Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports.

BACKGROUND: As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements. CASE REPORT: We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases. Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine. CONCLUSIONS: We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Essential role of CD155 glycosylation in functional binding to DNAM-1 on natural killer cells.

The cluster of differentiation 155 (CD155) is highly expressed on tumor cells and augments or inhibits the cytotoxic activities of natural killer (NK) cells and T cells through its receptor ligands DNAX accessory molecule 1 (DNAM-1) and T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), respectively. Although CD155 is heavily glycosylated, the role of glycosylation of CD155 in the cytotoxic activity of effector lymphocytes remains unknown. Here, we show that the N-linked glycosylation at residue 105 (N105 glycosylation) in the first Ig-like domain of CD155 is involved in the binding of CD155 to both DNAM-1 and TIGIT. The N105 glycosylation also plays an essential role to induce signaling in both DNAM-1 and TIGIT reporter cells. Moreover, we show that the N105 glycosylation of CD155 contributes preferentially to the DNAM-1-mediated activating signal over the TIGIT-mediated inhibitory signal in NK cells. Our results demonstrated the important role of the N105 glycosylation of CD155 in DNAM-1 and TIGIT functions and shed new light on the understanding of tumor immune responses.

CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT.

CD155 is a shared ligand for activating and inhibitory immunoreceptors DNAX accessory molecule 1 (DNAM-1), also called CD226, and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which are expressed on natural killer (NK) cells and T cells, and positively and negatively regulates tumor immune responses, respectively. A recent study showed that the single nucleotide polymorphism rs1058402G>A causing a mutation to Thr from Ala at residue 67 of CD155 is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased affinity of mutant CD155 for DNAM-1 as a result of the 3D structural analysis. Unexpectedly, however, we found that the mutation increased the binding affinity for TIGIT rather than decreased the binding affinity for DNAM-1 and induced a stronger signal than WT CD155. Our results suggest that the mutation suppresses tumor immune responses by generating a stronger inhibitory signal in immune cells in the tumor microenvironment.

[Development of exudative tuberculosis during treatment for aspiration pneumonia in an elderly post-stroke patient with symptomatic epilepsy].

A 90-year-old man with a previous history of brain infarction and diabetes mellitus presented with a gait disturbance. Although brain computed tomography (CT) showed no abnormalities, except for the old infarction, the patient experienced recurrent epileptic seizures. He was therefore admitted to our hospital for a further examination of the seizures. However, upon admission, he also presented with a fever and elevated C-reactive protein levels, indicating systemic inflammation. Based on the presence of bilateral infiltration visible on a chest X-radiograph, the patient was diagnosed with aspiration pneumonia. The administration of 4.5 g of sulbactam and ampicillin did not reduce the inflammation or resolve the abnormal lung findings. Therefore, he was intubated and placed on a ventilator. With the patient under ventilator management, we subsequently performed bronchoscopic alveolar lavage. Elevated neutrophil and lymphocyte counts were noted in the alveolar lavage fluid; therefore, we administered pulse steroid therapy with 500 mg of methylprednisolone. The sputum and alveolar lavage fluid samples collected 13 and 14 days, respectively, after admission were negative for Mycobacterium according to a smear test. In contrast, the cultured sputum samples collected on day 13 were positive for Mycobacterium tuberculosis; polymerase chain reaction testing confirmed the sputum culture results. A postmortem pathological examination of the lungs revealed neutrophilic exudative pneumonia as well as acute fibrinous and organizing pneumonia. Although Ziehl-Neelsen staining demonstrated a large number of positive bacteria, no epithelioid-cell granulomas were observed. M. tuberculosis lesions were also found in the liver, spleen, bones, and adrenal glands, suggesting hematogenous dissemination. Aspiration pneumonia is very common in elderly patients with a history of stroke, and these patients are also at risk of other pulmonary disorders and infections including M. tuberculosis. Prior to administering treatment for aspiration pneumonia, clinicians should consider the potential for other pulmonary infiltration disorders in the differential diagnosis, particularly in elderly post-stroke patients.