Favorable outcome of immunotherapy in a rare subtype of hepatocellular carcinoma: a case report and literature review.

Scirrhous hepatocellular carcinoma (S-HCC) represents an uncommon subtype of HCC. During radiological evaluation this unique subtype is frequently mistaken as cholangiocarcinoma, fibrolamellar HCC, or metastatic adenocarcinoma. Here, we present the case of a 50-year-old woman with a large hepatic mass. A triple-phase computed tomography of the liver revealed an arterial enhancing lesion without portovenous washout at hepatic segment 4a/8. The liver biopsy showed hepatocellular characteristics and was positive for Hep Par 1, CK7, CK19, Arginase 1 and CEA, indicating atypical S-HCC. This patient had achieved tumor control with combined treatment with atezolizumab plus bevacizumab and was then treated with lenvatinib after tumor progression. The patient died 15 months after the initial diagnosis.

Real-world evidence on health-related quality of life in patients with type 2 diabetes mellitus using sulphonylureas: An analysis of the Joint Asia Diabetes Evaluation (JADE) Register.

AIMS: To describe health-related quality of life (HRQoL) and identify associated factors in patients with type 2 diabetes mellitus (T2DM) treated with oral glucose-lowering drugs (OGLDs). METHODS: This retrospective, cross-sectional analysis included adults with T2DM from 11 Asian countries/regions prospectively enrolled in the Joint Asian Diabetes Evaluation (JADE) Register (2007-2019) with available EuroQol-5D (EQ-5D-3L) data. RESULTS: Of 47,895 included patients, 42,813 were treated with OGLDs + lifestyle modifications (LSM) and 5,082 with LSM only. Among those treated with OGLDs, 60% received sulphonylureas (SUs), of whom 47% received gliclazide. The OGLD + LSM group had a lower mean EQ-5D-3L index score than the LSM-only group (p < 0.001). The most affected EQ-5D-3L dimensions in OGLD + LSM-treated patients were pain/discomfort (26.2%) and anxiety/depression (22.6%). On multivariate analysis, good HRQoL was positively associated with male sex, education level, balanced diet and regular exercise, and negatively with complications/comorbidities, self-reported hypoglycaemia, smoking, HbA1c, age, body mass index and disease duration. Patients receiving gliclazide vs non-gliclazide SUs had lower HbA1c and better HRQoL in all dimensions (p < 0.001). CONCLUSIONS: Demographic, physical and psychosocial-behavioural factors were associated with HRQoL in patients with T2DM. Our real-world data add to previous evidence that gliclazide is an effective OGLD, with most treated patients reporting good HRQoL. A plain language summary of this manuscript is available here.

Real-world usage of sulphonylureas in Asian patients with type 2 diabetes using the Joint Asia Diabetes Evaluation (JADE) register.

AIMS: To explore the patterns of use of oral glucose-lowering drugs (OGLDs) in Asian patients with type 2 diabetes (T2D), focusing on sulphonylureas (SUs), and to describe patient profiles according to treatment regimen. METHODS: We conducted a cross-sectional analysis of data from adults with T2D from 11 Asian countries/regions with structured assessment enrolled in the prospective Joint Asia Diabetes Evaluation (JADE) register between November 2007 and December 2019. Patients receiving insulin and/or injectable glucagon-like peptide-1 receptor agonists were excluded. RESULTS: Amongst 62 512 patients (mean ± standard deviation age: 57.3 ± 11.8 years; 53.6% men), 54 783 (87.6%) were treated with OGLDs at enrolment. Most received one (37.5%) or two (44.2%) OGLDs. In the entire cohort, 59.4% of treated patients received SU-based therapy with variations amongst countries/regions. Overall, 79.5% of SU regimens were based on SUs plus metformin, and 22.1% on SUs plus dipeptidyl peptidase-4 inhibitors. Among SU users, gliclazide was most commonly prescribed (46.7%), followed by glimepiride (40.0%) and glibenclamide (8.1%). More gliclazide users entered the cohort with glycated haemoglobin levels <53 mmol/mol (7%) than non-gliclazide SU users (odds ratio [OR] 1.09, 95% CI 1.02-1.17), with less frequent self-reported hypoglycaemia in the 3 months before registration (OR 0.81, 95% CI 0.72-0.92; adjusted for sociodemographic factors, cardiometabolic risk factors, complications, use of other OGLDs, country/region and year of registration). CONCLUSION: In Asia, SUs are a popular OGLD class, often combined with metformin. Good glycaemic control and safety profiles associated with the use of SUs, including gliclazide, support their position as a key treatment option in patients with T2D.

2021 Asia-Pacific Graves' Disease Consortium Survey of Clinical Practice Patterns in the Management of Graves' Disease.

AIM: Although Graves' disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe. METHODS: A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions. RESULTS: A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and ß-blockers and adjunctive ATD-treatment during RAI in the APAC-group. CONCLUSION: Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts.

Osteitis Fibrosa Cystica and pathological fractures-the classic but neglected skeletal manifestation of primary hyperparathyroidism: a case report.

BACKGROUND: Osteitis fibrosa cystica is the classic manifestation of primary hyperparathyroidism (PHPT), occurs after prolonged exposure of bone to high serum parathyroid hormone (PTH) level. It has become increasingly rare due to early detection of PHPT. CASE PRESENTATION: A 37-year-old woman was referred to our institution for fixation of multiple fractures of upper and lower extremities that had been reoccurring in the past 5 years. Her medical history showed right-shoulder, left-elbow, and right-femur fractures after a fall 5 years previously. One month ago, she sustained fractures of the right distal humerus, left tibia, and left femur without history of trauma. Upon arrival to our hospital, a thorough review of her plain radiographs demonstrated brown tumors at multiple sites, along with a salt-and-pepper appearance of the skull and a rugger-jersey spine, compatible with osteitis fibrosa cystica. Patient was diagnosed with PHPT, confirmed by high-corrected serum calcium (13.6 [8.6-10.0] mg/dl), low serum phosphate (2.2 [2.5-4.5] mg/dL), high serum alkaline phosphatase (1482 [35-105] U/L), and significantly elevated parathyroid hormone (PTH 3850 [15-65] pg/mL). A histologically confirmed, 2.5-cm parathyroid adenoma was removed by parathyroidectomy. Ten days later, closed reduction and internal fixation of the left proximal femoral shaft was performed. Pain and ambulation were significantly improved 6 months postoperatively. At the 1.5-year follow-up, fracture unions and complete mineralization of brown tumors were noted; the patient could ambulate with neither pain nor an assistive device. CONCLUSIONS: PHPT has become more asymptomatic in countries where routine calcium screening is performed. Nevertheless, the classic skeletal involvement, osteitis fibrosa cystica, should not be overlooked, particularly in young patients who present with a low-energy fracture.

Effect of Preoperative Vitamin D Deficiency on Hypocalcemia in Patients with Acute Hypoparathyroidism after Thyroidectomy.

Postoperative hypoparathyroidism is a common complication of total or completion thyroidectomy. The association between preoperative vitamin D deficiency (VDD) and the development of more severe postoperative hypocalcemia is still unclear. Objectives. To evaluate the effect of preoperative VDD on severity of hypocalcemia in patients with hypoparathyroidism following thyroidectomy. Methods. Patients who developed acute hypoparathyroidism after total or completion thyroidectomy, defined as postoperative parathyroid hormone (PTH) level <15 pg/mL and albumin-adjusted calcium level <8.6 mg/dL, were prospectively recruited. Patients were divided into two groups according to their preoperative vitamin D status (VDD group: 25-hydroxyvitamin D (25(OH)D) level <20 ng/mL; non-VDD group: 25(OH) level ≥20 ng/mL). The primary outcome was severity of hypocalcemia in postoperative hypoparathyroidism. Significant hypocalcemia was defined as calcium level ≤7.5 mg/dL. Results. Forty-three patients (21 VDD, 22 non-VDD) were enrolled. Serum total albumin-adjusted calcium level was significantly lower in the VDD group (7.71 ± 0.5 vs. 8.16 ± 0.4 mg/dL, p < 0.01), and the incidence of symptomatic hypocalcemia was significantly higher in the VDD group (43% vs. 9%, p=0.01). The median maximal daily supplementary dose of elemental calcium was significantly higher in the VDD group (2,400 vs. 1,500 mg/day, p=0.02). Length of hospital stay was nonsignificantly longer in the VDD group (p=0.06). Preoperative vitamin D level <19.6 ng/mL could predict significant and symptomatic hypocalcemia in postoperative hypoparathyroidism with sensitivity of 90% and 82% and specificity of 70% and 69%, respectively. Conclusion. VDD is an independent risk factor for both significant and symptomatic hypocalcemia in hypoparathyroidism patients after thyroid surgery.

Diabetes insipidus and panhypopituitarism as a first presentation of silent adenocarcinoma of lung: a case report and literature review.

BACKGROUND: Pituitary metastasis is a rare condition with a poor prognosis. Very few patients with pituitary metastasis are symptomatic. It is often associated with presence of co-existing metastases to other organs. Isolated pituitary metastasis as the first presentation of primary malignancy is uncommon. CASE PRESENTATION: A 72-year-old woman presented with a 2-month history of polyuria, increasing thirst and unexplained weight loss. Esophagogastroduodenoscopy (EGD) was scheduled as part of the investigation. She was kept nil per os for 10 h prior to EGD, after which she developed alteration of consciousness. Further investigation revealed hypernatremia with sodium level of 161 mmol/L and low urine osmolality of 62 mOsm/kg. Her urine output was 300 mL per hour. Diabetes insipidus (DI) was diagnosed based on evidence of polyuria, hypernatremia, and low urine osmolality. Her urine output decreased and urine osmolality increased to 570 mOsm/kg in response to subcutaneous desmopressin acetate, confirming central DI. Pituitary magnetic resonance imaging showed a heterogeneous gadolinium enhancing lesion at the sellar and suprasellar regions, measuring 2.4 × 2.6 × 3.9 cm compressing both the hypothalamus bilaterally and the inferior aspect of optic chiasm as well as displacing the residual pituitary gland anteriorly. The posterior pituitary bright spot was absent. These MRI findings suggested pituitary macroadenoma. There were also multiple small gadolinium-enhancing lesions up to 0.7 cm in size with adjacent vasogenic brain edema at the subcortical and subpial regions of the left frontal and parietal areas, raising the concern of brain metastases. Pituitary hormonal evaluation was consistent with panhypopituitarism. Histopathological and immunohistochemical studies of the pituitary tissue revealed an adenocarcinoma, originating from the lung. Computed tomography of the chest and abdomen was subsequently performed, showing a 2.2-cm soft tissue mass at the proximal part of right bronchus. There was no evidence of distant metastases elsewhere. The final diagnosis was adenocarcinoma of the lung with pituitary metastasis manifesting as panhypopituitarism and central DI. Palliative care along with hormonal replacement therapy was offered to the patient. She died 4 months after diagnosis. CONCLUSION: Diagnosis of pituitary metastasis is challenging, especially in patients with previously undiagnosed primary cancer. It should be considered in the elderly patients presenting with new-onset central DI with or without anterior pituitary dysfunction.

Leukemic arthritis and severe hypercalcemia in a man with chronic myeloid leukemia: a case report and review of the literature.

BACKGROUND: Patients with chronic myeloid leukemia typically present with high white blood cell counts revealed during annual checkups. Leukemic arthritis and hypercalcemia are rare manifestations in patients with chronic myeloid leukemia. CASE PRESENTATION: A 35-year-old Thai man who had been diagnosed with chronic myeloid leukemia in the chronic phase developed blast crisis while he was receiving ongoing treatment with imatinib at 400 mg/day. Initially, he presented with oligoarthritis in both knees and ankles. A bone scintigraphy showed a prominent bony uptake, with a symmetrical, increased uptake in many bone areas. Induction therapy with a 7 + 3 induction regimen was prescribed in conjunction with 600 mg of imatinib once daily before switching to 140 mg of dasatinib. He subsequently developed severe hypercalcemia (total serum calcium of 17.8 mg/dL), with generalized osteolytic lesions detected on a bone survey. His serum vitamin D level was 50.64 ng/mL, while the serum parathyroid hormone level was 9.82 pg/mL. Despite the administration of an aggressive intravenously administered hydration, intravenously administered calcitonin, and 600 mg/day of imatinib, the severe hypercalcemia was refractory. We therefore decided to prescribe 20 mg/day of intravenously administered dexamethasone; fortunately, his serum calcium level decreased dramatically to normal range within a few days. CONCLUSIONS: Although leukemic arthritis and severe hypercalcemia are extraordinary presentations in patients with chronic myeloid leukemia, the advanced phase of the disease might bring on these symptoms. Apart from parathyroid hormone-related protein-related hypercalcemia, vitamin D is a mechanism of humoral-mediated hypercalcemia.

Transient adrenal insufficiency in diffuse large B cell lymphoma patients after chemotherapy with short-course, high-dose corticosteroids.

Data on the rate of adrenal insufficiency (AI) in patients receiving short-course and high-dose corticosteroids are limited. In this study, we aimed to determine the incidence of AI in newly diagnosed, diffuse large B cell lymphoma (DLBCL) patients after receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or prednisolone] (R-CHOP/CHOP) regimen. We enrolled newly diagnosed DLBCL patients who were scheduled to receive 6-8 cycles of R-CHOP/CHOP regimen. One-microgram adrenocorticotropic hormone (ACTH) stimulation tests were performed at the study entry and 3 weeks after each cycle of chemotherapy (CMT). AI was defined by a peak-stimulated serum cortisol of less than 18 µg/dL. For patients who had AI after completing a course of CMT, 1-µg ACTH stimulation tests were carried out at 60 and 90 days after the last CMT cycle to assess the duration of hypothalamic-pituitary-adrenal (HPA) axis recovery. Ten DLBCL patients were included in this study, with a total of 84 1-µg ACTH stimulation tests. Their mean age was 52 years. AI occurred in 3 out of the 10 patients (30%). The first occurrence of AI was after the third CMT cycle, and the incidence was highest after the fifth cycle. Adrenal function recovered completely 3 to 5 weeks after completing the course of CMT, except for 1 patient, whose HPA axis suppression persisted 90 days after the last CMT cycle. Receiver operating characteristic (ROC) analysis revealed that a basal cortisol level of < 8.7 µg/dL was predictive of AI, with a sensitivity and specificity of 80% and 72.2%, respectively. Transient HPA axis suppression can occur in DLBCL patients receiving R-CHOP/CHOP regimen. We strongly encourage careful observation and examination for potential adrenal insufficiency in such patients, particularly after the fifth cycle of chemotherapy.

Multiple myeloma concealed by adrenal Cushing syndrome: a case report and review of the literature.

BACKGROUND: Cushing syndrome coexisting with multiple myeloma has been previously described in a few reports. Overlapping clinical manifestations can lead to misdiagnoses. CASE PRESENTATION: We presented an extremely rare case of a 33-year-old Thai woman with concomitant kappa light chain myeloma with adrenal Cushing syndrome, both of which were related to skeletal manifestations. A precedence report indicated that treatment of the Cushing syndrome could exacerbate the myeloma symptoms. Therefore, we were faced with the dilemma of which disease should be addressed first. We decided to treat our patient with a combination chemotherapy followed by an autologous stem cell transplant. Subsequently, a left laparoscopic adrenalectomy was successfully undertaken. CONCLUSION: We have reported the first association between adrenocorticotropic hormone-independent Cushing syndrome resulting from a left autonomous cortisol-secreting adrenal adenoma, and multiple myeloma.

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Roux en Y gastric bypass hypoglycemia resolves with gastric feeding or reversal: Confirming a non-pancreatic etiology.

OBJECTIVE: Postprandial hypoglycemia is an infrequent but disabling complication of Roux-en-Y gastric bypass (RYGB) surgery. Controversy still exists as to whether the postprandial hyperinsulinemia observed is due to inherent changes in pancreatic ß-cell mass or function or to reversible alterations caused by RYGB anatomy. We aimed to determine if gastric feeding or reversal of RYGB would normalize postprandial glucose and hormone excursions in patients with symptomatic hypoglycemia. METHODS: We completed a prospective study of six patients with severe symptomatic RYGB hypoglycemia who underwent RYGB reversal. An additional subject without hypoglycemia who underwent RYGB reversal was also studied prospectively. Mixed meal tolerance testing (MTT) was done orally (RYGB anatomy), via gastrostomy tube in the excluded stomach in the setting of RYGB, and several months after RYGB reversal. RESULTS: All subjects reported symptomatic improvement of hypoglycemia after reversal of RYGB. Weight gain after reversal was moderate and variable. Postprandial glucose, insulin, and GLP-1 excursions were significantly diminished with gastric feeding and after reversal. Insulin secretion changed proportional to glucose levels and insulin clearance increased after reversal. Glucagon/insulin ratios were similar throughout study. We further compared the impact of modified sleeve gastrectomy reversal surgery to those with restoration of complete stomach and found no significant differences in weight regain or in postprandial glucose or hormone levels. CONCLUSIONS: Reversal of RYGB is an effective treatment option for severe postprandial hypoglycemia. The pathophysiology of this disorder is primarily due to RYGB anatomy resulting in altered glucose, gut, and pancreatic hormone levels and decreased insulin clearance, rather than inherent ß-cell hyperplasia or hyperfunction.

Cholecystokinin expression in the ß-cell leads to increased ß-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis.

Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ß-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ß-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ß-cell apoptosis. To determine the specific role of ß-cell-derived CCK in ß-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ß-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ß-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ß-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ß-cell apoptosis. Directed CCK overexpression in cultured ß-cells also protects from cytokine-induced apoptosis. We have identified an important new paracrine/autocrine effect of CCK in protection of ß-cells from apoptotic stress. Understanding the role of ß-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ß-cells from apoptosis.