Low Levels of Serum Sclerostin in Adult Patients With Tumor-Induced Osteomalacia Compared With X-linked Hypophosphatemia.

CONTEXT: Sclerostin inhibits Wnt-ß-catenin signaling, regulating bone formation. Circulating sclerostin was reported to be elevated in X-linked hypophosphatemia (XLH) patients, and sclerostin antibody (Scl-Ab) increased bone mass and normalized circulating phosphate in Hyp mice. However, circulating sclerostin levels in patients with acquired hypophosphatemia due to tumor-induced osteomalacia (TIO) are rarely reported. OBJECTIVE: This study was designed to evaluate serum sclerostin levels in TIO patients compared with age- and sex-matched healthy controls and XLH patients to analyze correlations with bone mineral density (BMD) and laboratory parameters. METHODS: This cross-sectional study determined serum sclerostin levels in 190 individuals, comprising 83 adult TIO patients, 83 adult healthy controls and 24 adult XLH patients. RESULTS: TIO patients (43 male, 40 female) aged 44.3 ±â€…8.7 (mean ± SD) years had lower levels of circulating sclerostin than controls (94.2 ±â€…45.8 vs 108.4 ±â€…42.3 pg/mL, P = 0.01), adjusted for age, gender, BMI, and diabetes rate. Sclerostin levels were positively associated with age (r = 0.238, P = 0.030). Male patients had higher sclerostin than female patients (104.7 ±â€…47.3 vs 83.0 ±â€…41.8 pg/mL, P = 0.014). Sclerostin levels were positively associated with L1-4 BMD (r = 0.255, P = 0.028), femoral neck BMD (r = 0.242, P = 0.039), and serum calcium (r = 0.231, P = 0.043). Comparison of sclerostin levels in TIO patients (n = 24, age 35.9 ±â€…7.3 years) vs XLH patients vs healthy controls revealed significant differences (respectively, 68.4 ±â€…31.3, 132.0 ±â€…68.8, and 98.6 ±â€…41.1 pg/mL, P < 0.001). CONCLUSION: Circulating sclerostin was decreased in TIO patients but increased in XLH patients, possibly due to histological abnormality and bone mass.

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

Myasthenia gravis associated with renal cell carcinoma: a paraneoplastic syndrome or just a coincidence.

BACKGROUND: Myasthenia gravis (MG) can occur as a paraneoplastic phenomenon associated with thymoma. The association of MG with renal cell carcinoma (RCC) is not clear. Herein, we describe six cases of MG associated with RCC. METHODS: There were 283 patients diagnosed with MG admitted to our hospital from 2014 to 2019. Among them, 6 patients also had RCC. None of them had immune checkpoint inhibitor therapies. We performed a retrospective clinical data collection and follow-up studies of these 6 patients. RESULTS: These 6 patients with an average MG onset age of 61.3 ± 13.3 years, were all positive for anti-acetylcholine receptor antibodies. MG symptoms appeared after RCC resection in 3 cases. RCC was discovered after the onset of MG in 2 cases, and synchronously with MG in 1 case. After nephrectomy, the MG symptoms showed a stable complete remission in 1 case. Among them, four patients met the diagnostic criteria of possible paraneoplastic neurological syndromes. CONCLUSIONS: Except for thymoma, patients with MG should pay attention to other tumors including RCC. MG may be a paraneoplastic syndrome of RCC, and further studies are needed to elucidate the relationship.

Prolonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report.

Introduction: Rare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized. Case Description: The current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up. Conclusions: The case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia.

Papel de la cianocobalamina en el abordaje práctico de la eritrodermia paraneoplásica / Role of Cyanocobalamin Levels in Managing Paraneoplastic Erythroderma: A Practical Approach

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Severe hypercalcemia caused by parathyroid hormone in a rectal cancer metastasis: a case report.

BACKGROUND: Hypercalcemia of malignancy is relatively common in several cancers. However, in colorectal cancer, paraneoplastic phenomena that cause hypercalcemia is uncommon. In the few cases that are reported, secretion of parathyroid hormone-related peptide mediates the effect. We describe the first case of severe hypercalcemia mediated by intact parathyroid hormone secretion from a bone metastasis of colorectal origin. This was a diagnostic and therapeutic challenge. CASE PRESENTATION: A 68-year-old male treated for rectal adenocarcinoma 10 years earlier developed a bone metastasis. After initial treatment of the metastasis with surgery and irradiation, he developed a relapse with severe hypercalcemia and corresponding elevated parathyroid hormone levels. The workup showed no signs of parathyroid adenomas, but the metastasis produced intact parathyroid hormone. The hypercalcemia was successfully treated by irradiation and osteoclast inhibitor, and the patient received chemotherapy. Survival was 24 months from the onset of hypercalcemia. CONCLUSIONS: Proper diagnosis of the uncommon endocrine disturbance allowed targeted therapy and avoidance of neck exploration for wrongly suspecting primary hyperparathyroidism. Intact parathyroid hormone should be measured in cases of malignant hypercalcemia.

Clinical Characteristics and Surgical Outcomes of Sinonasal Lesions Associated With Tumor-Induced Osteomalacia.

OBJECTIVE: To investigate the clinical characteristics and surgical outcomes of sinonasal tumors associated with tumor-induced osteomalacia (TIO). STUDY DESIGN: Retrospective case series. SETTING: Single tertiary center. METHODS: We studied the clinical characteristics and surgical outcomes of 43 patients (22 male, 21 female) who had lesions in the nasal cavity and paranasal sinus associated with TIO and underwent surgery between August 2006 and November 2019. RESULTS: The mean ± SD duration between the onset of symptoms and surgery was 3.9 ± 2.6 years. The most common tumor site was the ethmoid sinus (76.7%), and the skull base was involved in 12 cases. Phosphaturic mesenchymal tumors were diagnosed in 41 patients, among whom there was 1 multifocal case. Another 2 cases involved odontogenic fibroma and hemangiofibroma, respectively. Serum phosphorus normalized in 39 cases within 4.4 ± 2.3 days, and serum fibroblastic growth factor 23 normalized within 1 day; clinical symptoms, however, gradually improved within several months after the first operation. There was no significant difference in the recovery rate between endoscopic and open surgery (P = 0.639). Two patients with recurrent cases and 2 with nonremission cases recovered after a sinonasal reoperation. The patient with a multifocal case recovered after the resection of the tumors in the ethmoid sinus and mandible. The overall recovery rate was 97.7%. CONCLUSION: Most sinonasal tumors associated with TIO are located in the ethmoid sinus, and the skull base is involved in some cases. Complete excision of the tumor leads to recovery, and endoscopic surgery could achieve recovery rates similar to those of open surgery.

Paraneoplastic leukemoid reaction in a localised squamous cell oesophageal cancer with paracrine G-CSF production.

A 51-year-old-man presented with symptoms and baseline investigations suggestive of an infective process. Most strikingly, there was a pronounced neutrophil predominant leucocytosis. Lack of a clinical and biochemical response to empirical antibiotic therapy, prompted imaging for a deep-seated infective process, incidentally uncovering a gastro-oesophageal junction tumour. Resection of the tumour was followed by rapid resolution of the leucocytosis. He remains in clinical remission since tumour resection and adjuvant chemotherapy. Cancer-associated leukemoid reactions in non-disseminated tumours are rare. The role of polymorphonuclear (PMN) leucocytes both in the peripheral blood and the tumour itself is discussed herein. There is increasing recognition of the importance of the non-cancer cellular components of the tumour microenvironment. Myeloid suppressor cells are a subset of PMN leucocytes which play a role in tumour progression.The role of these cells and granulocyte colony-stimulating factor is highlighted in this case.

Detection of autoantibodies against alpha-2-macroglobulin-like 1 in paraneoplastic pemphigus sera utilizing novel green fluorescent protein-based immunoassays.

BACKGROUND: Paraneoplastic pemphigus (PNP) is a devastating autoimmune multiorgan syndrome associated with autoantibodies against several autoantigens, including the alpha-2-macroglobulin-like-1 (A2ML1). A2ML1 is recognized by up to 70 % of PNP sera. The currently recommended techniques for serological diagnosis of PNP are inadequate to detect anti-A2ML1 antibodies. OBJECTIVES: To develop novel assays which allow to easily and reliably detect anti-A2ML1 autoantibodies in PNP sera. METHODS: We produced full-length A2ML1 in fusion with enhanced green fluorescent protein (EGFP-A2ML1) in transfected human embryonic kidney 293 T cells. The recombinant protein was used as fluorescent ligand for immunoprecipitation studies. We further developed an enzyme-linked immunosorbent assay (ELISA) by immobilizing EGFP-A2ML1 on 96-well plates. RESULTS: A2ML1-positive PNP sera were able to immunoprecipitate EGFP-A2ML1. Direct measurement of fluorescence in immunoprecipitates correlates with the relative levels of anti-A2ML1 antibodies in the PNP sera. By the novel ELISA, based on the determined best cut-off value, 61 % of the tested 36 PNP sera were A2ML1 positive with a specificity of 88.9 % and a sensitivity of 95 %. The 20 tested normal sera (NHS) were negative, while 2 (10 %) of 20 pemphigus vulgaris and 3 (15 %) of 20 bullous pemphigoid sera showed borderline values. CONCLUSIONS: Our novel immunoassays enable rapid stratification of PNP patients. The novel green fluorescent protein-based ELISA utilizing an active eukaryotic A2ML1 is highly sensitive and reliable and, hence, is useful for a better understanding of the immunological background of PNP. This approach may be easily applied for the rapid detection of antibodies to various other antigens.

Anti-SOX1 antibody-positive paraneoplastic neurological syndrome presenting with Lambert-Eaton myasthenic syndrome and small cell lung cancer: A case report.

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti-SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61-year-old male patient who presented with an unusual anti-SOX1 positive PNS. The right tibialis anterior showed noticeable low-amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert-Eaton myasthenic syndrome (LEMS). Typical MRI and PET-CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5-6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

Tumor-Induced Osteomalacia and the Importance of Plasma Fibroblast Growth Factor 23 as an Indicator: Diagnostic Delay Leads to a Suicide Attempt.

Tumor-induced osteomalacia is a rare hypophosphatemic disease caused by unregulated production of fibroblast growth factor 23 by a tumor, thereby inducing renal phosphate wasting and inhibiting appropriate increase of calcitriol production. Symptoms of tumor-induced osteomalacia, including muscle weakness, bone pain, and pathologic fractures, are nonspecific and warrant further workup. We report the case of a 50-year-old African American female with no known psychiatric illness who was admitted after a failed suicide attempt provoked by severe bone pain. She had been treated for fibromyalgia and hypophosphatemic rickets at other facilities with no improvement. The findings of profound renal phosphate wasting initiated further evaluation, which revealed an elevated fibroblast growth factor 23 level and a right proximal fibular mesenchymal tumor on octreotide scintigraphy. Magnetic resonance imaging confirmed the findings of a solid intramuscular tumor corresponding to the octreotide avid lesion. After wide excision of the tumor, serum phosphate and parathyroid hormone levels began to normalize. This case highlights the importance of extensively investigating the cause of bone pain, weakness, and fatigue in patients without a family history of hypophosphatemia or bone disorders. The aforementioned symptoms may precede recurrent pathological fractures, and a thorough workup ensures that a diagnosis of tumor is not delayed or overlooked, as tumor resection confers a favorable prognosis and dramatic increase in the quality of life for patients.

Phosphodiesterase 10A IgG: A novel biomarker of paraneoplastic neurologic autoimmunity.

OBJECTIVE: To describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG). METHODS: We describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia-predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments. RESULTS: The median patient age was 70 years (range 66-76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry. CONCLUSIONS: PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.

Prognostic Impact of Increased Perioperative Platelet Count in Gastric Cancer Patients.

BACKGROUND: Solid tumors are a common cause of secondary (reactive) thrombocytosis, a paraneoplastic syndrome that is also a prognostic factor for various cancers. However, cutoff values for platelet count specific to gastric cancer and their prognostic roles are unknown. METHODS: We retrospectively analyzed records of 4643 patients with gastric cancer who underwent radical surgery from 2007 to 2010. The minimum P-value approach was used with the log-rank test to determine the optimal prognosis predicting threshold for preoperative platelet count. Change in perioperative platelet count over time was evaluated with a generalized estimating equation. Clinicopathologic features and prognostic significance were analyzed according to platelet count. RESULTS: Thrombocytosis prevalence (platelet count ≥40 × 104/µL) was 1.6% (75 of 4643 patients). The platelet count cutoff value with the lowest P-value was ≥25.5 × 104/µL, and patients with higher platelet count had more advanced disease. Multivariate analysis showed that cutoff value was an independent prognostic factor of overall survival (hazard ratio 1.19, 95% confidence interval 1.03-1.37, P = 0.017). Patients who underwent adjuvant chemotherapy (n = 1300) and had a greater than 10% increase in platelet count at postoperative 1 y compared to before surgery had significantly poorer overall survival (hazard ratio 1.65, 95% confidence interval 1.11-2.45, P = 0.013). CONCLUSIONS: Elevated preoperative platelet count (≥25.5 × 104/µL) and increased platelet count (≥10%) at postoperative 1 y in an adjuvant chemotherapy group were unfavorable prognostic factors. Platelet count could be a cost-effective biomarker for screening and monitoring patients with unfavorable survival outcomes.