Three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

We herein report three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1 was a man in his 60s with hepatitis C-related liver cirrhosis. He had been diagnosed with HCC and undergone surgical resection. However, HCC recurred 17 months after surgery. After 13 cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. The plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were decreased. He was diagnosed with central adrenal insufficiency associated with hypopituitarism. Glucocorticoid therapy rapidly improved his symptoms. Case 2 was a man in his 70s with HCC associated with non-alcoholic steatohepatitis (NASH). After eight cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. Hyponatremia and eosinophilia were observed. He was also diagnosed with hypopituitarism, and glucocorticoid therapy rapidly improved his symptoms. Case 3 was a man in his 60s with HCC associated with alcoholic liver cirrhosis. After 10 cycles of atezolizumab-bevacizumab therapy, hypopituitarism developed. In these cases, the presence of hyponatremia and/or eosinophilia was useful for making a diagnosis. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody is reported to be likely to induce hypophysitis two to three months after its administration. In contrast, anti-programmed cell death 1 (PD-1) antibody is likely to induce hypopituitarism six to seven months after its administration. These three patients treated with anti-programmed death ligand 1 (PD-L1) antibody developed hypopituitarism six to nine months later, close to the condition with anti-PD-1 antibody administration. Although immune-related hypopituitarism after atezolizumab-bevacizumab treatment is rare, we should be alert for hypopituitarism developing during atezolizumab-bevacizumab treatment.

Efficacy of Zinc Acetate Treatment for Patients with Decompensated Liver Cirrhosis Complicated by Hypozincemia.

The aim of this study was to evaluate the efficacy of zinc acetate treatment for patients with decompensated liver cirrhosis complicated by hypozincemia. We retrospectively analyzed 49 patients with decompensated liver cirrhosis complicated by hypozincemia who received zinc acetate treatment from August 2017 to March 2020. The relationships between serum zinc levels and several parameters including the prognosis, sarcopenia, and immunity were evaluated. Serum zinc levels measured at 3 months post-treatment and the incidence of adverse events were also determined. The median age was 69.0 years (IQR:59.5-78.8) and the male to female ratio was 29:20. Twenty-seven patients had a Child-Pugh classification of B and 22 had a Child-Pugh classification of C; the median Child-Pugh score was 9.0 (IQR, 8.0-11.0). The median serum zinc levels measured at 3 months post-treatment (74.7 (IQR, 50.0-101.0) µg/dL) were significantly elevated in comparison to the pre-treatment levels (43.0 (IQR, 34.0-51.0) µg/dL, P < 0.0001). The overall survival of patients with pre-treatment serum zinc levels of ≥60 µg/dL was significantly better than that of those with pre-treatment serum zinc levels of <60 µg/dL (P = 0.013). The survival of patients with zinc levels of ≥70 µg/dL at 3 months post-treatment was significantly better than those with levels of <70 µg/dL (P = 0.013). The serum albumin level, Child-Pugh score, albumin-bilirubin (ALBI) score and model for end-stage liver disease (MELD) score were identified as factors predicting a good response at 3 months post-treatment. There were no significant relations between the pretreatment serum zinc levels and skeletal muscle mass, lymphocyte count, and neutrophil lymphocyte ratio. There were no obvious problematic adverse events in patients who received zinc acetate treatment. The patients with higher basal zinc levels and good responders to zinc acetate treatment had a better prognosis. Zinc acetate was useful and safe for patients with decompensated liver cirrhosis complicated by hypozincemia.

ß-Hydroxy-ß-methyl Butyrate/L-Arginine/L-Glutamine Supplementation for Preventing Hand-Foot Skin Reaction in Sorafenib for Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC. PATIENTS AND METHODS: This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing ß-hydroxy-ß-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups. RESULTS: Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test). CONCLUSION: Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.