Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.
Adenocarcinoma of Lung/drug therapy* ; Adrenocorticotropic Hormone/therapeutic use* ; Aged ; B7-H1 Antigen/therapeutic use* ; Humans ; Hydrocortisone/therapeutic use* ; Hyponatremia/drug therapy* ; Hypopituitarism/drug therapy* ; Immune Checkpoint Inhibitors ; Lung Neoplasms/pathology* ; Male ; Methylprednisolone/therapeutic use* ; Middle Aged ; Nausea/drug therapy* ; Pituitary Gland/pathology* ; Pneumonia ; Prednisone/therapeutic use* ; Programmed Cell Death 1 Receptor/therapeutic use* ; Prolactin/therapeutic use*

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has various causes including central nervous system disorders, pulmonary and endocrine diseases, paraneoplastic syndromes, and use of certain drugs. SIADH induced by chemotherapy with irinotecan-cisplatin is not a common complication. Here, we review a case of SIADH after treatment with irinotecan-cisplatin. A 45-year-old woman received adjuvant chemotherapy (paclitaxel-carboplatin) for ovarian clear cell carcinoma, but the cancer recurred within 9 months of chemotherapy. Subsequently, a second line of combination chemotherapy containing irinotecan-cisplatin was initiated. However, 5 days after chemotherapy administration, her general condition began to deteriorate; her hematological tests revealed hyponatremia. Therefore, it is imperative to consider the possibility of SIADH in patients being treated with irinotecan-cisplatin–based chemotherapy. Proper monitoring of serum sodium levels and assessment of clinical symptoms should be performed in such patients for early diagnosis and prompt management.
Central Nervous System Diseases ; Chemotherapy, Adjuvant ; Cisplatin ; Drug Therapy ; Drug Therapy, Combination ; Early Diagnosis ; Endocrine System Diseases ; Female ; Hematologic Tests ; Humans ; Hyponatremia ; Inappropriate ADH Syndrome ; Middle Aged ; Paraneoplastic Syndromes ; Sodium

BACKGROUND/AIMS: Hyponatremia is a well-known risk factor for poor outcomes in Western studies of heart failure (HF) patients. We evaluated the predictive value of hyponatremia in hospitalized Asian HF patients. METHODS: The Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) study enrolled hospitalized patients with systolic HF (ejection fraction < 45%) at eight centers in South Korea, Taiwan, and China. The relationship between admission sodium level and clinical outcomes was analyzed in 1,470 patients. RESULTS: The mean admission sodium level was 138 +/- 4.7 mmol/L, and 247 patients (16.8%) had hyponatremia defined as Na+ < 135 mmol/L. The 12-month mortality was higher in hyponatremic patients (27.9% vs. 14.6%, p < 0.001), and hyponatremia was an independent predictor of 12-month mortality (hazard ratio, 1.72; 95% confidence interval, 1.12 to 2.65). During hospital admission, 57% of hyponatremic patients showed improvement without improvement in their clinical outcomes (p = 0.620). The proportion of patients with optimal medical treatment was only 26.5% and 44.2% at admission and discharge, respectively, defined as the combined use of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and beta-blocker. Underuse of optimal medical treatment was more pronounced in hyponatremic patients. CONCLUSIONS: In hospitalized Asian HF patients, hyponatremia at admission is common and is an independent predictor of poor clinical outcome. Furthermore, hyponatremic patients receive less optimal medical treatment than their counterparts.
Aged ; Aged, 80 and over ; Asia/epidemiology ; *Asian Continental Ancestry Group ; Biomarkers/blood ; Cardiovascular Agents/therapeutic use ; Disease-Free Survival ; Female ; Guideline Adherence ; Healthcare Disparities ; Heart Failure/*diagnosis/drug therapy/ethnology/mortality/physiopathology ; *Hospitalization ; Humans ; Hyponatremia/blood/*diagnosis/drug therapy/ethnology/mortality ; Male ; Middle Aged ; Practice Guidelines as Topic ; Predictive Value of Tests ; Proportional Hazards Models ; Risk Factors ; Sodium/*blood ; Stroke Volume ; Time Factors ; Treatment Outcome

A 60-year-old woman presented with cerebellar signs including dysarthria and ataxia, after intravenous infusion of cisplatin-based chemotherapy. Several blood tests showed mild neutropenia, normocytic normochromic anemia, but no evidence of a marked hyponatremia. Brain magnetic resonance imaging with diffusion-weighted sequences showed hyper-intense signal abnormalities in the extrapontine region, sparing the basis pontis. Here, we report on the case of a patient with reversible cerebellar ataxia related to extrapontine myelinolysis without hyponatremia after treatment with cisplatin-based chemotherapy for cholangiocarcinoma and discuss the literature on cerebellar ataxia in patients who underwent recent chemotherapy for malignancy.
Anemia ; Ataxia ; Brain ; Cerebellar Ataxia* ; Cholangiocarcinoma* ; Cisplatin ; Drug Therapy* ; Dysarthria ; Female ; Hematologic Tests ; Humans ; Hyponatremia* ; Infusions, Intravenous ; Magnetic Resonance Imaging ; Middle Aged ; Myelinolysis, Central Pontine* ; Neutropenia

The purpose of this study was to investigate the clinical characteristics and the treatments of patients with vinblastine-related hyponatremia which was aggravated by azole antifungal agents in children with acute lymphoblastic leukemia(ALL). A total of 93 children treated with vinblastine in our department during April 2013 to March 2014 were enrolled in this study and were divided into 3 groups:VDLD, VDLD with azoles antifungal, VDLD with non azoles antifungal. The incidence and severity of hyponatremia were statistically analysed. The results showed that (1) the incidence of hyponatremia in VDLD group was 93.1%(67/72),100%(13/13) in VDLD with azoles antifungal group, and 75%(6/8) in VDLD with non-azoles antifungal, there was no statistically difference between these three groups. (2) Incidence of moderate to severe hyponatremia (Na<129 mmol/L) in VDLD with azoles antifungal group was(9/13,69.2%),which was significartly higher than those in VDLD group (22/72, 30.6%) and in VDLD with non azoles antifungal group (1/8, 12.5%). However, the difference between VDLD group and VDLD with non azoles antifungal group were not statistical significant. (3) the lowest serum sodium level in VDLD with azoles antifungal group (124.0 ± 8.6 mmol/L) was significantly lower than that in VDLD group (130.8 ± 3.8 mmol/L)and VDLD+non azoles antifungal group(132.9 ± 4.9 mmol/L). Otherwise, the difference was not statistically significant between VDLD group and VDLD with non azoles antifungal group. (4) four children with severe hyponatremia showed convulsions and coma which all belong to VDLD with azoles antifungal group. The children with hyponatremia were restricted intake of fluid, adjusted the liquid tension, supplied hypertonic sodium and given diuretic, the serum sodium value gradually picked up in these children. In 4-11 months' follow-up, no hyponatremia happened again in these children. It is concluded that the incident of hyponatremia in children treated with vinblastine is high, but most of them seldom showed clinical characteristics. The combination of antifungal azoles with vinblastine can increase the incidence and severity of hyponatremia. Therefore, combined administration of azole antifungals with vinblastine should be avoided.
Acute Disease ; Antifungal Agents ; therapeutic use ; Azoles ; therapeutic use ; Child ; Humans ; Hyponatremia ; chemically induced ; prevention & control ; Incidence ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Vinblastine ; adverse effects

OBJECTIVETo study the clinical characteristics, antibiotics sensitivity and outcome of group B streptococcus (GBS) meningitis in neonates in order to provide the guide for early diagnosis and appropriate treatment.

METHODA retrospective review was performed and a total of 13 cases of neonatal purulent meningitis caused by GBS were identified in the Neonatal Intensive Care Unit of Yuying Children's Hospital of Wenzhou Medical University from January 1, 2005 to May 31, 2013. The clinical characteristics, antibiotics sensitivity test results and outcome were analyzed.

RESULTFever, poor feeding, seizure and lethargy were common clinical signs of neonatal purulent meningitis caused by GBS. Three cases of early onset GBS meningitis received prepartum antibiotics. All 13 cases had abnormal C-reactive protein (CRP) level, and 11 cases had increased CRP within hours after admission. Of the 13 patients, 7 were cured, 4 discharged with improvement, 2 patients died during hospitalization after being given up because of serious complication. The average length of stay for recovered patients was (47 ± 21)d. Acute complications mainly included hyponatremia (5 cases), intracranial hemorrhage (3 cases) , ventriculomegaly (3 cases) , subdural collection (2 cases) , hydrocephalus (2 cases), septic shock (2 cases), cerebral hernia (1 case), encephalomalacia (1 case). One preterm patient with early onset GBS meningitis died 1 month after hospital discharge. Among 7 survivors with 10-24 months follow-up, 3 were early onset GBS meningitis, 2 with normal results of neurologic examination, 1 with delayed motor development, 4 were late onset GBS meningitis, 1 with normal results of neurologic examination, 3 were neurologically impaired with manifestations including delayed motor development (2 cases) and seizures (1 case). All the GBS strains were sensitive to penicillin and linezolid (13/13, 10/10), the susceptibility to levofloxacin, ampicillin and vancomycin were 11/12, 9/10, 8/13 respectively.

CONCLUSIONThe clinical manifestations of neonatal purulent meningitis caused by GBS are usually non-specific. It is associated with long hospitalization, neurological impairments and sequelae. Monitoring of serum CRP level is valuable for early diagnosis. Antepartum prophylaxis, early diagnosis and therapy are vital. Large dose penicillin is the priority choice to treat the neonatal purulent meningitis caused by GBS, linezolid should be used in intractable cases.

Anti-Bacterial Agents ; therapeutic use ; C-Reactive Protein ; analysis ; Drug Resistance, Bacterial ; Female ; Fever ; diagnosis ; drug therapy ; pathology ; Follow-Up Studies ; Humans ; Hyponatremia ; etiology ; Infant, Newborn ; Leukocyte Count ; Male ; Meningitis, Bacterial ; diagnosis ; drug therapy ; pathology ; Microbial Sensitivity Tests ; Penicillins ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; Retrospective Studies ; Streptococcal Infections ; diagnosis ; drug therapy ; pathology ; Streptococcus agalactiae

OBJECTIVETo observe the level of blood sodium in patients hospitalized for heart failure with water-sodium retention treated with loop diuretics and risk factors of low blood sodium.

METHODSWe selected 1 378 acute decompensated heart failure patients who visited Anzhen Hospital, and they are treated with loop diuretics, 259 patients with weight loses more than 1 kg in one week was enrolled in the final analysis, and divided into 3 groups: Group A (weight reduction between 1-3 kg), Group B (weight reduction between 3-5 kg) and Group C (weight reduction over 5 kg). Blood sodium, creatinine and uric acid were compared among groups and risk factors of low blood sodium were analyzed.

RESULTSBlood sodium was similar before and post loop diuretics treatment in Group A, and reduced in group B ((138.28 ± 3.73) mmol/L vs. (139.34 ± 3.66) mmol/L, P < 0.05) and in Group C((137.60 ± 4.07) mmol/L vs. (139.44 ± 4.12) mmol/L, P < 0.05). Forty-six (17.8%) patients developed hyponatremia post loop diuretics treatment. Duration of loop diuretics use was the independent risk infector for hyponatremia (OR = 1.191, 95%CI 1.010-1.385).

CONCLUSIONSLoop diuretics use is safe for treating hospitalized patients for heart failure with water-sodium retention and the risk of developing hyponatremia is low. Duration of loop diuretics use is the independent risk factor of hyponatremia.

Acute Disease ; Creatinine ; Heart Failure ; complications ; drug therapy ; Humans ; Hyponatremia ; Risk Factors ; Sodium ; blood ; Sodium Potassium Chloride Symporter Inhibitors ; adverse effects ; therapeutic use ; Sodium, Dietary

Cerebral salt wasting is characterized by inappropriate natriuresis and volume contraction with associated cerebral pathology. It is distinct from the syndrome of inappropriate antidiuretic hormone secretion, which is characterized by inappropriate retention of free water. We report a patient with a porencephalic cyst who developed cerebral salt wasting. His initial treatment was supplementation of water and salt, which did not improve natriuresis or volume contraction. Fludrocortisone administration effectively managed the cerebral salt wasting.
Adolescent ; Fludrocortisone/*therapeutic use ; Humans ; Hyponatremia/*drug therapy ; Male ; Natriuresis/physiology ; Sodium Chloride/therapeutic use

We report a case of severe hyponatremia related to duloxetine and ziprasidone. A 50-year-old woman on duloxetine and ziprasidone treatment for major depressive disorder developed polydipsia, polyuria, and two episodes of seizures, followed by admission to the emergency department on the 10th day of treatment. Laboratory investigations revealed elevated creatine kinase (CK) as well as hyponatremia, hypo-osmolality, and increased urine sodium. Syndrome of Inappropriate Antidiuretic Hormone (SIADH) was considered, although urine osmolality was not measured. Duloxetine and ziprasidone were discontinued and the CK gradually normalized after correction of hyponatremia. Clinicians should be aware of the possibility of antipsychotic-induced hyponatremia, particularly in patients with symptoms of polydipsia.
Antidepressive Agents ; adverse effects ; Antipsychotic Agents ; adverse effects ; Creatine Kinase ; blood ; Depressive Disorder, Major ; drug therapy ; Duloxetine Hydrochloride ; Female ; Humans ; Hyponatremia ; chemically induced ; Middle Aged ; Piperazines ; adverse effects ; Thiazoles ; adverse effects ; Thiophenes ; adverse effects

Hyponatremia is a dangerous electrolyte disturbance in patients on chemotherapy and may cause sudden death if not detected early. SIADH (syndrome of inappropriate antidiuretic hormone) is one of the known causes of hyponatremia in patients undergoing chemotherapy. Few chemotherapeutic agents, however, are reported to cause SIADH. The current study reports that SIADH developed in a 55 year old woman on S-1 (80 mg/m2) and cisplatin (60 mg/m2) chemotherapy for the peritoneal metastasis of gastric cancer. The patient underwent a total gastrectomy, a splenectomy, and a segmental resection of the transverse colon for gastric cancer. She had used thiazide and betablocker to treat hypertension for 12 years. She admitted to our hospital with complaining of general weakness, dysarthria, loss of appetite, and urinary discomfort. The serum level of sodium and potassium were 94 mEq/L and 2.2 mEq/L respectively. The hyponatremia completely resolved uneventfully after 3% saline infusion, which led to normalized electrolyte balance. The patient was discharged on the 13th hospital day.
Appetite ; Cisplatin ; Colon, Transverse ; Death, Sudden ; Drug Therapy ; Dysarthria ; Female ; Gastrectomy ; Humans ; Hypertension ; Hyponatremia ; Inappropriate ADH Syndrome* ; Middle Aged ; Neoplasm Metastasis ; Potassium ; Sodium ; Splenectomy ; Stomach Neoplasms ; Water-Electrolyte Balance