We report a woman in her sixties who presented with cardiac involvement of immunoglobulin light chain (AL) amyloidosis, which was categorized into stage IV disease according to the revised Mayo clinic staging scheme. There were no myeloma-defining events at presentation. Although no M-protein was found in the serum, Bence-Jones protein κ was detected in the urine by immunofixation. The bone marrow showed hypocellularity but contained 25.6% plasma cells by examination of aspirate smears, and the cells exhibited cytoplasmic κ light chain restriction by flowcytometry and immunohistochemistry. Fluorescence in situ hybridization and G-banding revealed t(11;14)(q13;q32), leading to the generation of the CCND1-immunoglobulin heavy chain fusion gene. We obtained metaphase spreads that contained a homogeneous staining region on chromosome 8 at band q24, where multiple copies of the MYC gene were localized. However, the majority of interphase nuclei carried 2 or 3 copies of MYC and only occasional cells had four or more MYC signals, suggesting that MYC amplification occurred in a fraction of neoplastic cells. It is therefore possible that the MYC amplification represented intraclonal genetic heterogeneity and diverse subclones in terms of the copy number of MYC were present at presentation.

In patients with multiple myeloma (MM), when immunoglobulin (Ig) light chains are produced in excess of the corresponding heavy chains, the excess free light chains are freely filtered through the glomerular filtration barrier (i.e. 40–60 kDa) and excreted in the urine, referred to as Bence Jones protein (BJP). We report a patient with IgG-κ–type MM who excreted Ig γ heavy chain in the urine instead of BJP, which migrated at the fast-γ position on immunofixation. To determine the structure of the urinary Ig γ chain, we first performed Western blot (WB) analysis of the serum protein using anti-human Ig γ chain and found a 60-kDa protein band, which was larger than the 50-kDa IgG purified from normal human serum. We next subjected the urinary protein to a series of WB analyses under non-denaturing conditions against the Ig γ chain, Fc fragment, Fab fragment, and IgG subclasses, and found that the urinary protein contained 6–7 fragments of γ chain, ranging from 50 to 66 kDa, which reacted with anti-Fc and anti-IgG3 antibodies. This suggested that the IgG γ heavy chain in this MM patient belonged to the IgG3 subclass, characterized by the long hinge region and highest molecular weight among the IgG subclasses, and the urinary Ig γ chain was considered to represent dimers of the Fc fragments, which were generated by proteolytic cleavage at variable sites within the hinge region. As there are case reports of deposition of monoclonal IgG3 in the kidney, causing renal damage, our current approach may be applied to cases of MM in which a broad band at the fast-γ position that reacts with anti-IgG serum but lacks the associated light chain is detected on immunofixation of the urine in order to determine the subclass and structure of the excreted Ig γ chain.

We developed a LightCycler™ real-time polymerase chain reaction (RTPCR) and melting temperature (T_m) assay targeting the internal transcribed spacer 2 (ITS2) and D1/D2 regions of the fungal ribosomal DNA gene (rDNA), and applied it to differentiate and identify clinically isolated fungal strains, including 2 Scedosporium spp., 3 Aspergillus spp., and 8 yeast-like fungal species isolated in our laboratory between August 2008 and July 2016. PCR was carried out using the LightCycler™ 2.0 Instrument and T_m values of the two PCR products in each species were measured. The T_m values of the ITS2 and D1/D2 amplicons were (mean ± standard deviation [SD]) 89.6 ± 0.20 °C and 89.9 ± 0.07 °C for 3 strains of S. prolificans, and 91.0 °C and 91.7 °C for a single strain of S. apiospermum, effectively separating them. Furthermore, these T_m values were lower than those of Aspergillus spp., enabling differentiation between the two filamentous fungi. Of the 8 yeast-like fungi tested, 7 exhibited unique T_m profiles, whereas Candida krusei had a similar T_m profile to S. apiospermum. Taken together, the assay enabled the identification of 9 of 13 species studied. The T_m values of strains of C. albicans and A. fumigatus were determined with a sensitivity of 1 × 10⁴ (ITS2 and D1/D2), and 1 × 10⁵ (ITS2) and 1 × 10² (D1/D2) colony forming units per mL, respectively, and the assay consistently yielded T_m values for the ITS2 and D1/D2 products with SDs of ± 0.04–0.21 °C and ± 0.02–0.05 °C, respectively. The LightCycler™ RTPCR-T_m assay provides fast and reliable information for the differentiation and identification of clinically relevant fungal pathogens, and is of value to initiate effective antifungal therapy promptly.

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, is currently used for patients with a range of advanced cancers, including recurrent and metastatic head and neck cancer. The drug was first introduced at our department in April 2017 and had been used for 20 patients by October 2018. In this report, we describe 4 patients with recurrent/metastatic head and neck cancer who were markedly responsive to nivolumab. The first patient was a 71-year-old woman who presented with lung metastasis after treatment for laryngeal cancer. After 4 months of nivolumab treatment, the tumor of the lung markedly decreased in size and the response was maintained for 10 months despite patient-requested drug withdrawal at the 6th month. The second patient was a 71-year-old man who presented with recurrent nasopharyngeal cancer and lung metastasis, which were refractory to CyberKnife^® radiosurgery and chemotherapy. After 3 months of nivolumab treatment, both the primary tumor that extended to the skull base and metastatic lung tumor markedly decreased in size, and the response was maintained for 10 months despite drug withdrawal at the 6th month. The third patient was a 68-year-old man with relapsed oropharyngeal cancer. Although the tumor responded to nivolumab, he developed candidemia, resulting in drug withdrawal and regrowth of the tumor. However, the tumor again decreased in size in response to cetuximab, which was substituted for nivolumab. The last patient was a 73-year-old man who presented with recurrent laryngeal cancer 12 years after initial treatment. The tumor markedly decreased in size two months after nivolumab treatment, but he developed isolated adrenocorticotropic hormone deficiency. Although nivolumab was withdrawn, the response was maintained for 8 months. All 4 patients presented here were markedly responsive to nivolumab, leading to favorable clinical courses.

The prognosis of malignant melanoma is one of the poorest among all cancers, and there has been little progress in drug treatment, resulting in a markedly poor prognosis for advanced cases. However, since 2010, many new drugs have been developed and clinically applied, and new findings have been reported. The most recent change in Japanese pharmacotherapy for malignant melanoma was the coverage of immune checkpoint inhibitors (ICIs) by insurance in 2014 prior to their use for other cancers. The anti–PD-1 antibody drug nivolumab was approved in 2014, the anti-CTLA-4 antibody drug ipilimumab was approved in 2015, and the humanized anti-human PD-1 monoclonal antibody drug pembrolizumab was approved in 2016. We also use ICIs for patients with unresectable malignant melanoma. At our hospital, ten patients were treated using ICIs between December 2014 and November 2018. On evaluation of the treatment effects, only one patient had stable disease, whereas the others had progressive disease. Eight patients died after deciding to receive best supportive care. Immune-related adverse events (irAE) varied, but they were resolved after the interruption of ICIs and systemic administration of steroids. Although this study only included patients from our department, the effects of ICIs were limited and insufficient considering their cost effectiveness and irAE. Regarding the future use of ICIs, they should be administered to specific patients following a designated time course. In order to select patients, effective biomarkers that can predict the efficacy of treatment and the degree of irAE need to be developed.

Aim: To evaluate the predictive values of hyponatremia, eosinophilia, and hypoglycemia as biomarkers for the diagnosis of adrenocorticotropic hormone (ACTH) deficiency, which is referred to as an immune-related adverse event associated with immune checkpoint blockade. Methods: We examined 7 patients who developed secondary adrenal insufficiency caused by ACTH deficiency during immune checkpoint inhibitor treatment, and were referred to our department between December 2017 and November 2018. Their clinical symptoms, routine laboratory test results, endocrine data, and radiological findings at diagnosis of ACTH deficiency were collected. Results: The mean age was 69 years. All patients received anti-programmed death 1 (PD-1) antibodies. The median period between the date of the first dose of immune checkpoint inhibitors and the date of diagnosis of adrenal insufficiency was 154 days. Three patients presented with chronic fatigue and 4 with acute fatigue at diagnosis. Cortisol levels were lower than 4 µg/dL in 6 patients and lower than 10 µg/dL in the remaining 1. The levels of plasma ACTH in all patients were close to or below the lower limit of the normal range, suggesting secondary adrenal insufficiency caused by the insufficient secretion of ACTH. Secretion of anterior pituitary hormones other than ACTH was not affected. No inflammatory condition or apoplexy of the pituitary gland was identified by magnetic resonance imaging studies. Four patients exhibited new hyponatremia, eosinophilia, or hypoglycemia, whereas the remaining 3 lacked abnormalities. Conclusion: Routine laboratory test results do not effectively predict ACTH deficiency leading to secondary adrenal insufficiency caused by immune checkpoint blockade.