023, providing recommendations for substitutions and alternative regimens in the event of a critical shortage. In particular, we discuss how shortages of fludarabine, cytarabine, daunorubicin, methotrexate, and platinum agents may be addressed, including supporting clinical evidence. CONCLUSION: Further publications assessing possible alternatives and substitutions for chemotherapy agents and examining the efficacy of previous strategies are needed to mitigate potentially devastating interruptions to care for patients with cancer during severe drug shortages.

The Case for Neurosurgical Intervention in Cancer Neuroscience.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience.

Systematic Review-Role of MRI in Cervical Cancer Staging.

A systematic review of the diagnostic accuracy of MRI in the staging of cervical cancer was conducted based on the literature from the last 5 years. A literature search was performed in the Cochrane Library, EMBASE, MEDLINE and PubMed databases using the MeSH terms "cervical cancer", "MRI" and "neoplasm staging". A total of 110 studies were identified, of which 8 fit the inclusion criteria. MRI showed adequate accuracy (74-95%) and high sensitivity (92-100%) in assessing stromal invasion. The data for MRI in terms of assessing vaginal and pelvic side wall involvement were wide ranging and inconclusive. In assessing lymph node metastasis, MRI showed an adequate accuracy (73-90%), specificity (75-91%) and NPV (71-96%) but poor sensitivity (52-75%) and PPV (52-75%). MRI showed high accuracy (95%), sensitivity (78-96%), specificity (87-94%), and NPV (98-100%) but poor PPV (27-42%) in detecting bladder involvement. There was a paucity of data on the use of MRI in assessing rectal involvement in cervical cancer. Overall, the literature was heterogenous in the definitions and language used, which reduced the comparability between articles. More research is required into the diagnostic accuracy of MRI in the staging of cervical cancer and there must be increased consistency in the definitions and language used in the literature.

Case Report: Low-grade glioma with NF1 loss of function mimicking diffuse intrinsic pontine glioma.

Intrinsic, expansile pontine tumors typically occur in the pediatric population. These tumors characteristically present as diffuse intrinsic pontine glioma (DIPG), which is now considered as diffuse midline glioma (DMG), H3K27-mutated of the pons. DIPG has limited treatment options and a poor prognosis, and the value of tissue diagnosis from an invasive biopsy remains controversial. This study presents the case of a 19-year-old female with clinical and imaging hallmarks of DIPG, who underwent a biopsy of a tumor in the region of the right middle cerebellar peduncle. Her lesional cells were negative for H3K27M alterations and had low-grade histologic features. Next-generation sequencing revealed a frameshift mutation in the NF1 gene as the likely driver mutation. These features suggest a diagnosis of a low-grade glioma associated with NF1 loss of function, with far-reaching consequences regarding both treatment strategy and prognosis. This case provides support for the utility of diagnostic tissue biopsy in cases of suspected DIPG.

Chemoresistance to additive PARP/PI3K dual inhibition in triple-negative breast cancer cell lines is associated with adaptive stem cell-like prevalence.

Cancer stem-like cells (CSCs) are posited to exhibit specialized oncogenic capacity to drive malignancies. CSCs are distinguished by enhanced hallmarks of cancer, including apoptosis avoidance, phenotypic plasticity and aberrant growth pathway signaling. Standard-of-care chemotherapies targeted to rapidly cycling cells routinely fail to eliminate this resistant subpopulation, leading to disease recurrence and metastasis. Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, is enriched for tumor-propagating CD44+/CD24-/low CSCs, which are poorly ablated by chemotherapeutics and are associated with poor prognosis. CD44 governs sustained PI3K signaling in breast cancer, which is essential for CSC maintenance. PI3K inhibition can elicit DNA damage and down-regulate BRCA1 expression, which in turn enhance the synthetic lethality of PARP inhibitors. Here, we examined a dual chemotherapeutic approach targeting these pathways by combining a pan-PI3K inhibitor (Buparlisib) and a PARP1 inhibitor (Olaparib) on a panel of TNBC cell lines with distinct mutational profiles and proportions of CSCs. We observed differential sensitivity to this dual inhibition strategy and varying cellular stress and resistance responses across eight TNBC lines. The dual chemotherapeutic effect is associated with a reduction in S-phase cells, an increased in apoptotic cells and elevated expression of cleaved PARP, indicating a provoked replicative stress response. We observed that PARP/PI3K inhibition efficacy was potentiated by repeated administration in some TNBC lines and identified critical treatment schedules, which further potentiated the dual chemotherapeutic effect. Dual inhibition induced small but significant increases in CSC relative abundance as marked by CD44+/CD24-/low or ALDH1+ cells and increased stress and survival signaling in multiple TNBC cell lines, suggesting this sub-population contributes to TNBC chemoresistance. These results suggest the additive effects of PARP and PI3K inhibition against CSC phenotypes may be enhanced by temporally-staged administration in TNBC cells.

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy.

DNA density is a better indicator of a nuclear bleb than lamin B loss.

Nuclear blebs are herniations of the nucleus that occur in diseased nuclei that cause nuclear rupture leading to cellular dysfunction. Chromatin and lamins are two of the major structural components of the nucleus that maintain its shape and function, but their relative roles in nuclear blebbing remain elusive. Lamin B is reported to be lost in blebs by qualitative data while quantitative studies reveal a spectrum of lamin B levels in nuclear blebs dependent on perturbation and cell type. Chromatin has been reported to be decreased or de-compacted in nuclear blebs, but again the data are not conclusive. To determine the composition of nuclear blebs, we compared the immunofluorescence intensity of lamin B and DNA in the main nucleus body and nuclear bleb across cell types and perturbations. Lamin B nuclear bleb levels varied drastically across MEF wild type and chromatin or lamins perturbations, HCT116 lamin B1-GFP imaging, and human disease model cells of progeria and prostate cancer. However, DNA concentration was consistently decreased to about half that of the main nucleus body across all measured conditions. Using Partial Wave Spectroscopic (PWS) microscopy to measure chromatin density in the nuclear bleb vs body we find similar results that DNA is consistently less dense in nuclear blebs. Thus, our data spanning many different cell types and perturbations supports that decreased DNA is a better marker of a nuclear bleb than lamin B levels that vary widely.

The conformational landscape of human transthyretin revealed by cryo-EM.

Transthyretin (TTR) is a natively tetrameric thyroxine transporter found in blood and cerebrospinal fluid whose misfolding and aggregation causes transthyretin amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndaqel/Vyndamax) as an effective stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency-approved for the treatment of TTR amyloidosis. Despite 50 years of structural studies on TTR and this triumph of structure-based drug design, there remains a notable dearth of structural information available to understand ligand binding allostery and amyloidogenic TTR unfolding intermediates. We used single-particle cryo-electron microscopy (cryo-EM) to investigate the conformational landscape of this 55 kiloDalton tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states. These findings provide critical mechanistic insights into negatively cooperative ligand binding and the structural pathways responsible for TTR amyloidogenesis. This study underscores the capacity of cryo-EM to provide new insights into protein structures that have been historically considered too small to visualize and to identify pharmacological targets suppressed by the confines of the crystal lattice, opening uncharted territory in structure-based drug design.

Spindly reason for a pulmonary embolism.

Pulmonary artery intimal sarcomas (PAISs) are rare, malignant tumours that arise from the intimal or intramural wall of the pulmonary artery and are often mistaken for pulmonary emboli. Diagnosis and treatment of this condition are difficult due to the lack of formal guidelines. Initiating treatment as soon as possible after diagnosis is essential for maximising survival. Here, we present the case of a patient with a PAIS that initially presented similar to pulmonary thromboembolic disease and was treated with a multimodal approach.

Circular RNA Cdr1as inhibits proliferation and delays injury-induced regeneration of the intestinal epithelium.

Circular RNAs (circRNAs) are highly expressed in the mammalian intestinal epithelium, but their functions remain largely unknown. Here, we identified the circRNA Cdr1as as a repressor of intestinal epithelial regeneration and defense. Cdr1as levels increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with inflammatory bowel disease and sepsis. Ablation of the Cdr1as locus from the mouse genome enhanced renewal of the intestinal mucosa, promoted injury-induced epithelial regeneration, and protected the mucosa against colitis. We found approximately 40 microRNAs, including miR-195, differentially expressed between intestinal mucosa of Cdr1as-knockout (Cdr1as-/-) versus littermate mice. Increasing the levels of Cdr1as inhibited intestinal epithelial repair after wounding in cultured cells and repressed growth of intestinal organoids cultured ex vivo, but this inhibition was abolished by miR-195 silencing. The reduction in miR-195 levels in the Cdr1as-/- intestinal epithelium was the result of reduced stability and processing of the precursor miR-195. These findings indicate that Cdr1as reduces proliferation and repair of the intestinal epithelium at least in part via interaction with miR-195 and highlight a role for induced Cdr1as in the pathogenesis of unhealed wounds and disrupted renewal of the intestinal mucosa.

Patterns of interventions for central venous catheter-associated deep vein thrombosis and outcomes in cancer patients.

PURPOSE: This letter evaluated the impact of different management strategies, specifically the presence or absence of therapeutic anticoagulation, on clinical outcomes for central venous catheter (CVC)-associated deep vein thrombosis (DVT) in cancer patients. METHODS: One-hundred ninety-eight adult cancer patients with a confirmed CVC-associated DVT diagnosis from February 2013 and February 2021 were included. RESULTS: Incidence of symptomatic recurrent venous thromboembolism (VTE) was similar between patients who received therapeutic anticoagulation and those who did not (14% vs 16%, p = 0.807). In addition, therapeutic anticoagulation did not significantly alter the incidence of grade 3 and above bleeding events despite most patients having hematologic malignancies (9% vs 8%, p = 0.826). CONCLUSION AND RELEVANCE: Therapeutic anticoagulation was not associated with a reduction in the incidence of recurrent VTE or increase the incidence of bleeding in adult cancer patients following a CVC-associated DVT diagnosis.

Landmine Injury Resulting in Comminuted Lumbar Facet Fracture as a Cause of Lumbar Stenosis and Spondylolisthesis.

Lumbar facet fractures are rarely reported and have been linked to sports and spine surgery. We describe the case of a 77-year-old patient who sustained an injury from multiple landmine blasts during the Vietnam War. He had low back pain since that time, which was initially managed conservatively. However, the pain progressed over decades to severe neurogenic claudication that greatly restricted his quality of life. Neuroimaging revealed the presence of bone fragments impinging on the spinal canal at the L5/6 level (transitional anatomy) that resulted from a comminuted fracture of the lumbar facet at the inferior articular process. We performed an L5/6 decompressive laminectomy, with removal of these fragments, and posterior instrumented fusion, with substantial improvement in symptoms. This case illustrates a unique mechanism of lumbar facet fracture and the biomechanic origination, natural history, and optimal treatment of this entity. We expand on the spectrum of lumbosacral injuries associated with the combat blast injury that have only increased in prevalence in recent conflicts.

Cavernous venous malformations in and around the central nervous system. Part 1: Dural and extradural.

Cavernous-type malformations are venous lesions that occur in multiple locations throughout the body, and when present in the CNS, they have canonically been referred to as cavernomas, cavernous angiomas, and cerebral cavernous malformations. Herein all these lesions are referred to as "cavernous venous malformations" (CavVMs), which is congruent with the current International Society for the Study of Vascular Anomalies classification system. Even though histologically similar, depending on their location relative to the dura mater, these malformations can have different features. In Part 1 of this review, the authors discuss and review pertinent clinical knowledge with regard to CavVMs as influenced by anatomical location, starting with the dural and extradural malformations. They particularly emphasize dural CavVMs (including those in the cavernous sinus), orbital CavVMs, and spinal CavVMs. The genetic and histopathological features of CavVMs in these locations are reviewed, and commonalities in their presumed mechanisms of pathogenesis support the authors' conceptualization of a spectrum of a single disease entity. Illustrative cases for each subtype are presented, and the pathophysiological and genetic features linking dural and extradural to intradural CavVMs are examined. A new classification is proposed to segregate CavVMs based on the location from which they arise, which guides their natural history and treatment.

Brain AVM surgery without endovascular embolization in a low to middle income country.

We treated a 20-year-old woman in Paraguay with a ruptured intraventricular Spetzler-Martin Grade 3 AVM, and illustrate microsurgical resection without embolization in this video.

Patient perspectives on factors influencing active surveillance adherence for low-risk prostate cancer: A qualitative study.

BACKGROUND: Prostate cancer is the most common cancer among men in the United States. Treatment guidelines recommend active surveillance for low-risk prostate cancer, which involves monitoring for progression, to avoid or delay definitive treatments and their side effects. Despite increased uptake, adherence to surveillance remains a challenge. METHODS: We conducted semi-structured, qualitative, virtual interviews based on the Theoretical Domains Framework (TDF), with men (15) who were or had been on active surveillance for their low-risk prostate cancer in 2020. Interviews were transcribed and coded under TDF's behavioral theory-based domains. We analyzed domains related to adherence to surveillance using constructivist grounded theory to identify themes influencing decision processes in adherence. RESULTS: The TDF domains of emotion, beliefs about consequences, environmental context and resources, and social influences were most relevant to surveillance adherence-. From these four TDF domains, three themes emerged as underlying decision processes: trust in surveillance as treatment, quality of life, and experiences of self and others. Positive perceptions of these three themes supported adherence while negative perceptions contributed to non-adherence (i.e., not receiving follow-up or stopping surveillance). The relationship between the TDF domains and themes provided a theoretical process describing factors impacting active surveillance adherence for men with low-risk prostate cancer. CONCLUSIONS: Men identified key factors impacting active surveillance adherence that provide opportunities for clinical implementation and practice improvement. Future efforts should focus on multi-level interventions that foster trust in surveillance as treatment, emphasize quality of life benefits and enhance patients' interpersonal experiences while on surveillance to optimize adherence.

Prognostic factors for multisystem inflammatory syndrome in children: A systematic review and meta-analysis.

AIM: Multisystem inflammatory syndrome in children (MIS-C) is a novel condition that can occur post-SARS-CoV-2 infection in children and adolescents. There is a paucity of evidence on the prognostic factors associated with MIS-C. The aim of this systematic review and meta-analysis was to summarise the prognostic factors for MIS-C development. METHODS: Five databases were systematically searched from January 2020 to May 2023 for studies reporting on prognostic factors for MIS-C using multivariable regression models. Random-effects meta-analyses were conducted to pool odds ratios for each prognostic factor. Risk of bias was rated using QUIPS and the GRADE framework was used to assess the certainty of evidence for each unique factor. RESULTS: Twelve observational studies (N = 18 024) were included, and 13 unique prognostic factors were amenable to meta-analysis. With moderate certainty, age <12 years, male sex and Black race probably increase the risk of MIS-C. Malignancy and underlying respiratory disease probably decrease the risk of MIS-C. Low-certainty evidence suggests that Asian race may increase the risk of MIS-C, and comorbidity may decrease the risk of MIS-C. CONCLUSION: Current literature presents several prognostic factors related to MIS-C following SARS-CoV-2 infection. Further research is necessary to elucidate the pathophysiologic mechanisms related to MIS-C.

Syndrome of anterior neural stalk, vertebral abnormality, enteric duplication cyst, and diaphragmatic hernia related to persistent ventral neurenteric canal: report of two cases.

PURPOSE: Abnormalities in notochordal development can cause a range of developmental malformations, including the split notochord syndrome and split cord malformations. We describe two cases that appear related to unusual notochordal malformations, in a female and a male infant diagnosed in the early postnatal and prenatal periods, which were treated at our institution. These cases were unusual from prior cases given a shared constellation of an anterior cervicothoracic meningocele with a prominent "neural stalk," which coursed ventrally from the spinal cord into the thorax in proximity to a foregut duplication cyst. METHODS: Two patients with this unusual spinal cord anomaly were assessed clinically, and with neuroimaging and genetics studies. RESULTS: We describe common anatomical features (anterior neural stalk arising from the spinal cord, vertebral abnormality, enteric duplication cyst, and diaphragmatic hernia) that support a common etiopathogenesis and distinguish these cases. In both cases, we opted for conservative neurosurgical management in regards to the spinal cord anomaly. We proposed a preliminary theory of the embryogenesis that explains these findings related to a persistence of the ventral portion of the neurenteric canal. CONCLUSION: These cases may represent a form of spinal cord malformation due to a persistent neurenteric canal and affecting notochord development that has rarely been described. Over more than 1 year of follow-up while managed conservatively, there was no evidence of neurologic dysfunction, so far supporting a treatment strategy of observation.

Preventing Potential Patient Harm Through Clinical Content Interventions During Oncology Clinical Trial Implementation.

OBJECTIVES: Clinical trial documents are complex and may have inconsistencies, leading to potential site implementation errors and may compromise participant safety. This study characterizes the frequency and type of administrative and potential patient safety interventions (PPSIs) made during the review of oncology trial documents for clinical trial implementation by centralized clinical content specialists. METHODS: A dedicated group of centralized clinical content specialists reviewed trial documents, including the protocol, laboratory manual, and pharmacy/cellular therapy manual, and collected intervention data over a 1-year period. Each trial was categorized by study phase and sponsor type, and multiple interventions could be identified per trial. Interventions were deemed administrative or PPSIs, with PPSIs further subcategorized as medication, laboratory, procedure related, or other. RESULTS: Of 585 clinical trials reviewed, 269 (46%) required intervention(s). Among 1001 interventions, 171 (17.1%) were PPSIs. Most PPSIs were medication related (45.6%), with drug dosing interventions most frequently identified (53.8%). Phase 1 trials had the highest proportion of PPSIs (0.35:1) and administrative interventions (2:1) per trial compared with all other phases. Investigator-initiated trials saw the highest proportion of PPSIs per trial (0.44:1) of all sponsor types. CONCLUSIONS: This study demonstrates a gap in patient safety when assessing trial documents for clinical trial implementation. One solution to address this gap is the utilization of a centralized team of clinical specialists to preemptively review trial documents, thereby enhancing patient safety during clinical trial conduct.