A 65-year-old man with sigmoid colon cancer underwent sigmoidectomy, followed by 8 courses of oral S-1 as postoperative adjuvant chemotherapy. Three years and 3 months after surgery, the patient developed liver metastasis, lymphadenopathy at the root of the inferior mesenteric artery, and bilateral hydronephrosis. The left hydronephrosis was believed to be due to invasion by lymph node metastasis at the root ofthe inferior mesenteric artery. The patient underwent laparoscopic partial resection ofsegment 5 ofthe liver, excision ofthe lymph nodes at the root ofthe inferior mesenteric artery(combined resection ofthe left ureter), bilateral ureteral stent placement, and left ureteral reconstruction. The postoperative course was without complications, and he was discharged 12 days after surgery. Follow-up observation without postoperative adjuvant chemotherapy was planned, according to the patient's wishes.

We report a case of systemic chemotherapy after biliary stent placement for obstructive jaundice due to hepatic portal lymph node metastasis after colorectal cancer surgery. The patient was a 40s woman. Laparoscopic anterior resection for rectosigmoidRS cancer was performed. The pathological diagnosis was T3N0M0PUL0R0, pStage Ⅱ according to the 8th edition of colorectal cancer handling regulations. Because multiple liver metastases were observed 8 months after the surgery, partial resection of the posterior region of the liver was performed. Multiple lung metastases were observed 1 year after hepatectomy, but she wantedto undergo follow-up observation. Jaundice was observed 1 year after the diagnosis of lung metastasis, and obstructive jaundice due to hepatic portal lymph node metastasis was diagnosed. Endoscopic retrograde biliary drainage(ERBD)was performed, and a bile duct stent was placed. After improving jaundice, 12 courses of mFOLFOX6 plus cetuximab therapy were performed. Currently, because of the exacerbation of lung metastasis, FOLFIRI plus bevacizumab therapy is being administered. Systemic chemotherapy containing a molecular-targeted drug is being administered in our case, but complications relatedto the biliary stent have not been observed. There are few reports on similar cases, andfollow - up observation with careful attention to long-term safety is necessary.

We report a case of good quality of life(QOL)and favorable response to transarterial chemoembolization(TACE)against synchronous multiple liver metastases. An 85-year-old man was admitted to our hospital because of melena. Colonoscopy showed multiple type 2 tumors in the sigmoid colon and upper rectum. CT and EOB-MRI examinations revealed that there were multiple liver metastases. Because of his age and surgical stress, he underwent a laparoscopic Hartmann's procedure. After the resection of the primary tumor, he received tegafur/uracil for his liver metastases. However, he discontinued receiving the drugs 2 weeks later because of the development of adverse events. Instead of systemic chemotherapy, he chose to undergo TACE. He underwent TACE with irinotecan and HepaSphereTM(BioSphere Medical)8 times for his multiple liver metastases. Consequently, all multiple liver metastases disappeared. Therefore, TACE may be useful for patients who are not suitable for systemic chemotherapy.

The patient was a 79-year-old man. He had ascending colon carcinoma and multiple hepatic metastases, and right hemicolectomy( D2)was performed in June 2012(SE, N1, P0, M1[H3], Stage Ⅳ). After surgery, 8 courses of mFOLFOX6 plus panitumumab biweekly, then, 5-FU/l-LV biweekly and panitumumab every 4 weeks were administered because he had wild- type KRAS. Before chemotherapy, his serum CEA level was 122 ng/mL, but the value decreased rapidly to a normal level after 7months. The hepatic metastases also decreased, and the lesion was only slightly observed on CT after 7months. Five years after the surgery, images and his CEA level are both normal, and the effectiveness is maintained. Even for right colon cancer, anti-EGFR antibodies might be effective if RAS is wild-type.

A 16-year-old male with no previous medical history developed sudden fever and urinary dysfunction. He was admitted to our hospital due to bilateral leg weakness and sensory disturbance on the third day of weakness onset. A sagittal T2-weighted image displayed a longitudinal extensive lesion of transverse myelitis in the spinal column from the upper cervical (C2) to the thoracic region (Th9). The patient was diagnosed with autoimmune myelitis and treated with four courses of intravenous methylprednisolone (1 g/day for three consecutive days per week). This improved his signs, and his serum sample tested negative for anti-aquaporin-4 (AQP-4) antibody but positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody in cell-based assays. We report this case of longitudinally extensive transverse myelitis involving fifteen vertebral bodies positive for anti-MOG antibody.

A 67-year-old male was transferred to our hospital with diplopia, decreased deep tendon reflex and ataxia. He had been suspected Fisher syndrome because of previous upper respiratory tract infection. A cerebrospinal fluid examination showed marked hypoglycorrhachia, pleocytosis and elevated protein, and cytological examination suggested malignant lymphoma. Abdominal computed tomography revealed a left adrenal mass. A biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. He was treated with a combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin and prednisolone) and intrathecal administration of methotrexate, cytarabine and prednisolone. Neurological symptoms were gradually improved. Malignancy should be considered in addition to bacterial, fungal or tuberculous meningitis in a case with marked hypoglycorrhachia.

An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.

A 65-year-old woman was diagnosed with rheumatoid arthritis in 2010 and was treated with methotrexate (MTX). In 2012, she was diagnosed with sarcoidosis and underwent a follow-up therapy for mild peripheral neuropathy due to neurosarcoidosis. In 2018, she experienced primary splenic diffuse large B-cell lymphoma (DLBCL) and was diagnosed with sarcoidosis-lymphoma syndrome (SLS). MTX was discontinued, and six cycles of rituximab were administered combined with chemotherapy. Positron emission tomography combined with computed tomography performed 18 weeks after the last cycle of chemotherapy showed new abnormal fluoro-2-deoxy-D-glucose (FDG) uptake in the mediastinal and hilar lymph nodes and skeletal muscles. Sarcoidosis was suspected because of increased serum angiotensin-converting enzyme levels and magnetic resonance imaging findings in the lower limb muscles. However, pathological findings of DLBCL and sarcoidosis were not confirmed in the hilar lymph node biopsy. Therefore, malignant lymphoma can be distinguished from sarcoidosis using abnormal FDG uptake after chemotherapy for SLS.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of extranodal non-Hodgkin's lymphoma, and the absence of specific findings makes ante-mortem diagnosis difficult. This study was conducted to identify the clinical findings useful for timely diagnosis of IVLBCL. Ten patients who were diagnosed with IVLBCL in our institute between 2005 and 2017 were retrospectively analyzed. Eight of the 10 cases had fever and 7 cases presented with respiratory symptoms, including cough, sputum, and dyspnea. Cytopenias were noted in all patients, and serum lactate dehydrogenase levels were elevated in 9 of the 10 patients. Arterial partial pressures of oxygen were <80 mmHg in 6 of the 7 patients examined. Computed tomography scanning detected hepatosplenomegaly and chest abnormalities in 7 and 9 cases, respectively. These results suggest that IVLBCL has a higher frequency of lung involvement than those reported previously. Physicians must therefore be vigilant in the identification of IVLBCL in patients who demonstrate respiratory symptoms or hypoxemia of uncertain origin, because early diagnosis can decrease the severity and prevent mortality.

A 79 year-old-man visited our hospital with right back pain. Computed tomography suggested external iliac and para-aortic lymphadenopathy. Serum prostate specific antigen (PSA) increased to 335 ng/ml and prostate cancer was highly suspected. We performed transperineal prostate biopsies two times, but could not detect prostate carcinoma cells. Multiparametric magnetic resonance imaging (MRI) indicated no suspicious malignant lesions in the prostate. Laparoscopic biopsy of the right obturator lymph nodes was performed and histological examination, including immunohistochemical staining with PSA, confirmed lymphnode metastasis from prostate cancer. After endocrine therapy was started, serum PSA levels declined and lymph nodes shrunk. In cases of negative prostate biopsies despite high serum PSA levels, aggressive indication for biopsy of metastatic lesion and histological inspection is highly recommended.

A 69-year-old male with the complaint of a cough was referred to our hospital from a clinic where he was found to have simultaneous metastases of the left kidney tumor. We performed left cytoreductive nephrectomy, and administered sunitinib after the surgery. The first line treatment was not effective. Then we changed the therapeutic agent to pazopanib as the second line treatment. Lung and lymph node metastases gradually shrunk, but he developed right vision disorders and was diagnosed with bilateral metastatic retinal tumors. First, irradiation to the right eye was performed while discontinuing pazopanib. Sudden treatment withdrawal caused his general condition to worsen temporally, but irradiation could be continued by resuming administration of pazopanib. As a consequence, the progression of the visual field disorder was suppressed by the additional ophthalmologic treatment. Renal cell carcinoma choroidal metastases are rare, but we need to consider them when the patient has vision disorders.

Early detection and treatment are important for the successful eradication of various cancers; therefore, the development of economical, noninvasive novel cancer screening systems is critical. Previous reports using canine scent detection have demonstrated the existence of cancer-specific odors. However, it is difficult to introduce canine scent recognition into clinical practice because of the need to maintain accuracy. In this study, we developed a Nematode-Nose (N-NOSE) test using Caenorhabditis elegans to provide a novel, highly accurate cancer detection system that is economical, painless, rapid, and convenient. We demonstrated that wild-type C. elegans displayed attractive chemotaxis toward human cancer cell secretions, cancer tissues, and urine from cancer patients but avoided control urine. In parallel, C. elegans olfactory neurons showed a significantly stronger response to urine from cancer patients than to control urine. In contrast, G protein α mutants and animals with ablated olfactory neurons were not attracted to urine from cancer patients, suggesting that they sense odors in urine. We tested 242 samples to measure the performance of the N-NOSE test and found that the sensitivity was 95.8%, which is markedly higher than that of other existing tumor markers. Furthermore, the specificity was 95.0%. Importantly, this test could detect various cancer types tested at the early stage (stage 0 or 1). C. elegans scent-based analyses therefore might provide a new strategy for the detection and study of disease-associated scents.

Mitogen-activated protein kinase (MAPK) pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, and apoptosis. The Ras/Raf/MEK/ERK MAPK pathway is one of the most studied of the mammalian MAPK pathways and has attracted intense research interest because of its critical involvement in the regulation of cell proliferation. The mutational activation of upstream signaling components that constitutively activate ERK MAPKs as seen in various primary tumor samples has validated this pathway for drug discovery. The fission yeast Schizosaccharomyces pombe is an important tool for cancer research. This well-studied model organism has enabled groundbreaking, Nobel Prize-winning discoveries and has provided insights into how both normal and cancerous cells grow and divide. We performed chemical genetic screening using a fission yeast phenotypic assay and demonstrated that ACA-28, a synthetic derivative of 1'-acetoxychavicol acetate (ACA), effectively inhibited the growth of melanoma cancer cells wherein ERK MAPK signaling is hyperactivated due to mutations in the upstream activating regulators. Importantly, the growth of normal human epidermal melanocytes was less affected by ACA-28. In addition, ACA-28 specifically induced apoptosis in NIH/3T3 cells oncogenically transformed with HER2/ErbB2 but not in the parental cells. Notably, the ACA-28-induced apoptosis was abrogated when ERK activation was blocked with the specific MEK inhibitor U0126. Consistently, ACA-28 more strongly stimulated ERK phosphorylation in melanoma cells as compared with normal human epidermal melanocytes. ACA-28 might serve as a promising seed compound to combat ERK-dependent cancers by stimulating oncogenic signaling.

Stress-responsive signaling pathways convert cellular stresses into various physiological responses, such as cell proliferation, apoptosis, and inflammation. Signal pathway dysfunction thus induces abnormal cellular behaviors that may lead to tumorigenesis and tumor progression, including metastasis. Tumor metastasis is the spread of tumor cells from primary lesions to other distant tissues/organs. Several types of murine model which mimic the progression of human cancer have been established for preclinical studies to understand the biology of cancer. Mitogen-activated protein kinase (MAPK) cascades are one of the stress-responsive signaling pathways and are intricately involved in both tumor promotion and suppression. Here, we present the diverse roles of apoptosis signal-regulating kinase (ASK) family molecules in tumor formation and progression. ASK family is a member of MAPK kinase kinase (MAP3K) family in the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways and comprises three family members, ASK1, ASK2, and ASK3. Accumulating evidence indicates that ASK1 controls tumorigenesis through the regulation of innate immunity and apoptosis. ASK2 also regulates tumorigenesis via apoptosis. Furthermore, analysis of the experimental lung metastasis model in mice suggests that host ASK1 deficiency attenuates tumor lung metastasis. In this symposium review, we discuss the potential roles of ASK family in the context of tumor metastasis.

Since the 1980s, zebrafish (Danio rerio) have been used as a valuable model system to investigate developmental processes because they: 1) grow outside their mothers; 2) are transparent during the embryonic stage; and 3) have organs similar to those in humans. Recently, zebrafish have emerged as a powerful model animal for studying not only developmental biology but also human diseases, especially cancer. Owing to the significant advantages of zebrafish, such as low-cost breeding, high efficiency of transgenesis, and ease of in vivo imaging and oncogenic/tumor cell induction, zebrafish offer a unique opportunity to unveil novel mechanisms of cancer progression, invasion, and metastasis. In addition, the small size of zebrafish larvae enables high-throughput chemical screening, and this advantage contributes to generating useful platforms for antitumor drug discovery. Owing to these various merits, which other model animals (such as fly, mouse, and rat) do not possess, zebrafish could achieve a unique status in cancer research. In this review, we discuss the availability of zebrafish for studying cancer and introduce recent cancer studies that have used zebrafish.

A 52-year-old man was admitted to our hospital because of two episodes of bacterial meningitis within a 6-month period. CSF examination showed neutrophilic pleocytosis with marked elevation of protein and hypoglycorrhachia, but the inflammatory reaction was mild and blood and CSF cultures were negative. At the time of the second admission, intermittent watery nasal discharge caused by CSF rhinorrhea was evident. CT and MR imaging revealed a tiny clival bone defect, and transnasal endoscopic repair was performed successfully. The pathological diagnosis was chordoma based on immunohistochemical staining for brachyury. Although chordoma presenting as recurrent bacterial meningitis occurs extremely rare, asking patients detailed questions about the CSF rhinorrhea must be essential for disclosing unclear infection sources.

Lymphomatosis cerebri (LC) is a variant of primary central nervous system lymphoma, which demonstrates diffuse white matter infiltrates without showing definite enhanced mass lesions on MR scans. We present a case of seventy-one year-old immunocompetent male who manifested with progressive truncal ataxia and drowsiness. The MRI exhibited diffuse white matter lesions from brainstem to cerebral hemispheres with minimum enhanced lesions at the first presentation. Because the diagnosis of LC was suspected, we performed a brain biopsy from the enhanced lesion near the right thalamus, which revealed diffuse large B cell lymphoma. After he underwent methylprednisolone pulse therapy and methotrexate chemotherapy, he obtained remission. Making a diagnosis of LC is often difficult because image findings resemble those of inflammatory or autoimmune diseases. LC is an important differential diagnosis to be considered in patients presenting with diffuse white matter disease. Performing a brain biopsy at the early phase is essential for the correct diagnosis and the favorable prognosis.

Xeroderma pigmentosum is a DNA repair disorder characterized by the occurrence of pigmented freckles and skin cancers on sun-exposed areas. Additionally, more than 50% of patients present with progressive degenerative neurological symptoms. Eight clinical subtypes of this condition are known, and neurological symptoms can be seen in XP-A, B, D, F, G complementation groups.

Cockayne syndrome (CS) is an autosomal recessive disorder characterized by severe photosensitive genodermatosis that is associated with premature aging caused by defects in the UV-induced DNA damage repair system, particularly the transcription-coupled nucleotide excision repair. The clinical features of CS include photosensitivity, a characteristic senile face, significant developmental abnormalities, such as short stature, underweight, and microcephaly, progressive cachexia, severe visual impairment, and sensorineural deafness. CS is clinically classified into type I (classical type), type II (congenital or severe type) and type III (late-onset or adult-onset type). Additionally, there exists a rare form of xerodema pigmentosum-Cockayne syndrome (XP/CS) complex. The incidence of CS is 2.7 in 1,000,000 individuals in Japan and 90% of the cases are type I. Unlike XP, in CS, skin cancer is not known to occur in areas of skin exposed to sunlight. However, we observed a case where solar keratosis developed in adult-onset CS patients (CS type III) with a pathological mutation in the CSB gene. In XP/CS, patients easily develop skin cancer from early childhood in areas of the skin exposed to sunlight.

The cutaneous findings associated with Sturge-Weber syndrome (SWS) are characterized by a port-wine stain at the site of the first branching of the trigeminal nerve. Recently, a new vascular classification for the port-wine stain is proposed in association with SWS. There is no consensus regarding the screening of SWS, but suspected cases of SWS are recommended for early referral to ophthalmologists. Magnetic resonance imaging (MRI) of the brain in infants, when they are younger than 6 months, leaves the possibility of false-negatives of SWS.