Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents.

Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse. A number of reports have indicated that patients with malignancies who receive anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we present a patient with non-small cell lung cancer who developed pulmonary tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB treatment. We suggest that anti-PD-1 agents not only induce the development of pulmonary TB, but also development of PR after anti-MTB treatment, through upregulation of the immune response. Furthermore, based on their radiological and immunological similarity, we speculate that the schema of development of PR closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.

Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody titers during treatment with nivolumab in a patient with NSCLC.

Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a 78-year-old man, was being treated with nivolumab as a third-line treatment for squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt flare-up of the blood glucose within half a day. His blood glucose further increased without clinical symptoms until his hospital visit. Laboratory data showed the complete exhaustion of intrinsic insulin and the elevation of serum antibody titer to glutamic acid decarboxylase (GAD). Although the patient was previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease activity had been well controlled with oral medication and low-dose insulin therapy until just before the flare-up. Because of the laboratory findings and the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than the rapid onset, type 1 diabetes related to nivolumab therapy was strongly suspected. Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored.

Malignant involvement of the iliopsoas muscle associated with non-small cell lung cancer: Two case reports.

Under the current progression of molecular targeting or immune therapy, early detection and radiation therapy of iliopsoas metastasis will not only improve performance status but also enable the continuation of effective systemic cancer treatment.

The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment.

BACKGROUND: EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified. METHODS: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas® ), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360® . Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed. RESULTS: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation. CONCLUSIONS: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M.

A case of successful concurrent anti-cancer treatment in a patient who developed follicular lymphoma during treatment with afatinib for advanced lung adenocarcinoma.

The present report describes the case of a 64-year-old woman with advanced lung adenocarcinoma expressing mutant epidermal growth factor receptor (EGFR). The patient developed follicular lymphoma during treatment with the EGFR-tyrosine kinase inhibitor afatinib. Standard immunochemotherapy for follicular lymphoma was introduced in addition to continuing treatment with afatinib for lung cancer. Immunochemotherapy was effective and improved the patient's performance status while afatinib controlled the progression of lung cancer. Our case study suggests that it is safe to introduce standard immunochemotherapy for patients who develop malignant lymphoma while continuing treatment with tyrosine kinase inhibitors for lung adenocarcinoma expressing mutant EGFR.

Concurrent combination of irradiation and immune checkpoint inhibitor for recurrent pleomorphic carcinoma of the lung.

We report the case of a 49-year-old patient who developed brain, sternal, and spine metastases almost simultaneously after the radical resection of a yp-T4N0M0 pulmonary pleomorphic carcinoma of the right upper lobe following induction chemotherapy. The left occipital brain metastasis was surgically removed and followed by radiation therapy. The sternal and vertebral metastases were treated with radiation therapy. Concurrently, the immune checkpoint inhibitor nivolumab was administered. After 12 cycles of nivolumab, the two bone metastases were well-controlled. However, the brain metastasis recurred and was surgically removed again. We were able to investigate the tumor-infiltrating lymphocytes in brain metastases resected before and after radio-immunotherapy. The results revealed the increased number of CD8- and CD68-positive cells after the combined therapy compared with before the therapy. In addition, the high-level expression of program death-ligand 1 was maintained in the brain metastasis.

[Acute myelomonocytic leukemia complicated with multiple lower intestinal ulcers induced by nonsteroidal anti-inflammatory drugs].

We report an 18-year-old woman with acute myelomonocytic leukemia, who developed massive lower intestinal bleeding following induction chemotherapy. Colonoscopy revealed multiple circular ulcers but no infectious colitis or infiltration of leukemia. The biopsy specimen showed mild non-specific inflammatory changes and scattered apoptosis bodies. She took nonsteroidal anti-inflammatory drugs (NASIDs) for pyrexia and pharyngalgia for a long time. We concluded these were signs of ulcers induced by NSAIDs. Despite discontinuance of NSAIDs, melena did not improve. Transarterial embolization therapy using microcoils was tried with unsatisfactory results. Finally, colonoscopic clipping therapy and continuous arterial injection of vasopressin were performed. Subsequently, her condition improved markedly. In conclusion, NSAID-induced intestinal bleeding is not limited to the upper GI tract but may occur in the lower GI tract after long-term NSAID use. The possibility of lower GI tract complications from NSAID should be kept in mind.

Infliximab for the treatment of severe steroid refractory acute graft-versus-host disease in three patients after allogeneic hematopoietic transplantation.

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.