Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety.

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

Correlation between Skeletal Muscle Mass and Adverse Events of Neoadjuvant Chemotherapy in Patients with Gastric Cancer.

PURPOSE: Neoadjuvant chemotherapy (NAC) followed by surgery is a promising treatment strategy for patients with advanced gastric cancer. Severe toxicity associated with the treatment may reduce the dose intensity of chemotherapy, resulting in the effect of chemotherapy being attenuated. Recently, skeletal muscle mass has been reported to be associated with the treatment outcomes of cancer patients. The purpose of this study was to clarify whether pretreatment skeletal muscle mass is a predictor of adverse events as well as the relationship between changes in skeletal muscle mass and adverse events during NAC. METHODS: This study included 41 advanced gastric cancer patients who were treated with NAC followed by surgery. Body composition was assessed before and after NAC. The relationship between the pre-NAC body composition and adverse events was investigated as well as the relationship between changes in body composition and adverse events. RESULTS: Univariate and multivariate analyses revealed that low pre-NAC skeletal muscle mass was the only factor significantly associated with severe diarrhea (p = 0.03). There was no significant difference in body weight before and after NAC, but skeletal muscle mass was significantly reduced after NAC (-5.93 ± 7.69%, p < 0.01). Furthermore, patients who experienced severe diarrhea showed significantly greater relative skeletal muscle decrease than those who did not (p = 0.03). CONCLUSIONS: Pre-NAC low skeletal muscle mass was a useful predictor of severe diarrhea. Prevention of severe adverse events may contribute to maintaining the skeletal muscle mass.

Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction.

The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of ATyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-γ secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.

[A Case of Lymph Node Recurrence with Invasion to the Trachea after the Resection of Esophageal Cancer Treated by Multidisciplinary Treatment].

A 78-year-old man who underwent esophagectomy for middle thoracic esophageal squamous cell carcinoma(pT1bN0M0, pStage Ⅰ)was diagnosed with lymph node recurrence 12 months after the initial surgery. He received chemoradiotherapy(5- fluorouracil plus cisplatin); however, the treatment was terminated at the middle of the treatment course because of progressive disease. He received chemotherapy(docetaxel plus 5-fluorouracil plus cisplatin)as a second-line treatment, which was also canceled due to serious adverse events. Partial response was achieved after the second therapy; therefore, surgical excision was performed. Thirteen months after the second surgery, he was diagnosed with second local recurrence with invasion to the trachea. Another course of chemotherapy(docetaxel[2-weekly]plus 5-fluorouracil plus cisplatin)was administered, which also achieved a partial response. Thus, surgical excision with partial tracheal resection and mediastinal tracheostomy was performed. He has been alive without recurrence for 6 months after the final operation. In case of postoperative solitary lymph node recurrence of esophageal cancer, long-term survival can be expected with multidisciplinary treatment.

[A Case of Adenosquamous Carcinoma of Pancreas Treated with Conversion Surgery after Systemic Chemotherapy].

CASE: A man in his 60s reported upper abdominal pain; close examination revealed a tumor in the body-tail of the pancreas that was suspected to be infiltrating the stomach. Multiple liver lesions(S3, S4)were also detected. Histological examination by EUS-FNA showed poorly-differentiated carcinoma; thus, this case was diagnosed with unresectable pancreatic cancer with liver metastases(cT3, cN1[No. 7], cM1[P0, H1], cStage Ⅳ: JPS 7th). After 2 kinds of systemic chemotherapy(9 courses of GEM plus nab-PTX and 9 courses of modified FOLFIRINOX), obvious distant metastases or local progression did not appear and conversion surgery was scheduled. Although a metastatic lesion was identified at S5 of the liver just before the surgery, it was assumed that an R0 resection could be achieved; therefore, the operation(distal pancreatectomy with combined proximal gastrectomy, left adrenalectomy, lymph node dissection, partial hepatectomy of S5, and cholecystectomy)was performed. Histopathological examination showed squamous metaplasia of the epithelial tissue combined with glandular formation. This case was, thus, diagnosed as adenosquamous carcinoma of pancreas. This patient was discharged 90 days after the operation. The patient is still alive 2 years and 2 months since the first diagnosis.

Skeletal Muscle Loss during Neoadjuvant Chemotherapy Is an Independent Risk Factor for Postoperative Infectious Complications in Patients with Advanced Esophageal Cancer.

OBJECTIVE: Neoadjuvant therapy followed by surgery has been the standard treatment for advanced esophageal cancer. Severe toxicities may influence body composition, including skeletal muscle mass, and increase postoperative complications. The purpose of this study was to evaluate the influence of sarcopenia, changes in body composition, and adverse events during neoadjuvant chemotherapy (NACT) on postoperative complications in esophageal cancer patients. METHODS: A total of 83 patients with esophageal cancer undergoing NACT followed by esophagectomy were included. Body composition was assessed before chemotherapy and before esophagectomy. The relationships between postoperative infectious complications and sarcopenia, changes in body composition, and adverse events during NACT were investigated. RESULTS: Univariate analysis revealed that skeletal muscle loss during NACT, but not preoperative sarcopenia, was significantly higher in the complication (+) group. Febrile neutropenia tended to occur frequently in the complication (+) group. Multivariate analysis demonstrated that skeletal muscle loss was the only factor significantly associated with infectious complications (p = 0.029). Among adverse events, febrile neutropenia was significantly associated with a decrease in skeletal muscle mass. CONCLUSION: Loss of skeletal muscle mass during NACT was a significant risk factor for postoperative infectious complications in patients with esophageal cancer. Prevention of severe adverse events may reduce postoperative infectious complications.

[Two Cases of Locally Recurrent Rectal Cancer Undergoing Preoperative Chemoradiationtherapy].

Case 1 is a 68-year-old woman with locally recurrent rectal cancer(LRRC)developed 5 years after resection of primary rectal cancer. The tumor seized right lateral side in pelvic. We performed tumor excision after preoperative chemoradiation comprised external beam radiation with oral S-1(tegafur/gimeracil/oteracil). He has been relapse-free for 3 years 3months after surgery. Case 2 is a 74-year-old man with LRRC developed 2 years after resection of primary rectal cancer. The tumor was located dorsal to anastomosis site in pelvic. We performed abdominoperineal resection for LRRC after preoperative chemoradiation with oral S-1. He has been relapse-free for 2 years. It was suggested that preoperative radiotherapy combined with oral FU for local recurrence after rectal cancer may contribute to distant and local control.

[Investigation of Administration Technique of Regorafenib in Our Center].

Regorafenib is an oral multikinase inhibitor; the CORRECTtrial evaluated its efficacy in patients with metastatic colorectal cancer following disease progression with standard therapies. However, regorafenib has toxicities that develop quickly. Few studies have reported the safe dose and usage of regorafenib to avoid these adverse events in Japanese patients. We examined the side effects and safe administration technique of regorafenib in this study. We administered regorafenib to 15 patients with metastatic colorectal cancer following disease progression with standard therapies. Between August 2013 and January 2014, 5 patients received 160 mg oral regorafenib once daily on days 1-21 of a 28 day course(group A). Between February 2014 and July 2015, 10 patients received initiating therapy with 120 mg regorafenib, with the intention of increasing the dose(group B). We retrospectively assessed side effects, number of dose courses, and total dose of regorafenib in both groups. The median dosing course was 5 coureses in group B, which was more than the 1 course in group A. The median total dose was 10,800 mg in group B, which is about 4 times as much as the 2,400 mg in group A. In group B, 7 out of 10 patients (70%)were successful in the dose escalation of regorafenib from 120 to 160 mg daily over 3-5 courses. The disease control rate was 40% in both groups. The rate of adverse events of Grade 3 or higher was 60% in group A, compared to 40% in group B within 2 courses. The overall survival time was 308 days in group B, which was significantly longer than the 168 days in group A. Initiating therapy with 120 mg regorafenib with the intention of increasing the dose improves safety and allows an increase in dosing courses, as well as in the total dose of regorafenib and overall survival time.

[A Case of Diaphragmatic Metastasis from Adenocarcinoma of the Rectum Treated via Surgical Resection].

A 67-year-oldman underwent lower anterior resection for rectal cancer andresection of liver metastatic tumor 5 years later. Seven years and 2 months after the initial surgery, a soft tissue mass was detected in the left diaphragm. Further retrospective review of CT scan images showedthat the diaphragmatic tumor was present just before the hepatectomy. Partial resection of the left diaphragm was performed, and no relapse has occurred since then for 2 years. Most cases of diaphragmatic metastasis are considered to arise from dissemination, but we considered this case as more likely to be hematogenous. When surgery is chosen to treat metastatic tumors of colorectal cancer, checking for other metastasis via preoperative imaging andperforming curative resection is important.

A Cancer Reprogramming Method Using MicroRNAs as a Novel Therapeutic Approach against Colon Cancer: Research for Reprogramming of Cancer Cells by MicroRNAs.

BACKGROUND: We previously generated induced pluripotent stem cells by reprograming adipose stem cells through the introduction of microRNAs targeting four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4). In this study, we aimed to reprogram cancer cells using microRNAs to explore their therapeutic potential. METHODS: Mature microRNAs (mir-302a-d, 369-3p and 5p, and mir-200c, as needed) were introduced into colon cancer cells (DLD-1, RKO, and HCT116) using lipofection. RESULTS: The transfected cells exhibited an embryonic stem cell-like morphology and expressed the undifferentiated marker genes Nanog, Oct3/4, SOX2, and Klf4, as well as tumor-related antigen-1-60. These cells expressed neurogenic or adipogenic markers, indicating that reprogramming of the cancer cells was partially successful. Moreover, we found that miRNA-expressing DLD-1 cells showed low proliferative activity in vitro and in vivo, accompanied by increased expression of the tumor suppressor genes p16 (ink4a) and p21 (waf1) . miRNA-expressing DLD-1 cells also exhibited enhanced sensitivity to 5-fluorouracil, possibly through the downregulation of multidrug-resistant protein 8. The reprogrammed cells from DLD-1, RKO, and HCT116 cells exhibited reduced c-Myc expression, in contrast to the high c-Myc expression in the induced pluripotent cancer cells that were generated using four transcription factors. CONCLUSIONS: Our cancer reprogramming method employing simple lipofection of mature microRNAs is safe and well suited for clinical application, because it avoids integration of exogenous genes into the host genome and allows escape from augmentation of c-Myc gene expression.

[Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas Showing High Accumulation of 18F-Fluorodeoxyglucose (FDG)--A Case Report].

The diagnosis of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas includes radiographic (CT, MRI) and endoscopic evaluation (ERCP, EUS). The treatment strategy is outlined in the 2012 International Consensus Guidelines (ICG). Herein, we report a case initially not indicated for surgery. Four months after the initial diagnosis, the cystic lesion transformed into a solid mass-like lesion visible on CT. FDG-PET showed abnormal FDG uptake at the same location. Surgical resection was performed immediately, and the tumor was diagnosed as IPMN with inflammation. FDG-PET showed a false-positive diagnosis for the malignancy in this case of IPMN.

[Interventional Radiology for Intra-Abdominal Abscess after Gastrectomy].

Approximately 20% of patients develop some complications after gastrectomy. These complications should be treated appropriately to achieve a positive outcome. The records of 6 patients with postoperative intra-abdominal abscesses treated with interventional radiology (IVR) were analyzed. The cause of abscess was anastomotic leakage in 4 patients and contaminated surgery after gastric perforation in 2 patients. Intra-abdominal abscesses were detected on postoperative day 12 (median), and an IVR-guided drainage tube was inserted with a median interval of 1 day. The drainage tube was kept in place for 26 days (median), and patients were discharged 6.5 days (median) after drainage tube removal. No patients were converted to open surgery. Early IVR-guided drainage was essential and effective for intra-abdominal abscess treatment after gastrectomy.

[Analysis of Chemotherapy with Trastuzumab in Advanced Gastric Cancer].

PURPOSE: Here, we investigated the efficacy of chemotherapy with trastuzumab for patients with advanced or recurrent gastric cancer. MATERIALS AND METHODS: We investigated the progression free survival (PFS) and overall survival (OS) of advanced gastric cancer patients who received first-line chemotherapy with trastuzumab in our hospital. RESULT: After first-line chemotherapy, the median PFS and median OS of patients who received trastuzumab combined with capecitabine/cisplatin chemotherapy was not significantly longer than those of patients who received trastuzumab combined with S-1/cisplatin chemotherapy (PFS, 138 [95%CI: 118-187] vs 169 [95%CI: 83-251] days, p=0.9684; OS, 393 [95%CI: 240-469] vs 466 [95%CI: 256-482] days, p=0.4703). After second-line chemotherapy, the median PFS of patients who received trastuzumab plus irinotecan chemotherapy was not significantly longer than that of patients who received trastuzumab plus paclitaxel chemotherapy (PFS, 63 [95%CI: 52-266] vs 58 [95%CI: 26-184] days, p=0.5447).

[A Case of Unresectable Advanced Gastric Cancer Treated with Radiotherapy and Trans-Arterial Embolization, Resulting in Effective Hemostasis].

We report the case of a 70-year-old man with unresectable advanced gastric cancer because of invasion to the pancreas and multiple liver metastases. He could have continued with fourth-line chemotherapy by controlling intermittent bleeding from the cancer by means of 2 rounds of radiotherapy and trans-arterial embolization. The serum hemoglobin level declined to 4.5 g/dL during second-line chemotherapy. As the venous bleeding from the cancer was difficult to control by endoscopic hemostasis, radiotherapy with 40 Gy/20 fractions was applied to the cancer. We were able to restart chemotherapy after the hemostasis, but 6 months later, the serum hemoglobin level declined to 6.1 g/dL. Additional radiotherapy of 20 Gy/10 fractions was delivered to the tumor, and successful hemostasis was achieved; the serum hemoglobin level reached 7.5 g/dL. However, a contrast-enhanced CT, which was performed 3 weeks later, demonstrated extravasation from the cancer into the gastric cavity. We conducted trans-arterial embolization, and the patient no longer required transfusion. We planned to restart chemotherapy soon, but after 1 month, he died of pneumonia.

[A Case of Resected Gastric Cancer Occurring Simultaneously with Intrahepatic Cholangiocarcinoma after S-1 plus Cisplatin Chemotherapy].

It is sometimes difficult to differentiate between metastatic and primary liver tumors, when the liver tumor occurs simultaneously with a gastric cancer. We encountered a case of resected gastric cancer, which occurred concomitantly with intrahepatic cholangiocarcinoma after S-1 plus cisplatin chemotherapy, in a patient who was previously diagnosed with metastatic liver tumor before treatment. An 80-year-old man was admitted to our hospital because of epigastralgia. Endoscopic study of the upper gastrointestinal tract showed a type 3 tumor at the upper body of the stomach. A plain CT scan showed an irregular, low-density area, which was enhanced by contrast medium in the lateral segment of the liver. We performed an ultrasound- guided needle biopsy, because it was impossible to make a definitive diagnosis by dynamic CT, contrast-enhanced ultrasonography, and MRI. Immunohistochemical analysis for cytokeratin 7/20 resulted in 7 (+)/20 (-) for both the gastric cancer and the liver tumor. Therefore, we diagnosed the patient with gastric cancer, which occurred concomitantly with the metastatic liver tumor, and administered chemotherapy with S-1 plus cisplatin. After 3 courses of the regimen, a reduction in the size of mass was observed in the stomach and the liver. We subsequently performed left hepatectomy and total gastrectomy with lymph node dissection. Microscopic examination revealed the gastric cancer, which occurred simultaneously with the intrahepatic cholangiocarcinoma. The postoperative course was uneventful, and the patient remains well without recurrences.

[A Case of Esophageal Cancer Metastases to the Skin].

Skin metastases from esophageal cancer are comparatively rare but have poor prognosis. Here, we report a case of esophageal cancer metastases to the skin. A 70-year-old man was admitted to our hospital for nodules with ulceration in the nose, and biopsy revealed a metastatic carcinoma. FDG-PET indicated FDG accumulation in the skin, liver, and esophagus, while an endoscopic study of the upper gastrointestinal tract showed a type 3 tumor at the upper mid-thoracic esophagus. We diagnosed the patient with metastatic esophageal cancer and administered chemotherapy. Radiation therapy (40 Gy/20 Fr) was simultaneously administered for the tumor in the nose because the patient's quality of life (QOL) decreased daily owing to pain and bleeding caused by metastatic skin cancer. The radiation therapy reduced the size of the tumor in the nose, but the tumor had remained along with the presence of a scar 3 to 6 months after the start of radiation therapy. Radiation effectively promoted the QOL of our patient with skin metastases.

[Analysis of Esophageal Cancer Patients Undergoing Non-Curative Resection].

The prognosis of esophageal cancer patients who undergo non-curative resection is very poor. Here, we retrospectively analyzed the factors associated with non-curative resection. Thirty-five patients with cT3 or T4 thoracic esophageal cancer treated with neoadjuvant chemotherapy or chemoradiotherapy followed by esophageal resection were included in this study. Among the 35 patients, 27 underwent curative resection (R0 group), while 8 underwent non-curative resection (R1R2 group). A comparison of the clinicopathological factors between groups revealed no significant differences in presurgical factors. The pathological T factor was significantly deeper in the R1R2 group than in the R0 group (p=0.0086). Histopathological response tended to be higher in the R0 group (p=0.055). An accurate preoperative diagnosis of T factor is important.

[Two Cases of Pathological Complete Response with Neoadjuvant Therapy for Advanced Rectal Cancer].

We report the cases of 2 patients with advanced rectal cancer who achieved pathological complete response to treatment with preoperative therapy. Case 1 was a 72-year-old man diagnosed with cT3N1M0 advanced rectal cancer. Neoadjuvant chemoradiotherapy with S-1 (120 mg/day) and radiation (50 Gy/25 Fr) was administered. Eight weeks after the last chemoradiation therapy, we performed laparoscopic Hartmann's operation. Case 2 was a 59-year-old man diagnosed with cT4aN0M0 advanced rectal cancer. He was treated with XELOX plus bevacizumab as neoadjuvant chemotherapy. Four weeks after 4 courses of treatment, he underwent laparoscopic Mile's operation. Neoadjuvant therapy was performed without any complications, and a pathological complete response was achieved in both patients. These cases demonstrated that neoadjuvant therapy can be a promising option for locally advanced rectal cancer.

[Tolerability of XELOX in postoperative adjuvant chemotherapy for colorectal cancer].

A regimen of capecitabine plus oxaliplatin(XELOX)has become one of the standard postoperative adjuvant chemotherapies for colon cancer. However, few tolerability studies have been conducted in Japan. In this study, we retrospectively examined treatment continuation and the adverse events that occurred during 8 courses of postoperative adjuvant chemotherapy with XELOX in 21 patients with colorectal cancer who had undergone curative resection. The completion rate for 8 courses of treatment with XELOX was 71.4%, while the median relative dose intensities of capecitabine and oxaliplatin were 85.0% and 75.0%, respectively. Although the incidence of subsequent Grade 3 or higher hand-foot syndrome was 14.3%, the rate of peripheral neuropathy was 0%. Our hospital had a high rate of XELOX treatment continuation, suggesting that XELOX adjuvant chemotherapy would be well tolerated in clinical practice as well.

[Chemotherapy for gastric cancer patients over 75 years of age].

PURPOSE: The efficacy of chemotherapy for advanced or recurrent gastric cancer in patients who were aged over 75 years was investigated. MATERIALS AND METHODS: Progression free survival (PFS) and overall survival (OS) of advanced gastric cancer patients who received first-line chemotherapy with TS-1 plus cisplatin or TS-1 in our hospital from 2009 to 2013 were determined. The patients were divided into two groups: H and L. H group patients were aged over 75 years, and L group patients were aged less than 75 years. RESULTS: Median PFS and median OS of patients in the H and L groups who received TS-1 plus cisplatin chemotherapy were not significantly different. PFS was 77[range, 13-211] days and 139[range, 53-211]days for the H and L groups, respectively(p=0.141), while OS was 523[range, 22-1,030] days and 402 [range, 322-623] days, respectively (p=0.620). Similarly, median PFS and median OS of patients who received TS-1 chemotherapy were not significantly different between the H and L groups. PFS was 103[range, 51-156]days and 152.5[range, 85-278]days for the H and L groups, respectively (p=0.230), while OS was 414 [range, 224-714]days and 605[range, 452-1,077] days, respectively ( p=0.1337). CONCLUSION: PFS and OS were not significantly different in younger patients with advanced gastric cancer who received TS-1 plus cisplatin or TS-1 chemotherapy compared to that in similarly treated elderly patients with advanced gastric cancer.