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We report the sensitivity of immune checkpoint inhibitors for tumors developing in a patient bearing the MSH2 c.1808A > T (Asp603Val) variant belonging to a pedigree of Lynch syndrome. This variant was previously thought to be of unknown significance, but we recently found that this missense mutation was likely pathogenic. At that time, there were no active members with malignancies that could be treated with chemotherapy. Thereafter, an 81-year-old woman bearing this variant, who was a cousin of the proband of this family, had multiple lymph node metastases from her resected gastric cancer. An immune checkpoint inhibitor, pembrolizumab, an anti-PD-1 antibody, was used to treat these tumors. After 3 months of treatment, almost all tumors disappeared, and elevated CA19–9 levels normalized. She survives over 15 months safely. It was indicated that the tumors bearing this germline variant were sensitive to pembrolizumab. This observation suggests that an MSH2 c.1808A > T (Asp603Val) variant induces mismatch repair deficiency, resulting in sensitization to immune checkpoint inhibition.

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen-4 inhibitors, and inhibitors of programmed cell death 1 and its ligand, are widely used in the treatment of several malignant tumors. Immune-related adverse events occur in two-thirds of recipients. Among them, cardiotoxicities are very rare (about 1%), albeit fatal. Pembrolizumab-induced cardiotoxicity in a patient was successfully treated with high-dose corticosteroids, and his cardiac function was maintained by adrenergic drugs and intra-aortic balloon pumping in the intensive care unit for 1 week. Cardiotoxicity with ICIs is an oncologic emergency, and should be managed in a pluridisciplinary setting involving cardiologists.

We report the first pedigree of Lynch syndrome bearing a germ-line MSH2 missense mutation c.1808A>T (Asp603Val). Until now, this missense mutation, in exon 12 of MSH2, was identified as a variant of unknown significance in the International Society for Gastrointestinal Hereditary Tumours database. In vitro induction mutagenesis experiments indicated that the MSH2 mutant protein (Asp603Val) is easily degraded in embryonic stem cells, albeit there is no clinical information concerning this mutant. Our pedigree includes four patients with Lynch syndrome-associated malignancies and clinically matches the Amsterdam II criteria. The proband, a female, first had an endometrial cancer at the age of 49 and then mantle cell lymphoma, colonic and gastric adenocarcinomas and neuroendocrine carcinoma, successively. Her mother also had Lynch syndrome-associated malignancies, including colonic, uterine and gastric cancers, and her elder son had rectal cancer. In the germline of the proband and her son, an MSH2 missense mutation c.1808A>T was discovered. Immunohistochemical analyses indicated that the expression of the MSH2 protein was decreased in the tumors, such as gastric cancer and neuroendocrine carcinoma, due to the missense mutation c.1808A>T. This study showed that the MSH2 missense mutation c.1808A>T (Asp603Val) is a likely pathogenic mutation and is responsible for typical Lynch syndrome-associated malignancies, including neuroendocrine carcinoma.

BACKGROUND Angiogenesis inhibitors (AIs) combination with cytotoxic chemotherapy is a promising treatment for patients with colorectal cancer (CRC). Aflibercept (AFL) is an option for second-line treatment of CRC, according to the ‘VELOUR’ trial. Currently, we can choose from three AIs, including bevacizumab, ramucirumab, and AFL. Different AIs can be used in subsequent treatment because of their distinctive mechanisms of action. We addressed the uncertainty regarding AFL efficacy and safety in heavily-treated patients by comparing outcomes of survival treatment with second-line treatment. AIM To determine and compare the efficacy and safety profiles of AFL in the second-line and salvage therapy settings. METHODS Clinical data of 41 patients with advanced CRC who received intravenous AFL combined with the folinic acid-fluorouracil-irinotecan (FOLFIRI) regimen were collected retrospectively from six institutions in Japan, for the period from May 2017 to March 2019. Patient characteristics collected included age, sex, tumor location, RAS and RAF status, metastatic sites, number of previous treatment cycles, therapeutic response, adverse events, duration of previous AI treatment, and survival time. The end points were time to AFL treatment failure (aTTF) and median survival time post-AFL (aMST). Statistical analyses were performed to compare the efficacy and safety in the second-line setting with those of the salvage therapy setting, which was defined as the days since the end of second-line therapy. RESULTS All 41 patients who received AFL + FOLFIRI for advanced CRC had metastatic or unresectable cancer. Twenty-two patients received AFL in the second-line setting and nineteen in the salvage therapy setting. The patient characteristics were similar in the two groups, except for two factors. The median duration of the previous AI administration was shorter in the second-line patients compared with that in the salvage therapy patients (144 d vs 323 d, P = 0.006). In the second-line and salvage therapy groups, the objective response rates were 11% and 0%, respectively (P = 0.50), and the disease control rates were 53% and 50%, respectively (P = 1.00). In the second-line and salvage therapy groups, the aTTF (123 d vs 71 d, respectively), aMST (673 d vs 396 d, respectively), and incidence of adverse events of grade 3 [8 (36%) vs 9 (47%)] were not significantly different between the two groups. CONCLUSION AFL can be used to treat advanced CRC patients, with a similar safety and efficacy in the salvage therapy setting as in the second-line setting.

Germline mutations of TP53 are responsible for Li–Fraumeni syndrome in its 60–80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. In patients who were receiving regorafenib 40–160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318–9467, 34–3594, and 38–3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.

Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3+Tregs from naïve CD4+T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at theFoxp3locus and inducesFoxp3gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β.In vivotumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3+Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.

Diamond-Blackfan anemia is an autosomal dominant syndrome, characterized by anemia and a predisposition for malignancies. Ribosomal proteins are responsible for this syndrome, and the incidence of colorectal cancer in patients with this syndrome is higher than the general population. This patient's Diamond-Blackfan anemia was caused by a novel ribosomal protein S19 gene mutation, and he received chemotherapy for colorectal cancer caused by it. In his cancer, ribosomal proteins S19 and TP53 were overexpressed. He received 5FU and cetuximab; however, his anemia made chemotherapy difficult, and he did not survive long. Patients with Diamond-Blackfan anemia should be screened earlier and more often for colorectal cancer than usual.

Gastric cancer is the second leading cause of cancer-related mortality worldwide. Curcumin, a phytochemical, possesses molecular inhibitory potentials for regulating malignancies. However, the lower potential of curcumin warrants improvement. Thus, we synthesized diarylpentanoid analogs with higher potency; however, these differed structurally from curcumin—a heptanoid. Recently, one diarylpentanoid was formed following pyrolysis of curcumin, which is identical to our GO-Y022. The growth inhibition of gastric cancer cells by GO-Y022 was five-fold higher than by curcumin; GO-Y022 displayed superior apoptosis induction ability. Besides, it suppressed the gastric tumor growth to a third in a mouse model. GO-Y022 was moved to the epithelial and gastric tumors but not detected in the bloodstream. Moreover, oral GO-Y022 was effective topically, exhibited no adverse events in mice, and was detected in the commercially available curry paste. Briefly, GO-Y022 can inhibit gastric carcinogenesis; it is dietary and can be safely used as an oral functional food.

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75 μmol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078.

We describe a case of Guillain–Barré syndrome (GBS) in a patient treated with bevacizumab. Our case is a 60-year-old woman with Stewart–Treves syndrome (STS), and angiosarcoma of her left forearm, with onset 12 years after diagnosis with stage IIIA left breast cancer. She suffered from repeated distal metastases including skin, bone, and liver metastases. She underwent numerous treatments including left arm amputation, radiation, and chemotherapy, but her disease was resistant. Thereafter, she received bevacizumab. Two weeks following the first administration, she presented in poor physical condition. Although the cause was not specified at that time, bevacizumab was discontinued. At 1 month following first bevacizumab administration, she gradually developed dyspnea, and numbness in her tongue and hands. Soon after, she was emergently admitted to the hospital due to hyperventilation syndrome. On hospital day 4, she developed quadriparesis, and on hospital day 8, she was diagnosed with GBS following neurological testing. Treatment with intravenous immunoglobulins was started immediately upon diagnosis, and her neurological symptoms eventually resolved. A repeat challenge course of bevacizumab was avoided. Five months later, the patient perished from STS progression. GBS associated with malignancies and/or chemotherapies has been rarely described in patients with malignant lymphomas. Of note, there is only one reported case of GBS with bevacizumab. Furthermore, in some cases, GBS is lethal, and it should be considered in the differential diagnosis of patients treated with bevacizumab.

Immunomodulation treatment using anti-programmed cell death protein 1 antibody is a very promising treatment for various types of advanced cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. However, the therapeutic effects on early cancers are still unknown. We experienced 2 cases of early gastric cancers coexisting advanced melanomas. In both cases, early gastric cancers did not respond to nivolumab. Both early gastric cancers did not express programed death ligand 1. It was speculated that immunotolerance was not fully established responsible for nivolumab in early gastric cancer, and for this reason, nivolumab could not shrink these tumors. We experienced 2 cases of early gastric cancer, where PD-L1 was negative, not responding to nivolumab.

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia. One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed. Grade ≥2 severe hypophosphatemia (

Introduction: New drugs have improved the outcome of metastatic colorectal cancer treatment. In Japan, more than 10 agents with at least seven different mechanisms such as 5-fluorouracil (5-FU), irinotecan (IRI), oxaliplatin, angiogenesis inhibitors, anti-epidermal growth factor receptor antibodies, regrafenib, and TAS-102, have been approved. With the increase in the number of alternatives, the importance of choosing the agents increases. To suppress the toxicities of agents is also necessary. To increase the quality of life of the patients should be taken into consideration for their longer survival. TAS-102 has proved to be an effective and safe agent for the 3rd or 4th lines of advanced colorectal cancer. Presentation of case: We report a case of a patient who had suffered severe adverse events from standard firstline chemotherapy with 5-FU derivative and IRI. She did not want to undergo any more intensive chemotherapy. Toxicity and anxiety made her evade the standard combination chemotherapy. For this patient, TAS-102 achieved over 30% tumor shrinkage and more than 1-year progression-free survival with acceptable toxicities. Conclusion: TAS-102 can result in a better outcome for a responder when given as an earlier line of therapy. In future, predictive biomarkers of TAS-102 should be identified for better use of this agent.

e15518 Background: Gastric cancer is the second cause of cancer death in the world, killing more than 700,000 people in 2012. The risk factors are Helicobacter pyloriinfection, obesity, smoking, consumption of red meat or alcohol. However, an effective preventive measure of this disease has bot been established. Curcumin, a dietary pigment, that has been used for more than three thousand years, has an anti-tumor potential. However, bioavailability of curcumin is very poor, and it is not used in clinics. Researchers are trying to overcome this short point. To synthesize a new analog bearing higher anti-tumor potential is our solution, and we have successfully developed a series of new diarylpentanoid analogs. Our diarylpentanoid analogs are structurally different from curcumin, a diarylheptanoid. Recently, a breakthrough finding that a deketene curcumin is formed as a result of pyrolysis of curcumin during cooking of curry, was published. This deketene curcumin is identical to one of our analogs, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one, named GO-Y022. For this reason, we investigate the efficacy and safety issues of GO-Y022 in a mouse gastric cancer model. Methods: We assessed anti-tumor potential of GO-Y022 on gastric cancer cell lines, KATO Ⅲ, H-111-TC, GCIY and SH-10-TC. We also examined the potential to inhibit β-Catenin and pSTAT3 levels. We conducted mouse experiment using transgenic mouse model overexpressing Wnt signaling, COX2 and Prostaglandin E2. This mouse is highly seceptible to gastric carcinogenesis. We orally administrated GO-Y022 mixed with food. We checked the safety issues of the treated mouse, and measured the tissue concentration of GO-Y022 by HPLC method. Results: GO-Y022 can inhibit the growth of gastric cancer cell lines significantly. The average IC50value of GO-Y022 was 5.05 ± 0.93 μm. That is about five times lower than curcumin. This potential was confirmed in mice. Blood concentration and the tissue distribution of GO-Y022 were negligible except gastrointestinal epithelia. GO-Y022 was safe for mouse models. Conclusions: GO-Y022 can inhibit the growth of gastric carcer in vivo. Oral administration of GO-Y022 can suppress gastic cancer topically.