Hypoalbuminemia and hypercalcemia are independently associated with poor treatment outcomes of anti-PD-1 immune checkpoint inhibitors in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Recent randomized phase III trials have demonstrated the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in treating patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC). However, a large proportion of such patients still have poor response. This study aimed to identify biomarkers for predicting anti-PD-1 ICI treatment outcomes . METHODS: We retrospectively analyzed 144 patients with RMHNSCC who received anti-PD-1 ICIs after progression to platinum-based chemotherapy between January 2017 and December 2022 at Kaohsiung Chang Gung Memorial Hospital. Data on clinicopathological parameters, albumin levels, calcium levels, and other pretreatment peripheral blood biomarkers, including total lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI) were collected and correlated with the treatment outcome of anti-PD-1 ICIs. RESULTS: Low tumor proportion score (TPS), low combined positive score (CPS), NLR ≥ 5, PLR ≥ 300, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly correlated with poor response of ICIs. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL, respectively (P = 0.007). The overall response rates were 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL, respectively (P < 0.001). Univariate survival analysis showed that low TPS, low CPS, NLR ≥ 5,, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly associated with worse progression-free survival (PFS) and inferior overall survival (OS). Multivariate analysis revealed that calcium ≥ 10 mg/dL and albumin < 4 g/dL were independent poor prognosticators for worse PFS and inferior OS. The two-year OS rates were 26% and 9% in patients with calcium < 10 mg/dL and ≥ 10 mg/dL, respectively (P < 0.001). The two-year OS rates were 10% and 33% in patients with albumin < 4 g/dL and ≥ 4 g/dL, respectively (P < 0.001). CONCLUSIONS: Hypercalcemia and hypoalbuminemia can potentially predict poor treatment outcomes of anti-PD-1 ICIs in patients with RMHNSCC. Blood calcium and albumin levels may be helpful in individualizing treatment strategies for patients with RMHNSCC.

Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight.

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Risedronate prevents exercise-induced hypercalcemia but not nausea or vomit in humans: a double blind randomized controlled trial.

Reportedly, nausea or vomiting after heavy exercise was associated with post-exercise increased blood calcium (Ca) levels, which was correlated with enhanced bone resorption. We conducted a randomized, double-blind, placebo-controlled trial, enrolling 104 healthy trained male members of the Japan Ground Self-Defense Forces. Risedronate (17.5 mg) or placebo was prescribed 3 and 10 days before heavy exercise lasting approximately 5 h. The primary outcome was the severity of nausea or vomiting assessed by a visual analog scale during or post-exercise. The secondary outcomes included clinical symptoms associated with heat illness, post-exercise serum total Ca (tCa), whole blood ionized Ca (iCa), and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels. The mean age was 26 years. The exercise resulted in a 4.5% weight loss. The two groups were comparable in terms of the symptoms, including primary outcome. However, post-exercise tCa and TRACP-5b were significantly lower with risedronate. A similar result was observed for iCa. The post-exercise urinary Ca/Magnesium ratio and the incidence of hypercalcemia (defined as tCa or iCa levels ≥ each median value of all subjects) were significantly lower with risedronate (78.0% vs. 58.5%). A stronger treatment effect of risedronate on blood Ca levels was observed in participants who lost substantial body weight. Post-exercise hypercalcemia is attributed to enhanced bone resorption but not the cause of nausea.

A rare case of ovarian hypercalcemia type small cell carcinoma.

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Posterior Reversible Encephalopathy Syndrome Due to Vitamin D Toxicity.

Although toxicity from excessive exogenous vitamin D supplementation is rare, a range of symptoms can occur, most of which result from hypercalcemia. We report a novel case of posterior reversible encephalopathy syndrome (PRES) in a young child who required intensive care after presenting with hypercalcemia, hypertensive emergency, acute kidney injury, and hypercarbic respiratory failure, which ultimately were attributed to vitamin D toxicity (VDT). We report a young child who developed PRES in association with VDT. Our report informs pediatric outpatient, hospitalist, and intensivist providers about rare but life-threatening complications from hypervitaminosis D, adds VDT to the differential diagnosis for children with similar presentations, and highlights the importance of vitamin supplementation safety guidance for families.

Electrolyte and Acid-Base Abnormalities After Kidney Transplantation.

Kidney transplantation is the optimal therapeutic approach for individuals with end-stage kidney disease. The Scientific Registry of Transplant Recipients has reported a continuous rise in the total number of kidney transplants performed in the United States, with 25,500 new kidney recipients in 2022 alone. Despite an improved glomerular filtration rate, the post-transplant period introduces a unique set of electrolyte abnormalities that differ from those encountered in chronic kidney disease. A variety of factors contribute to the high prevalence of hypomagnesemia, hyperkalemia, metabolic acidosis, hypercalcemia, and hypophosphatemia seen after kidney transplantation. These include the degree of allograft function, immunosuppressive medications and their diverse mechanisms of action, and metabolic changes after transplant. This article aims to provide a comprehensive review of the key aspects surrounding the most commonly encountered electrolyte and acid-base abnormalities in the post-transplant setting.

Massive cerebral tuberculomas, Pott's disease and hypercalcaemia secondary to Mycobacterium bovis in a patient with chronic kidney disease on peritoneal dialysis.

Tuberculosis (TB) is still a health problem in developing countries. Pulmonary involvement remains the most common clinical presentation. However, multiorgan involvement can be life-threatening. We present the case of a young woman on peritoneal dialysis who was admitted to hospitalisation for hypercalcaemia and low back pain. In his biochemical evaluation, suppressed intact parthyroid hormone (iPTH) and elevated 1,25-hydroxyvitamin D were detected. On a lumbar CT scan, a hypodense lesion in vertebral bodies compatible with Pott's disease was found. Positive cultures for Mycobacterium bovis were obtained in bronchoalveolar lavage and peritoneal fluid, for which specific treatment was initiated. Due to neurological deterioration, a CT scan was performed showing the presence of multiple tuberculomas. Retrospectively, the lack of an etiological diagnosis of chronic kidney disease, the initiation of dialysis 8 months before and the clear evidence of long-standing TB strongly suggest mycobacterium infection as the cause or trigger for the rapid decline in kidney function.

[Familial Hypocalciuric Hypercalcemia Type 1 Likely Secondary to a New Inactivating Mutation of CASR].

Familial Hypocalciuria Hypercalcemia (FHH) is an inherited disease with autosomal dominant transmission characterized by the presence of usually mild-to-moderate hypercalcemia, hypophosphatemia, hypocalciuria, and normal or moderately increased PTH values. Generally, FFH is asymptomatic although symptoms related to elevated plasma calcium values such as asthenia, intense thirst, polyuria, polydipsia or confusional state may occur. Three types of FHH, which differ in the genetic alterations underlying the condition, are described. The majority of FHH cases are classified as type 1 (about 65 percent of cases), due to mutation in the gene for the calcium-sensitive receptor CASR, expressed on chromosome (Chr) 3q13.3-21, which encodes for a calcium-sensitive receptor G-protein-coupled protein of the plasma membrane. FHH types 2 and 3 are due to GNA11 and AP2S1 mutations, respectively, and other genes involved in the pathogenesis of the disease have likely yet to be identified. Rarely, familial hypocalciuric hypercalcemia may not recognize a genetic cause but be caused by autoantibodies directed against CASR. The frequency of the disease is not known and is estimated, probably by default, because of paucisymptomatic presentation of the disease, to be around 1:80000 cases. Recognition of FHH is especially important for differential diagnosis with primary hyperparathyroidism, which has a much higher incidence, about 1:1000 cases. This allows for the identification of patients at risk for chondrocalcinosis and/or pancreatitis. Clinical suspicion must be raised in cases of hypercalcaemia associated with hypocalciuria, and genetic analysis is fundamental in the differential diagnosis toward forms of primary hyperparathyroidism that might result in unnecessary surgical interventions. We describe a clinical case in which a novel inactivating mutation of CASR leading to FHH type 1 was found.

Lithium-associated hypercalcemia and hyperparathyroidism: A systematic review and meta-analysis.

OBJECTIVES: We aimed to review and summarise the existing human literature on the association between lithium and hyperparathyroidism. METHODS: A systematic literature search was carried out according to PRISMA guidelines (last search 27 February 2024), using MEDLINE, Web of Science, Embase and the Cochrane Library. A meta-analysis was performed to determine the prevalence of lithium-associated hypercalcemia (LAHca) in lithium-treated patients. RESULTS: The pooled prevalence of LAHca based on total calcium and ionised calcium was comparable, at 3.17% and 4.23%, respectively. Calcium, and PTH if the patient is hypercalcaemic, is insufficiently measured in lithium-treated patients in clinical practice. Lithium use is associated with higher calcium and PTH levels, as well as a higher incidence of hyperparathyroidism. There is a high prevalence of multiglandular disease in lithium-associated hyperparathyroidism (LAH), with a pooled prevalence of 51.28%. Parathyroid surgery and cinacalcet are effective treatments for LAH. Regarding lithium discontinuation, there is anecdotal but conflicting evidence suggesting that it can result in the resolution of LAH in selected cases. CONCLUSIONS: Lithium treatment increases the risk of hyperparathyroidism, a treatable complication with a pooled prevalence of around 4%, compared to 0.5% in the healthy population.

Regional citrate anticoagulation with continuous renal replacement therapy as a cause of hypercalcemia.

CLINICAL RELEVANCE: Awareness of the causes of hypercalcemia is essential for timely diagnosis of calcium disorders and optimal treatment. Citrate is commonly used as an anticoagulant during continuous renal replacement therapy (CRRT). Accumulation of citrate in the systemic circulation during CRRT may induce several metabolic disturbances, including total hypercalcemia and ionized hypocalcemia. The aim of the present study is to increase awareness of citrate accumulation and toxicity as a cause of hypercalcemia by relating three cases and reviewing the pathophysiology and clinical implications. OBSERVATIONS: We utilized electronic health records to examine the clinical cases and outlined key studies to review the consequences of citrate toxicity and general approaches to management. CONCLUSIONS: Citrate toxicity is associated with high mortality. A safe threshold for tolerating hypercalcemia during citrate anticoagulation is not clearly defined, and whether citrate toxicity independently increases mortality has not been resolved. Greater attention to citrate toxicity as a cause of hypercalcemia may lead to earlier detection, help to optimize the management of systemic calcium levels, and foster interest in future clinical studies.

Familial hypocalciuric hypercalcemia in an infant: diagnosis and management quandaries.

Familial hypocalciuric hypercalcemia (FHH) is typically a benign condition characterized by elevated serum calcium, low urinary calcium excretion, and non-suppressed circulating levels of parathyroid hormone (PTH), usually requiring no intervention. FHH is inherited in an autosomal-dominant manner. Three subtypes are described, representing variants in genes with critical roles in extracellular calcium-sensing. FHH1, due to heterozygous inactivating variants in the calcium-sensing receptor gene (CASR), accounts for the majority of cases. FHH2, due to variants in GNA11, encoding the α-subunit of the downstream signaling protein, G11, is the rarest form of FHH. FHH3, resulting from variants in AP2S1, may present with a more pronounced phenotype than FHH1 or FHH2. We describe herein a newborn girl presenting with in utero femoral fractures, hypercalcemia, hypophosphatemia, and elevated circulating PTH. She was diagnosed with mild hyperparathyroidism and provided supplemental phosphate upon hospital discharge. However, serum calcium and PTH remained elevated at 5 mo of age. The combination of low-calcium formula and cinacalcet improved the biochemical profile. No pathogenic variants in the coding region of CASR were identified; subsequent whole exome sequencing revealed a G- > T transition at c.44 (p.R15L) in AP2S1. Family studies identified this variant in the father and an affected brother. The mother was unexpectedly found to be hypocalcemic and was diagnosed with idiopathic hypoparathyroidism. This case demonstrates successful treatment of FHH3 using a low-calcium formula to limit dietary calcium availability and cinacalcet to modify PTH levels.

An infant girl with a history of an in utero femoral fracture and a maternal history of hypoparathyroidism presented with persistent hypercalcemia, hypophosphatemia, and elevated parathyroid hormone levels. Despite receiving supplemental phosphorus upon hospital discharge, her serum calcium and PTH levels remained elevated at 4 mo of age, and she was diagnosed with FHH type 3. Family studies also identified the presence of this variant in her father and an affected brother. After a trial with bisphosphonate failed to decrease calcium levels, she was treated with a combination of low-calcium formula and cinacalcet, which improved her biochemical profile. The patient remained on a stable clinical course on this regimen until she was weaned off cinacalcet at the age of 4 yr.

MR imaging diagnosis of small-cell carcinoma of the ovary, hypercalcemic type: A case report and literature review.

RATIONALE: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive gynecological tumor. We retrospectively analyzed the clinical manifestations and imaging findings of this patient and analyzed the relevant literature, with the aim of improving the ability of radiologists to differentiate SCCOHT from other ovarian tumors. PATIENT CONCERNS: We report a case of 36-year-old woman who was diagnosed with SCCOHT. MRI suggested a malignant tumor of the left ovary. The immunohistochemical markers shows SMARCA4 negativity. Notably, hypercalcemia was not detected. Microscopically, it was consistent with the large-cell variants. LESSIONS: Despite its rarity, SCCOHT should still be considered in the differential diagnosis of ovarian malignancies. When a young female patient presents with a large unilateral tumor on MRI with a predominant solid component and significant enhancement on the contrast enhanced scans, along with hypercalcemia, SCCOHT should be considered.

Early detection of multiple endocrine neoplasia type 1: A case report.

BACKGROUND: Multiple endocrine neoplasias (MENs) are a group of hereditary diseases involving multiple endocrine glands, and their prevalence is low. MEN type 1 (MEN1) has diverse clinical manifestations, mainly involving the parathyroid glands, gastrointestinal tract, pancreas and pituitary gland, making it easy to miss the clinical diagnosis. CASE SUMMARY: We present the case of a patient in whom MEN1 was detected early. A middle-aged male with recurrent abdominal pain and diarrhea was admitted to the hospital. Blood tests at admission revealed hypercalcemia and hypophosphatemia, and emission computed tomography of the parathyroid glands revealed a hyperfunctioning parathyroid lesion. Gastroscopy findings suggested a duodenal bulge and ulceration. Ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb. Further blood tests revealed elevated levels of serum gastrin. Surgery was performed, and pathological analysis of the surgical specimens revealed a parathyroid adenoma after parathyroidectomy and a neuroendocrine tumor after duodenal bulbectomy. The time from onset to the definitive diagnosis of MEN1 was only approximately 1 year. CONCLUSION: For patients who present with gastrointestinal symptoms accompanied by hypercalcemia and hypophosphatemia, clinicians need to be alert to the possibility of MEN1.

Clinical improvement after removal of hypercalcemia-causing granulomas.

In this report, we present the case of a woman with clinical characteristics of hypercalcemia due to ectopic production of 1,25(OH)2D. She reported a history of aesthetic surgery with gluteal fillers. The formation of granulomas after these interventions were previously described. In this case, surgical removal of the foreign formations was attempted with clinical stability during 3 years.

Presentamos el caso de una mujer con características clínicas de hipercalcemia secundaria a la producción ectópica de 1,25(OH)2D. La paciente informó una historia de rellenos glúteos con fines estéticos. La formación de granulomas posterior a este tipo de intervenciones fue previamente descrita por otros autores. En este caso se intentó la extirpación quirúrgica de las formaciones extrañas con estabilidad clínica durante 3 años.

Parathyroid Hormone Related Protein Mediated Hypercalcaemia Due to Metastatic Squamous Cell Carcinoma Originating from Pilonidal Disease: A Case Report.

A 56-year-old male presented with a longstanding, gradually enlarging, painful, skin lesion over the natal cleft. This was initially thought to be a pilonidal abscess but, following multiple surgeries, he was diagnosed with Stage IVb squamous cell carcinoma of the natal cleft skin with bilateral inguinal lymph node metastases and subcutaneous metastatic deposits. Complete surgical cure was not possible. He underwent radiotherapy, cisplatin chemotherapy and cemiplimab immunotherapy to control his disease. His course was complicated by severe humoral hypercalcaemia of malignancy (HHM) resistant to medical therapy. His disease progressed, and he developed widespread metastases. He was thus transferred to palliative care with pain control being the major priority. He died within a year of diagnosis.

Electrolyte disorders related emergencies in children.

This article provides a comprehensive overview of electrolyte and water homeostasis in pediatric patients, focusing on some of the common serum electrolyte abnormalities encountered in clinical practice. Understanding pathophysiology, taking a detailed history, performing comprehensive physical examinations, and ordering basic laboratory investigations are essential for the timely proper management of these conditions. We will discuss the pathophysiology, clinical manifestations, diagnostic approaches, and treatment strategies for each electrolyte disorder. This article aims to enhance the clinical approach to pediatric patients with electrolyte imbalance-related emergencies, ultimately improving patient outcomes.Trial registration This manuscript does not include a clinical trial; instead, it provides an updated review of literature.

Gitelman syndrome with primary hyperparathyroidism: A case report.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy, typically devoid of hypercalcemia. Herein, we described one patient of GS presenting with hypercalcemia concomitant with primary hyperparathyroidism (PHPT). METHODS: On September 28, 2020, a middle-aged female patient was admitted to our hospital with a 12-year history of hypokalemia and hypomagnesemia. Laboratory examinations unveiled hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hypocalciuria, and gene sequencing revealed a homozygous mutation in SLC12A3 (c.179C > T [p.T60M]). Subsequently, the diagnosis of GS was confirmed. In addition, the patient exhibited hypercalcemia and elevated levels of parathyroid hormone. Parathyroid ultrasound revealed left parathyroid hyperplasia, consistent with PHPT. Following aggressive treatment with potassium chloride and magnesium oxide, her serum potassium rose to 3.23 mmol/L, serum magnesium was 0.29 mmol/L, and her joint pain was relieved. RESULTS: Based on the patient's medical history, laboratory findings, and gene sequencing results, the definitive diagnosis was GS concomitant with PHPT. CONCLUSION: PHPT should be taken into consideration when patients diagnosed with GS exhibit hypercalcemia. While the serum potassium level readily exceeded the target threshold, correcting hypomagnesemia proved challenging, primarily because PHPT augments urinary magnesium excretion.

Characterization of a cohort of patients with hypercalcemia in a tertiary pediatric hospital. / Caracterización de una cohorte de pacientes con hipercalcemia en un centro pediátrico de tercer nivel.

Introduction. Hypercalcemia is infrequent in pediatrics, of diverse etiology, and with multiorgan morbidity. Objective. Describe the etiology, biochemistry, clinical, and treatment in pediatric patients with hypercalcemia. Population and methods. Retrospective and descriptive study of a cohort of patients with hypercalcemia between 2008 and 2022. They were classified into three groups (G): hypercalcemia of iatrogenic cause (G1), parathyroid hormone (PTH) independent (G2), or PTH-dependent (G3). Results. One hundred forty-seven patients were included; 57% were male, with a median age of 3.7 years, median calcemia of 11.8 mg/dl, and mean phosphatemia of 4.9 mg/dl. Symptoms were present in 29% of patients, and 28.6% required additional treatments to those of the first line. In G1, 76 patients (51.7%) were included; in G2, 58 (39.4%), and in G3, 13 (8.8%). Median calcemia was lower in G1 vs. G2 and G3 (11.6 mg/dl, 12.6 mg/dl, and 12.3 mg/dl), and mean phosphatemia was lower in G3 vs. G1 and G2 (3.7 mg/dl, 5.3 mg/dl, and 4.9 mg/dl). Most of the patients with hypercalcemia were asymptomatic and did not require additional treatments. The percentage of symptomatic patients and the percentage requiring additional treatment were lower in G1 than in the other two groups. Conclusions. Iatrogenesis was the most frequent cause, presenting lower calcemia, while PTH-dependent causes presented the lowest phosphatemia. PTH-independent causes represented a diagnostic and therapeutic challenge due to lacking a characteristic biochemical profile.

Introducción. La hipercalcemia es infrecuente en pediatría, de etiología diversa y con morbilidad multiorgánica. Objetivo. Describir etiología, bioquímica, clínica y tratamiento en pacientes pediátricos con hipercalcemia. Población y métodos. Estudio retrospectivo y descriptivo de una cohorte de pacientes con hipercalcemia entre 2008 y 2022. Se clasificaron en tres grupos (G): hipercalcemia de causa iatrogénica (G1), paratohormona (PTH) independiente (G2) o PTH dependiente (G3). Resultados. Se incluyeron 147 pacientes; el 57 % eran varones, edad mediana de 3,7 años, calcemia mediana 11,8 mg/dl y fosfatemia media 4,9 mg/dl. El 29,9 % de los pacientes fueron sintomáticos y el 28,6 % requirió tratamientos adicionales a los de la primera línea. En G1 se incluyeron 76 pacientes (51,7 %); en G2, 58 (39,4 %), y en G3, 13 (8,8 %). La calcemia mediana fue menor en G1 vs. G2 y G3 (11,6 mg/dl, 12,6 mg/dl y 12,3 mg/dl). La fosfatemia media fue menor en G3 vs. G1 y G2 (3,7 mg/dl, 5,3 mg/dl y 4,9 mg/dl). La mayoría de los pacientes con hipercalcemia fueron asintomáticos sin requerimientos de tratamientos adicionales. El porcentaje de pacientes sintomáticos y el de requerimiento de tratamientos adicionales fue menor en G1 que en los otros dos grupos. Conclusiones. La iatrogenia fue la causa más frecuente, y se presentó con calcemias más bajas; mientras que las causas PTH dependientes presentaron las fosfatemias más bajas. Las causas PTH independientes representaron un desafío diagnóstico y terapéutico por la falta de un perfil bioquímico característico.