Lambert-Eaton syndrome antibodies target multiple subunits of voltage-gated Ca2+ channels.

INTRODUCTION: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune presynaptic neuromuscular disorder. Autoantibodies against subunits of voltage-gated calcium channels (VGCCs) associated with acetylcholine release are thought to cause LEMS. METHODS: HEK293 cells expressing specific individual recombinant subunits of α(1A), α(1B), α(1C), and α(1E); ß(3); and α(2)δ of human neuronal VGCCs were exposed to antibodies from 3 LEMS patients, 1 patient with small-cell lung carcinoma, and 1 with myasthenia gravis. RESULTS: All LEMS patient antibodies bound to cells containing any of the α(1) or ß(3) subunits alone or combined with α(2)δ subunits, but not α(2)δ alone. Autoantibodies from the patient with small-cell lung carcinoma but not the myasthenia gravis patient targeted the same VGCC subunits. CONCLUSIONS: Autoantibodies from LEMS patients bind directly to multiple VGCC α(1) subunits as well as the ß(3) subunit. Thus, multiple components of the presynaptic VGCC complex are prospective targets for antibodies in LEMS.

Malignant primary tumors of scalp with cranial extension: multidisciplinary surgical strategies and outcomes.

OBJECTIVE: Malignant cancers arising in the scalp may exhibit calvarial invasion, dural extension, and rarely cerebral involvement. Typically, such lesions require a multidisciplinary approach involving both neurosurgery and plastic surgery for optimal resection and reconstruction. The authors present a retrospective analysis of patients with scalp malignancies who underwent resection and reconstruction. METHODS: Patients presenting with scalp malignancies (1993-2021, n = 84) who required neurosurgical assistance for tumor resection were prospectively entered into a database. These data were retrospectively reviewed for this case series. The extent of neurosurgical resection was classified into four levels of involvement: scalp (level I), calvarial (level II), dural (level III), or intraparenchymal (level IV). Complications and evidence of local, locoregional, or regional recurrence were documented. RESULTS: Patients underwent level I (n = 2), level II (n = 61), level III (n = 13), and level IV (n = 8) resections. Pathologies consisted of primarily squamous cell carcinoma (n = 50, 59.5%), basal cell carcinoma (n = 11, 13.1%), and melanoma (n = 9, 10.7%), with infrequent lesions including sarcoma, atypical fibroxanthoma, and malignant fibrous histiocytoma. For cases requiring a cranioplasty, 92.2% were done using titanium mesh and 7.8% with methylmethacrylate. At a mean follow-up of 35.5 ± 45.9 months, the overall survival was 48.8% (n = 41) and recurrence-free survival was 31.0% (n = 43). Scalp-based reconstruction involving plastic surgery was performed in 75 (89.3%) patients. The most commonly used free flap was a latissimus dorsi muscle flap (n = 46, 61.3%). One or more postoperative complications occurred in 21.4% of all patients, the most common being wound dehiscence or delayed wound healing in 13% (n = 11). CONCLUSIONS: A multidisciplinary approach with aggressive neurosurgical resection is associated with good outcomes in patients with primary malignant scalp tumors, despite invasive disease on presentation. This analysis suggests that aggressive resection (level II and higher) is effective at reducing locoregional recurrence and is not associated with a higher risk of complications relative to resection without craniectomy. As most patients require scalp reconstruction to close the postresection defect, usually with vascularized free tissue transfer, involving a plastic surgeon in the surgical planning and execution is essential.

Ventriculoperitoneal shunting with an on-off valve for patients with leptomeningeal metastases and intracranial hypertension.

Background: We report our experience with using a ventriculoperitoneal shunt (VPS) with an on-off valve and in-line Ommaya reservoir for the treatment of hydrocephalus or intracranial hypertension in patients with leptomeningeal disease (LMD). Our goal was to determine whether control of intracranial pressure elevation combined with intrathecal (IT) chemotherapy would extend patient survival. Methods: In this IRB-approved retrospective study, we reviewed 58 cases of adult patients with LMD from solid cancers who received a VPS with a reservoir and an on-off valve at M D Anderson Cancer Center from November 1996 through December 2021. Primary tumors were most often melanoma (n = 19) or breast carcinoma (n = 20). Hydrocephalus was diagnosed by clinical symptoms and findings on magnetic resonance imaging (MRI), and LMD by MRI or cerebrospinal fluid analysis. Differences in overall survival (OS) were assessed with standard statistical techniques. Results: Patients who received a VPS and more than 3 IT chemotherapy sessions survived longer (n = 26; OS time from implantation 11.7 ± 3.6 months) than those who received an occludable shunt but no IT chemotherapy (n = 24; OS time from implantation 2.8 ± 0.7 months, P < .018). Peritoneal seeding appeared after shunt insertion in only two patients (3%). Conclusions: This is the largest series reported to date of patients with LMD who had had shunts with on-off valves placed to relieve symptoms of intracranial hypertension. Use of IT chemotherapy and control of hydrocephalus via such shunts was associated with improved survival.

Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function.

Mutations of succinate dehydrogenase subunit B (SDHB) play a crucial role in the pathogenesis of the most aggressive and metastatic pheochromocytomas (PHEOs) and paragangliomas (PGLs). Although a variety of missense mutations in the coding sequence of the SDHB gene have been found in PHEOs and PGLs, it has been unclear whether these mutations impair mRNA expression, protein stability, subcellular localization, or intrinsic protein function. RT-PCR and Western blot analysis of SDHB mRNA and protein expression from SDHB-related PHEOs and PGLs demonstrated intact mRNA expression but significantly reduced protein expression compared to non-SDHB PHEOs and PGLs. A pulse-chase assay of common SDHB missense mutations in transfected HeLa cell lines demonstrated that the loss of SDHB function was due to a reduction in mutant protein half-life, whereas colocalization of SDHB with mitochondria and immunoprecipitation with SDHA demonstrated intact subcellular localization and complex formation. The half-life of the SDHB protein increased after treatment with histone deacetylase inhibitors (HDACis), implicating the protein quality control machinery in the degradation of mutant SDHB protein. These findings provide the first direct mechanism of functional loss resulting from SDHB mutations and suggest that reducing protein degradation with HDACis may serve as a novel therapeutic paradigm for preventing the development of SDHB-related tumors.

Self-reported evaluation of competencies and attitudes by physicians-in-training before and after a single day legislative advocacy experience.

BACKGROUND: Advocacy is increasingly being recognized as a core element of medical professionalism and efforts are underway to incorporate advocacy training into graduate and undergraduate medical school curricula. While limited data exist to quantify physician attitudes toward advocacy, even less has been done to assess the knowledge, skills, and attitudes of future physicians. The purpose of this study was to assess students' experiences and attitudes toward legislative advocacy, cutting out using a convience sample. METHODS: A paper survey based on previously validated surveys was administered to a convenience sample of premedical and medical student participants attending a National Advocacy Day in Washington, DC, in March 2011, both before and after their advocacy experiences. Responses were anonymous and either categorical ( or ordinal, using a 5-point Likert scale. Data were analyzed statistically to evaluate demographics and compare changes in pre- and post-experience attitude and skills. RESULTS: Data from 108 pre-advocacy and 50 post-advocacy surveys were analyzed yielding a response rate of 46.3%. Following a single advocacy experience, subjects felt they were more likely to contact their legislators about healthcare issues (p = 0.03), to meet in person with their legislators (p < 0.01), and to advocate for populations' health needs (p = 0.04). Participants endorsed an increased perception of the role of a physician advocate extending beyond individual patients (p = 0.03). Participants disagreed with the statement that their formal curricula adequately covered legislative healthcare advocacy. Additionally, respondents indicated that they plan to engage in legislative advocacy activities in the future (p < 0.01). CONCLUSIONS: A one-time practical advocacy experience has a positive influence on students' knowledge, skills and attitudes towards legislative advocacy. Practical experience is an important method of furthering medical education in advocacy and further research is necessary to assess its impact in a broader population.

A Case Report of Siblings with Dystonia: A Potential Link Between DYT11 Mutation and Platelet Dysfunction.

Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon-sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.

A case of multiple synchronously diagnosed brain metastases from alveolar soft part sarcoma without concurrent lung involvement.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a propensity for early hematogenous dissemination to the lungs and frequent brain metastasis. The development of lung metastasis almost invariably precedes intracranial involvement. There are no previously reported cases in which a patient was synchronously diagnosed with ASPS and multiple brain metastasis without lung involvement. CASE DESCRIPTION: A 29-year-old gentleman was found to have three intracranial lesions following the onset of generalized seizures. Staging studies identified a soft-tissue mass in the left thigh and an adjacent femoral lesion. Biopsy of the soft-tissue mass was consistent with ASPS. The patient then underwent neoadjuvant stereotactic radiotherapy to all three brain lesions, followed by en bloc resection of the dominant lesion. The patient was then started on a programmed death-ligand 1 (PD-L1) inhibitor. Subsequent surgical resection of the primary lesion and femur metastasis demonstrates a histopathologic complete response of the bony metastasis and partial response of the primary lesion. At present, the patient has received 14 cycles of atezolizumab without recurrence of the primary or bony lesions and the irradiated intracranial disease has remained stable without recurrence of the resected dominant lesion. CONCLUSION: While intracranial involvement is relatively common in ASPS, a case with multiple, synchronously diagnosed brain metastasis without concurrent lung metastasis has not been described. The presented case discusses the safety and efficacy of aggressive management of intracranial disease in the setting of atezolizumab. Prospective evaluation of the efficacy of checkpoint inhibitors and the prognostic value of PD-L1 expression in ASPS with brain metastasis are necessary.

Venous infarction secondary to congestive encephalopathy from central venous occlusive disease in a chronic hemodialysis patient: A case report.

Central venous occlusive disease secondary to chronic hemodialysis catheterization rarely progresses to encephalopathy, cerebral infarction, and/or hemorrhage. A 59-year-old male with 15 years of haemodialysis-dependent end-stage renal disease presented with acutely altered mental status, extensor rigidity with left hemiparesis and equal, but small and nonreactive pupils. Magnetic resonance imaging demonstrated infarction and cerebral edema. Cranial angiogram through right brachial artery injection revealed right subclavian vein opacification via a patent AV-fistula and retrograde flow to the right internal jugular vein and superior sagittal sinus secondary to occlusion of the brachiocephalic vein. All cerebral and right upper extremity venous drainage occurred via the contralateral venous outflow tract. Internal carotid artery injections revealed significant venous congestion. Despite successful angioplasty with stenting and resolution of venous flow reversal, the patient failed to recover neurologically. The devastating nature of the presented case emphasizes the need for frequent neurologic evaluation of such patients to avoid catastrophic cerebrovascular injury.

Direct Comparison of Posterior Subthalamic Area Stimulation versus Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

In this case report, we describe successful tremor capture via stimulation of the posterior subthalamic area (PSA) for a patient with tremor-predominant Parkinson's disease. In this scenario, the patient had a deep brain stimulation (DBS) lead placed in the PSA of the right hemisphere and a DBS lead placed in the subthalmic nucleus (STN) of the left hemisphere. Therefore, we were able to directly compare tremor capture in the same patient receiving stimulation in two different brain areas. We show that both placements are equally efficacious for tremor suppression, though the DBS lead placed in the PSA required slightly higher current intensity. This comparison in the same patient confirms that stimulation of the PSA can successfully suppress tremor in Parkinson's disease.

The acute phase protein haptoglobin regulates host immunity.

The contribution of acute phase plasma proteins to host immune responses remains poorly characterized. To better understand the role of the acute phase reactant and major hemoglobin-binding protein haptoglobin (Hp) on the function of immune cells, we generated Hp-deficient C57BL/6J mice. These mice exhibit stunted development of lymphoid organs associated with lower counts of mature T and B cells in the blood and secondary lymphoid compartments. Moreover, these mice show markedly reduced adaptive immune responses as represented by reduced accumulation of IgG antibody after immunization with adjuvant and nominal antigen, abrogation of Th1-dominated delayed-type hypersensitivity reaction, loss of mitogenic responses mounted by T cells, and reduced T cell responses conveyed by APCs. Collectively, these defects are in agreement with the observations that Hp-deficient mice are not capable of generating a recall response or deterring a Salmonella infection as well as failing to generate tumor antigen-specific responses. The administration of Hp to lymphocytes in tissue culture partially ameliorates these functional defects, lending further support to our contention that the acute phase response protein Hp has the ability to regulate immune cell responses and host immunity. The phenotype of Hp-deficient mice suggests a major regulatory activity for Hp in supporting proliferation and functional differentiation of B and T cells as part of homeostasis and in response to antigen stimulation.

The Preventable Shunt Revision Rate: A Multicenter Evaluation.

BACKGROUND: The Preventable Shunt Revision Rate (PSRR) was recently introduced as a novel quality metric. OBJECTIVE: To evaluate the PSRR across multiple centers and determine associated variables. METHODS: Nine participating centers in North America provided at least 2 years of consecutive shunt operations. Index surgery was defined as new shunt implantation, or revision of an existing shunt. For any index surgery that resulted in a reoperation within 90-days, index surgery information (demographic, clinical, and procedural) was collected and a decision made whether the failure was potentially preventable. The 90-day shunt failure rate and PSRR were calculated per institution and combined. Bivariate analyses were performed to evaluate individual effects of each independent variable on preventable shunt failure followed by a final multivariable model using a backward model selection approach. RESULTS: A total of 5092 shunt operations were performed; 861 failed within 90 days of index operation, resulting in a 16.9% combined 90-day shunt failure rate and 17.6% median failure rate (range, 8.7%-26.9%). Of the failures, 307 were potentially preventable (overall and median 90-day PSRR, 35.7% and 33.9%, respectively; range, 16.1%-55.4%). The most common etiologies of avoidable failure were infection (n = 134, 44%) and proximal catheter malposition (n = 83, 27%). Independent predictors of preventable failure (P < .05) were lack of endoscopy (odds ratio [OR] = 2.26), recent shunt infection (OR = 3.65), shunt type (OR = 2.06) and center. CONCLUSION: PSRR is variable across institutions, but can be 50% or higher. While the PSRR may never reach zero, this study demonstrates that overall about a third of early failures are potentially preventable.

A unique form of haptoglobin produced by murine hematopoietic cells supports B-cell survival, differentiation and immune response.

Haptoglobin (Hp), an acute phase reactant and major hemoglobin-binding protein, has a unique role in host immunity. Previously, we demonstrated that Hp-deficient C57BL/6J mice exhibit stunted development of mature T- and B-cells resulting in markedly lower levels of antigen-specific IgG. The current study identified leukocyte-derived pro-Hp as a relevant mediator of an optimal immune response. Reconstitution of Hp-/- mice with Hp+/+ bone marrow restored normal immune response to ovalbumin. Furthermore, transplanting a mixture of bone marrow-derived from B-cell-deficient and Hp-deficient mice into Rag1-/-/Hp+/+ recipients resulted in mice with a defective immune response similar to Hp-/- mice. This suggests that Hp generated by the B-cell compartment, rather than by the liver, is functionally contributing to a normal immune response. Leukocytes isolated from the spleen express Hp and release a non-proteolytically processed pro-Hp that uniquely differed from liver-derived Hp by not binding to hemoglobin. While addition of purified plasma Hp to cultured B-cells did not alter responses, pro-Hp isolated from splenocytes enhanced cellular proliferation and production of IgG. Collectively, the comparison of wild-type and Hp-deficient mice suggests a novel regulatory activity for lymphocyte-derived Hp, including Hp produced by B-cells themselves, that supports in vivo survival and functional differentiation of the B-cells to ensure an optimal immune response.

Healthcare reform and the next generation: United States medical student attitudes toward the Patient Protection and Affordable Care Act.

CONTEXT: Over one year after passage of the Patient Protection and Affordable Care Act (PPACA), legislators, healthcare experts, physicians, and the general public continue to debate the implications of the law and its repeal. The PPACA will have a significant impact on future physicians, yet medical student perspectives on the legislation have not been well documented. OBJECTIVE: To evaluate medical students' understanding of and attitudes toward healthcare reform and the PPACA including issues of quality, access and cost. DESIGN, SETTING, AND PARTICIPANTS: An anonymous electronic survey was sent to medical students at 10 medical schools (total of 6982 students) between October-December 2010, with 1232 students responding and a response rate of 18%. MAIN OUTCOME MEASURES: Medical students' views and attitudes regarding the PPACA and related topics, measured with Likert scale and open response items. RESULTS: Of medical students surveyed, 94.8% agreed that the existing United States healthcare system needs to be reformed, 31.4% believed the PPACA will improve healthcare quality, while 20.9% disagreed and almost half (47.7%) were unsure if quality will be improved. Two thirds (67.6%) believed that the PPACA will increase access, 6.5% disagreed and the remaining 25.9% were unsure. With regard to containing healthcare costs, 45.4% of participants indicated that they are unsure if the provisions of the PPACA will do so. Overall, 80.1% of respondents indicated that they support the PPACA, and 78.3% also indicated that they did not feel that reform efforts had gone far enough. A majority of respondents (58.8%) opposed repeal of the PPACA, while 15.0% supported repeal, and 26.1% were undecided. CONCLUSION: The overwhelming majority of medical students recognized healthcare reform is needed and expressed support for the PPACA but echoed concerns about whether it will address issues of quality or cost containment.