A 75-year-old man with a history of early gastric cancer, phimosis and bronchial asthma experienced pain and palpated a mass in the penis in March 2015. After 2 months, he noticed bleeding from the tumor and visited our hospital. Pelvic computed tomography and magnetic resonance imaging revealed a pelvic tumor, bilateral lymphadenopathy, and para-aortic lymphadenopathy. After partial penis excision and left inguinal lymph node biopsy, the pathological result was penile squamous cell carcinoma sarcomatoid type, stage IV. As controlling bleeding from the left inguinal lymph node metastasis was difficult, radiotherapy and appropriate debridement were performed. However, the size of the metastasis increased, and the general condition of the patient gradually worsened, the patient died two months after the operation. On pathological autopsy, metastasis to the right ventricle was observed in addition to the left inguinal lymph node metastasis. Herein, we present the first autopsy report of metastatic squamous cell carcinoma sarcomatoid type in Japan, along witha literature review.

We report a case of renal pelvic cancer found after left renal trauma. A 63-year-old man was admitted to our hospital because of gross hematuria after he had fallen down the stairs two days earlier. He had asymptomatic severe anemia (Hb : 3. 6 g/dl). Abdominal computed tomography (CT) scan revealed bilateral ureteropelvic stones, bilateral severe hydronephrosis and hematoma of the left upper renal pelvis. We diagnosed him with left renal pelvic hemorrhage by trauma, and transcatheter arterial embolization (TAE) was performed. After TAE, gross hematuria improved, but some hematuria continued to be noted. We suspected malignancy, and examined the patient with contrast-enhanced CT, transurethral resection and retrograde pyelography combined with urine cytology in the upper urinary tract, all with no evidence of malignancy. However, four months after the left renal injury, follow-up CT revealed multiple metastatic lesions. We performed a left nephrectomy, and the resulting pathological diagnosis was invasive urothelial carcinoma with squamous differentiation of the renal pelvis. We performed 7 courses of chemotherapy, but the multiple metastatic lesions progressed, and he died of the disease 19 months after the operation.

A 66-year-old man underwent nephrectomy for right renal cell carcinoma (cT3bNOMl (PUL)). Thereafter, he was treated with sunitinib for lung metastasis as the first-line therapy for 5 months and then axitinib as the second-line therapy for 2 months. Because lung metastasis progressed despite molecular targeted therapies, nivolumab was used as the third-line treatment. Three months later, he complained of painful stiffness in hands and wrist joints symmetrically. He was diagnosed as having rheumatoid arthritis. Treatment with nivolumab was discontinued and prednisolone and methotrexate were started. Although the painful stiffness in joints was improved l month later, synovitis remained partially 6 months after starting treatment of disease with anti-rheumatic drugs. Therefore, treatment for rheumatoid arthritis was continued. On the other hand, because the lung lesion had progressed 2 months after discontining nivolumab, everolimus was used as the fourth-line therapy.

A 66-year-old man had undergone multiple treatments for metastatic renal cell carcinoma, including 11 cycles of nivolumab, which was discontinued because of disease progression. About three weeks after discontinuing nivolumab, he reported suffering from worsening of dyspnea. Pulse oximetry showed no desaturation. His cardiovascular and pulmonary functions were normal. His dyspnea slowly worsened with no underlying diagnosis. Two months after symptoms developed, he was diagnosed with isolated adrenocorticotropic hormone deficiency. His dyspnea disappeared soon after receiving hydrocortisone. Nivolumab-induced isolated adrenocorticotropic hormone deficiency may not present with typical symptoms, and can occur even after discontinuing nivolumab. Cortisol levels should be routinely monitored in patients who receive nivolumab.

Nivolumab was approved as a new agent for advanced renal cell carcinoma (RCC) in Japan on September 2016. Nivolumab is an immune checkpoint inhibitor that activates the cytotoxic immune response and has exerted antitumor effects in a mechanism different from other available molecular targeted agents. Therefore, its response pattern, efficacy and adverse events are different from those of the molecular targeted agents for RCC. Here, we report our initial clinical experience with nivolumab. From December 2016 to September 2017, we applied nivolumab to 7 patients with metastatic RCC. The most common metastatic site was the lungs, followed by lymph nodes, bones and brain. According to the immune-related response criteria, the efficacy was stable disease in 2 patients and progressive disease in 5 patients. In 5 cases with multiple metastases, responses differed with the site of metastasis. The response was best in lung metastasis and worst in brain metastasis. Six cases had minor adverse events. In two cases, we discontinued administration of nivolumab temporarily. The patients recovered completely and we considered nivolumab effective and safe for treatment of metastatic RCC.

Resistance to the breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor (TKI), imatinib, poses a major problem in the treatment of chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, the basis of this BCR-ABL1-independent resistance in the absence of such mutation remains to be elucidated. The aim of the present study is to identify the mechanism of imatinib resistance in CML. To gain insight into BCR-ABL1-independent imatinib resistance mechanisms, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, focusing on the receptor tyrosine kinase MET. Treatment with an MET inhibitor resensitized K562/IR cells to BCR-ABL TKIs. A treatment combining imatinib and a MET inhibitor in K562/IR cells inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Moreover, the combination of MET inhibitor and imatinib suppressed tumor growth in vivo. These results indicate that the activation of MET/ERK and MET/JNK are potential mechanisms of BCR-ABL TKI resistance. Our findings provide new and important information concerning the mechanisms of imatinib resistance in CML, and reveal new proteins potentially involved in BCR-ABL TKI resistance.

Silurus asotus egg lectin (SAL) is an α-galactoside-binding protein, isolated from the egg of catfish. It belongs to the rhamnose-binding lectin family that binds to Gb3 glycan (Galα1-4Galβ1-4Glc). SAL has resulted in the induction of early apoptosis in the Raji cell line, which is a Burkitt's lymphoma cell line expressing Gb3. The apoptosis was characterized by i) increased externalization of phosphatidylserin via multidrug resistance 1 P-glycoprotein (MDR1 P-gp), and ii) reduced cell size through the activation of voltage-gated potassium channel Kv1.3. Although the incorporation of propidium iodide (PI) was observed, SAL did not cause apoptosis in Raji cells. This event may be due to an increased expression of membrane-anchored tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) after the binding of SAL to Gb3. Moreover, SAL arrested the cell cycle at the G0/1 phase, thus inhibiting cell proliferation. The suppression of cell proliferation by SAL was likely due to the enhanced expression of p21 caused by the phosphorylation of ERK1/2 through the Ras-MEK-ERK1/2 pathway. Combination of SAL with anti-cancer drugs was also examined in this study. Interestingly, SAL increased the incorporation of doxorubicin (Dox) into Raji cells, consequently enhancing its cytotoxic effect. Similarly, the cytotoxic effects of vinblastine and irinotecan were also significantly increased in Raji cells treated with SAL. These studies demonstrate that SAL may be applied to cancer therapy.

Papillary thyroid carcinoma is the most common thyroid malignancy and usually has an indolent clinical course with a good prognosis. Brain metastasis from thyroid cancer is very rare, occurring in only 0.8-1.3% of all papillary thyroid carcinomas; therefore, the prognosis and treatment of the metastatic tumor are unclear. We describe 5 cases of brain metastases from papillary thyroid carcinoma treated with surgery between 2013 and 2017. Intracranial tumor resection was performed and brain metastases were pathologically diagnosed as papillary thyroid carcinoma in 2 men and 3 women aged 62-72 years(mean 67 years). The surgical treatment for the thyroid cancer was total thyroidectomy in 3 patients, hemithyroidectomy in 1, and no treatment in 1. The duration from initial diagnosis to brain metastasis was 0-155 months(mean 73.2 months). Two patients also received radioiodine therapy. Three patients had multiple lesions and 2 had single lesions. Four patients also had other metastases. Neuroimaging demonstrated intratumoral hemorrhages in 2 patients. The other 2 patients had intratumoral hemorrhage during the course of the disease. All patients received radiation therapy after surgery for brain metastases. Two patients died, but the other 3 have survived to date. The other 2 patients who had intratumoral hemorrhage during the course of the disease received 131I radioiodine therapy. It was reported that 131I radioiodine therapy resulted in collapse of the fragile peritumoral vessels. It is safe to perform head magnetic resonance imaging(MRI)before radioiodine therapy for thyroid cancer. Papillary thyroid carcinomas carry a good prognosis but some brain metastases have a poor prognosis due to the presence of other metastases or the patient's poor general condition. Treatments for patients in good general condition are needed to improve the clinical course and prognosis.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is associated with pre-existing infections or autoimmune disorders. We report a case of lung cancer initially suspected of MALT lymphoma. The patient was a 73-year-old woman. Complete screening examinations identified a tumor in the right middle lobe. Transbronchial lung biopsy revealed the infiltration of CD20+/CD79a+ lymphocytes invading the structure of the alveolus. MALT lymphoma was suspected, and the middle lobe was resected. The tumor was primarily invasive mucinous carcinoma, and lymphocytic infiltration was observed around the tumor. The monoclonal expansion of B cells and genetic and chromosomal abnormalities which are criteria for the diagnosis of MALT lymphoma were not demonstrated and the lesion was diagnosed as reactive lymphoid infiltrates. Marked lymphocytic infiltration regardless of neoplastic or reactive may suggest the presence of latent lesions.

Regorafenib is widely used for patients with metastatic colorectal cancer, following disease progression with standard therapies.However, regorafenib has severe toxicities; therefore, careful monitoring and treatment are necessary.Several studies have investigated the efficacy of initial dose reductions.We started regorafenib doses from 80 mg, with a duration of 1 week on and 1 week off, after which we gradually increased the dosage and duration.From September 2015 to March 2017, we treated 7 consecutive patients who received regorafenib following standard chemotherapy for metastatic colorectal cancer.The average age was 73 years and average BMI was 23.3.The average total dose was 15,960(2,240-28,000)mg, and the average treatment duration was 243(50-379)days.The mean survival from the start of regorafenib was 399(median 407, 262-622)days.Adverse events of Grade 3 or higher were observed in 1 patient(14%).

In order to reduce the frequency and the severity of oxaliplatin-related sensory-neuropathy and preserve antitumor efficacy, we performed alternating 4 mFOLFOX6 and 4 FOLFIRI cycles, in combination with bevacizumab, in patients with metastatic colorectal cancer. The response rate of alternating mFOLFOX6 and FOLFIRI regimens(FIREFOX)plus bevacizumab was 100%. However, during neoadjuvant chemotherapy for colon cancer, we cannot use bevacizumab due to the concern of adverse events, such as bleeding and perforation. Therefore, we used cetuximab in 8 courses of FIREFOX. As a result, the volumes of the rectum cancers and liver metastases decreased. Thereafter, we used bevacizumab in another 8 courses of FIREFOX. A 77- year-old woman suffered from II type rectum cancer, which was localized 7 cm from the anal verge, with multiple liver metastases. We performed 8 courses of FIREFOX plus cetuximab. After observing a decrease in tumor burden, we performed another 8 courses FIREFOX plus bevacizumab. As a result, CEA and CA19-9 decreased to the normal range, and the size of the rectum cancer and liver metastases decreased. She underwent laparoscopic lower anterior and liver resections in the highvolume center. She presently remains alive with no sighs of recurrence, 18 months after resection.

A 57-year-old female patient received ileocecal colon resection because of colon cancer. Pathological findings showed pSSN2M0(pStage III b). After surgery, CapeOX was administered as an adjuvant chemotherapy. On day 13 of CapeOX treatment, severe oral mucositis and Grade 4 myelosuppression appeared, and the CapeOX treatment was immediately stopped. However, these adverse effects continued for 19 days, and she gradually recovered. The severe myelosuppression was caused bydeficiencyof DPD, which is a keyenzy me that metabolizes 5-FU. While DPD deficiencyis veryrare, we need to consider that 5-FU causes severe adverse events in patients with DPD deficiency.

The patient was a 69-year-old female diagnosed with cecum cancer, pMP, pN1, sH1, sP0, cM0, fStage IV. A laparoscopic cecal resection with D3 dissection was performed against the primary cecal cancer in January 2015. The histological diagnosis was moderately differentiated adenocarcinoma>mucinous adenocarcinoma, ly1, v0, RAS wild type(not known to start chemotherapy for primary treatment). Liver metastasis is very likely to invade the inferior vena cava, so the liver metastasis was judged unresectable, and mFOLFOX6 and bevacizumab(Bmab)chemotherapy was performed. After 4 courses of chemotherapy, the patient exhibited progressive disease(PD)and was transitioned to a secondary treatment with FOLFIRI plus panitumumab(Pmab)therapy. Lung metastases was observed(PD)upon computed tomography after 16 courses. Therefore, salvage line chemotherapy with TFTD and Bmab was performed. Long stable disease(SD)was obtained by the salvage line chemotherapy with TFTD and Bmab. We suspect that the effects of TFID increased in combination with Bmab. Moreover, the TFTD and Bmab chemotherapy was performed relatively safely.

A 67-year-old man was diagnosed with esophageal cancer. Computed tomography(CT)revealed multiple sites of bilateral mediastinal lymph node swelling. Serum levels of soluble interleukin-2 receptor(sIL-2R)were elevated; however, serum levels of angiotensin-converting enzyme(ACE)were normal. Thus, we could not confirm a diagnosis of sarcoidosis. Esophagectomy with neck lymph node dissection was performed. The resected specimen, comprising the mediastinal lymph nodes, showed noncaseating epithelioid cell granuloma; this supported the diagnosis of sarcoidosis. Cases of sarcoidosis associated with esophageal cancer are rare. It is difficult to distinguish between metastasis and sarcoid-like reactions from swollen lymph nodes using preoperative CT or positron emission tomography(PET). It is possible to differentiate lymph node metastasis from its sarcoid reaction it the patient received.

The patient was a 66-year-old male. Following surgery for pulmonary adenocarcinoma in the upper right lobe and adjuvant chemotherapy, the patient relapsed. We carried out treatment using the immune checkpoint inhibitor pembrolizumab (KEYTRUDA®)for high expression of PD-L1. Following the first administration, severe drug eruption occurred and despite temporary improvement seen by intravenous infusion of steroids in combination with oral administration and external use thereof, it relapsed in the early stages and toxic epidermal necrosis developed. Skin problems were improved by multidisciplinary treatments such as gammaglobulin therapy, systemic steroid administration, and broad-spectrum antibiotics. There were no reports oftoxic epidermal necrosis occurring during pembrolizumab administration for lung cancer. This case went through a unique course in which the disease relapsed into a more severe condition at an early stage following temporary remission.

Here we report the case of an 88-year-old female with serious respiratory discomfort who exhibited significant heart enlargement and left pleural effusion in her chest X-ray. She developed cardiac tamponade with massive pericardial effusion, and the cytological analysis and diagnostic imaging revealed adenocarcinoma of an unknown primary site. Although supportive care was offered, due to her super-age and malignant pericardial effusion presenting cardiac tamponade, she and her family requested a detailed examination and active treatment. She was enrolled into our medical oncology department, and we immediately performed a cell block cytological examination procedure and drained the pleural effusion. The immunohistochemical and FISH analyses revealed anaplastic lymphoma kinase(ALK)-rearranged non-small cell lung cancer. An ALK tyrosine kinase inhibitor, alectinib, was administered and resulted in a prompt and effective improvement in clinical outcome. This case indicates that we should attempt to achieve an accurate diagnosis, even when patients are super-aged and exhibit serious progress disease conditions. The pleural effusion cell block analysis may be highly useful for the prompt and precise diagnosis of malignancies.

Pemetrexed(Alimta®)is a multi-targeted antifolate that shows antitumor effects by inhibiting enzymes in the folate metabolic pathway essential for cell replication. Pemetrexed is a standard treatment for Japanese patients with nonsquamous, non-small-cell lung cancer. In this review, we summarize the evidence of clinical studies for the efficacy and safety of pemetrexed in the treatment of nonsquamous non-small-cell lung cancer as first-line chemotherapy and continuation maintenance therapy. In addition, we describe future prospects for pemetrexed in combination with a recent approved PD-1 path- way inhibitor.

MSI-H tumors are drove with molecular mechanism different from ordinary carcinoma, and thus the morphological features could be distinct. Particularly, MSI-H colorectal carcinoma has peculiar morphological characteristics, which are listed as one of the criteria to recommend MSI-testing. In this article, morphological characteristics and immunohistological detection of MSI-H colorectal cancer are reviewed, with contrasting to those of gynecological tumors.