Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports

Abstract Background Since 2011 six immune checkpoint inhibitors (ICI) have been approved to treat patients with many advanced solid tumor and hematological malignancies to improve their prognosis. Case reports of their endocrine immune-related adverse events [irAEs]) are increasingly published as more real-world patients with these malignancies are treated with these drugs. They alert physicians of a drug’s AEs (which may change during a drug’s life cycle) and contribute to post-marketing safety surveillance. Using a modified framework of Arksey and O’Malley, we conducted a scoping review of the spectrum and characteristics of ICI-induced endocrinopathies case reports before and after ICIs are marketed. Methods In July 2017, we searched, without date and language restrictions, 4 citation databases for ICI-induced endocrinopathies. We also hand-searched articles’ references, contents of relevant journals, and ran supplemental searches to capture recent reports through January 2018. For this study, a case should have information on type of cancer, type of ICI, clinical presentation, biochemical tests, treatment plus temporal association of ICI initiation with endocrinopathies. Two endocrinologists independently extracted the data which were then summarized and categorized. Results One hundred seventy nine articles reported 451 cases of ICI-induced endocrinopathies - 222 hypopituitarism, 152 thyroid disorders, 66 diabetes mellitus, 6 primary adrenal insufficiencies, 1 ACTH-dependent Cushing’s syndrome, 1 hypoparathyroidism and 3 diabetes insipidus cases. Their clinical presentations reflect hormone excess or deficiency. Some were asymptomatic and others life-threatening. One or more endocrine glands could be affected. Polyglandular endocrinopathies could present simultaneously or in sequence. Many occur within 5 months of therapy initiation; a few occurred after ICI was stopped. Mostly irreversible, they required long-term hormone replacement. High dose steroids were used when non-endocrine AEs coexisted or as therapy in adrenal insufficiency. There was variability of information in the case reports but all met the study criteria to make a diagnosis. Conclusions The spectrum of ICI-induced endocrinopathies is wide (5 glands affected) and their presentation varied (12 endocrinopathies). Clinical reasoning integrating clinical, biochemical and treatment information is needed to properly diagnose and manage them. Physicians should be vigilant for their occurrence and be able to diagnose, investigate and manage them appropriately at onset and follow-up.https://deepblue.lib.umich.edu/bitstream/2027.42/147443/1/40842_2018_Article_73.pd

No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations.

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Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

Background/aim: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. Methods: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. Results: Genotype C, CP-MT, T1653, HBV DNA levels ≥4 log 10 copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log 10 copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA ≥4 log 10 copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels ≥4 log 10 copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log 10 copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. Conclusions: CP-MT, T1653, HBV DNA levels ≥4 log 10 copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.published_or_final_versio

Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance

ArticleLIVER INTERNATIONAL. 26(1): 90-96 (2006)journal articl

New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia

Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09 ratio 01 (P = 1.36 x 10(-6); OR= 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02 ratio 01 (P = 5.22 x 10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02 ratio 01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55 x 10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.published_or_final_versio

Vegetable, fruit and antioxidant nutrient consumption and subsequent risk of hepatocellular carcinoma: a prospective cohort study in Japan

In a population-based prospective study of 19 998 Japanese individuals, consumption of vegetables, green–yellow and green leafy vegetables was inversely associated with the risk of hepatocellular carcinoma (101 cases), with multivariable hazard ratios for the highest vs lowest tertile of 0.61 (95% confidence interval (CI)=0.36–1.03, Ptrend=0.07), 0.65 (95% CI=0.39–1.08, Ptrend=0.06) and 0.59 (95% CI=0.35–1.01, Ptrend=0.04), respectively

Effect of Pictorial Depth Cues, Binocular Disparity Cues and Motion Parallax Depth Cues on Lightness Perception in Three-Dimensional Virtual Scenes

Surface lightness perception is affected by scene interpretation. There is some experimental evidence that perceived lightness under bi-ocular viewing conditions is different from perceived lightness in actual scenes but there are also reports that viewing conditions have little or no effect on perceived color. We investigated how mixes of depth cues affect perception of lightness in three-dimensional rendered scenes containing strong gradients of illumination in depth.Observers viewed a virtual room (4 m width x 5 m height x 17.5 m depth) with checkerboard walls and floor. In four conditions, the room was presented with or without binocular disparity (BD) depth cues and with or without motion parallax (MP) depth cues. In all conditions, observers were asked to adjust the luminance of a comparison surface to match the lightness of test surfaces placed at seven different depths (8.5-17.5 m) in the scene. We estimated lightness versus depth profiles in all four depth cue conditions. Even when observers had only pictorial depth cues (no MP, no BD), they partially but significantly discounted the illumination gradient in judging lightness. Adding either MP or BD led to significantly greater discounting and both cues together produced the greatest discounting. The effects of MP and BD were approximately additive. BD had greater influence at near distances than far.These results suggest the surface lightness perception is modulated by three-dimensional perception/interpretation using pictorial, binocular-disparity, and motion-parallax cues additively. We propose a two-stage (2D and 3D) processing model for lightness perception

Should patients with localized prostate cancer receive primary androgen deprivation therapy?: Commentary

金沢大学医薬保健研究域医学系This Practice Point commentary discusses the study by Lu-Yao et al. in which primary androgen deprivation therapy (PADT) was compared with conservative treatment in elderly men with localized prostate cancer. Overall, PADT was associated with worse cancer-specific survival than conservative management; however, in the subgroup of patients with poorly differentiated cancer, PADT was associated with improved cancer-specific survival. Although the authors defined conservative treatment as no definitive treatment during the 180 days after diagnosis, many patients in the conservative treatment group would have subsequently received definite treatments, including surgery or radiation therapy. The results of this study, therefore, do not necessarily demonstrate inferiority of PADT to conservative treatment. Accurate evaluation of the efficacy of PADT is confounded by a number of factors, such as the type of androgen deprivation therapy used. Efforts should be made to reduce the adverse effects of androgen deprivation therapy because a high proportion of patients actively choose this treatment modality as primary therapy.全文公開20090

Genotyping the hepatitis B virus with a fragment of the HBV DNA polymerase gene in Shenyang, China

The hepatitis B virus (HBV) has been classified into eight genotypes (A-H) based on intergenotypic divergence of at least 8% in the complete nucleotide sequence or more than 4% in the S gene. To facilitate the investigation of the relationship between the efficacy of drug treatment and the mutation with specific genotype of HBV, we have established a new genotyping strategy based on a fragment of the HBV DNA polymerase gene. Pairwise sequence and phylogenetic analyses were performed using CLUSTAL V (DNASTAR) on the eight (A-H) standard full-length nucleotide sequences of HBV DNA from GenBank (NCBI) and the corresponding semi-nested PCR products from the HBV DNA polymerase gene. The differences in the semi-nested PCR fragments of the polymerase genes among genotypes A through F were greater than 4%, which is consistent with the intergenotypic divergence of at least 4% in HBV DNA S gene sequences. Genotyping using the semi-nested PCR products of the DNA polymerase genes revealed that only genotypes B, C, and D were present in the 50 cases, from Shenyang, China, with a distribution of 11 cases (22%), 25 cases (50%), and 14 cases (28%) respectively. These results demonstrate that our new genotyping method utilizing a fragment of the HBV DNA polymerase gene is valid and can be employed as a general genotyping strategy in areas with prevalent HBV genotypes A through F. In Shenyang, China, genotypes C, B, and D were identified with this new genotyping method, and genotype C was demonstrated to be the dominant genotype