Prognosis of repeat hepatectomy for liver transplantable hepatocellular carcinoma recurrence after hepatectomy: a Retrospective Cohort Study with the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO).

PURPOSE: Factors affecting the prognosis of repeat hepatectomy for transplantable hepatocellular carcinoma (HCC) recurrence after hepatectomy remain unclear. We aimed to clarify the prognostic factors for transplantable hepatocellular carcinoma recurrence after hepatectomy. METHODS: We included 1758 primary and 486 repeat hepatectomies out of 2244 for HCC performed between 2006 and 2017 using the Hiroshima Study Group for Clinical Oncology and Surgery database. We first compared survival rates of primary and repeat hepatectomy patients. Subsequently, prognostic factors were analyzed in patients who underwent a repeat hepatectomy for transplantable hepatocellular carcinoma recurrence after hepatectomy (defined as age < 70 years at the time of recurrence and recurrent tumor morphology that meets the Milan criteria). RESULTS: The 5-year overall survival rate (OS) after repeat hepatectomy was 63.2%, while the 5-year recurrence-free survival rate (RFS) was 23.7%. RFS demonstrated significant inferiority in the repeat hepatectomy group than in the primary hepatectomy group; however, OS did not present a notable difference between the two cohorts. In the transplantable recurrence group, mALBI grade 2b, max tumor size > 20 mm, and multiple tumors were independent prognostic risk factors for overall survival. Patients with two or more risk factors had a significantly lower survival rate (only 30.6% at 5 years) compared to those with one or fewer risk factors (81.8% at 5 years). CONCLUSIONS: We identified the risk factors involved in post-hepatectomy survival for patients with transplantable recurrence after hepatectomy. The results are a potential indicator of whether salvage liver transplantation should be considered during repeat hepatectomy.

Genetics of mouse behavioral and peripheral neural responses to sucrose.

Mice of the C57BL/6ByJ (B6) strain have higher consumption of sucrose, and stronger peripheral neural responses to it, than do mice of the 129P3/J (129) strain. To identify quantitative trait loci (QTLs) responsible for this strain difference and to evaluate the contribution of peripheral taste responsiveness to individual differences in sucrose intake, we produced an intercross (F2) of 627 mice, measured their sucrose consumption in two-bottle choice tests, recorded the electrophysiological activity of the chorda tympani nerve elicited by sucrose in a subset of F2 mice, and genotyped the mice with DNA markers distributed in every mouse chromosome. We confirmed a sucrose consumption QTL (Scon2, or Sac) on mouse chromosome (Chr) 4, harboring the Tas1r3 gene, which encodes the sweet taste receptor subunit TAS1R3 and affects both behavioral and neural responses to sucrose. For sucrose consumption, we also detected five new main-effect QTLs, Scon6 (Chr2), Scon7 (Chr5), Scon8 (Chr8), Scon3 (Chr9), and Scon9 (Chr15), and an epistatically interacting QTL pair Scon4 (Chr1) and Scon3 (Chr9). No additional QTLs for the taste nerve responses to sucrose were detected besides Scon2 (Tas1r3) on Chr4. Identification of the causal genes and variants for these sucrose consumption QTLs may point to novel mechanisms beyond peripheral taste sensitivity that could be harnessed to control obesity and diabetes.

Genetic controls of Tas1r3-independent sucrose consumption in mice.

We have previously used crosses between C57BL/6ByJ (B6) and 129P3/J (129) inbred strains to map a quantitative trait locus (QTL) on mouse chromosome (Chr) 4 that affects behavioral and neural responses to sucrose. We have named it the sucrose consumption QTL 2 (Scon2), and shown that it corresponds to the Tas1r3 gene, which encodes a sweet taste receptor subunit TAS1R3. To discover other sucrose consumption QTLs, we have intercrossed B6 inbred and 129.B6-Tas1r3 congenic mice to produce F2 hybrids, in which Scon2 (Tas1r3) does not segregate, and hence does not contribute to phenotypical variation. Chromosome mapping using this F2 intercross identified two main-effect QTLs, Scon3 (Chr9) and Scon10 (Chr14), and an epistatically interacting QTL pair Scon3 (Chr9)-Scon4 (Chr1). Using serial backcrosses, congenic and consomic strains, we conducted high-resolution mapping of Scon3 and Scon4 and analyzed their epistatic interactions. We used mice with different Scon3 or Scon4 genotypes to understand whether these two QTLs influence sucrose intake via gustatory or postoral mechanisms. These studies found no evidence for involvement of the taste mechanisms, but suggested involvement of energy metabolism. Mice with the B6 Scon4 genotype drank less sucrose in two-bottle tests, and also had a higher respiratory exchange ratio and lower energy expenditure under basal conditions (when they had only chow and water available). Our results provide evidence that Scon3 and Scon4 influence mouse-to-mouse variation in sucrose intake and that both likely act through a common postoral mechanism.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS).

PURPOSE: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. METHODS: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. RESULTS: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. CONCLUSIONS: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Observational and Accelerometer Analysis of Head Movement Patterns in Psychotherapeutic Dialogue.

Psychotherapists, who use their communicative skills to assist people, review their dialogue practices and improve their skills from their experiences. However, technology has not been fully exploited for this purpose. In this study, we analyze the use of head movements during actual psychotherapeutic dialogues between two participants-therapist and client-using video recordings and head-mounted accelerometers. Accelerometers have been utilized in the mental health domain but not for analyzing mental health related communications. We examined the relationship between the state of the interaction and temporally varying head nod and movement patterns in psychological counseling sessions. Head nods were manually annotated and the head movements were measured using accelerometers. Head nod counts were analyzed based on annotations taken from video data. We conducted cross-correlation analysis of the head movements of the two participants using the accelerometer data. The results of two case studies suggest that upward and downward head nod count patterns may reflect stage transitions in counseling dialogues and that peaks of head movement synchrony may be related to emphasis in the interaction.

Our experience of repeat laparoscopic liver resection in patients with recurrent hepatocellular carcinoma.

BACKGROUND: Repeat liver resection is an effective treatment approach for patients with recurrent hepatocellular cell carcinoma (HCC). However, the surgical feasibility and oncological significance of repeat laparoscopic liver resection (r-LLR) remain unproven. This study evaluates and compares the clinical outcomes of non-anatomic r-LLR applied towards recurrent HCC, with those of primary LLR (p-LLR) for primary HCC. METHODS: This retrospective study reports 104 patients with HCC, treated with LLR between 2014 and 2018. Twenty eight of these patients underwent r-LLR for recurrent HCC. The clinical and surgical variables were reviewed for all cases. RESULTS: The analysis was limited to non-anatomic resection across both groups (r-LLR: 89% (25/28) vs. p-LLR: 80% (61/76)). There were no statistically significant differences about patient background between the two groups, with the exception of Child-Pugh classification. r-LLR surgical techniques included single-site laparoscopic adhesiolysis (32%, 8/25), Pringle maneuver (8%, 2/25), and crush-clamp method using BiClamp for hepatic parenchymal transection (72%, 18/25). No severe postoperative complications were observed in the r-LLR group. Postoperative hospital stays and procedure-related postoperative survival were similar for both groups. CONCLUSIONS: Non-anatomical r-LLR renders comparable surgical and oncological outcomes. Our data suggest that non-anatomical r-LLR is a safe and feasible therapeutic approach to recurrent HCC.

[A Resectable Case of TS-1 Therapy Useful in Distinguishing Primary Lung Cancer from Lung Metastases of Pancreatic Cancer].

We report a case of pneumonectomy followed by radical pancreatectomy after oral administration of TS-1 for pancreatic cancer with complications ofa lung tumor. The patient was a 66-year-old woman. A pancreatic tail tumor and 2 lung nodules were detected on CT scans, and were diagnosed as pancreatic cancer and metastatic lung cancer. During a total of1 1 courses ofTS -1 therapy, the pancreatic tumor tended to contract, but both pulmonary nodules remained unchanged. Due to differences in treatment effect, double cancers of the lung and pancreas were suspected, rather than metastatic lung cancers. We performed a VATS partial resection of the left lower lobe for diagnostic therapy. The pathological diagnosis revealed an inflammatory myofibroblastic tumor and a primary lung cancer. We diagnosed that a radical pancreatectomy was possible and performed distal pancreatectomy. Pathological diagnosis confirmed an invasive pancreatic ductal carcinoma. Oral administration ofTS -1 was performed as adjuvant chemotherapy after surgery. Liver metastasis was observed 10 months after pancreatectomy, and GEM therapy was initiated. Peritoneal dissemination was observed at 2 years following pancreatectomy, and the patient died at 2 years and 9 months. TS-1 therapy for synchronous lung tumors and pancreatic cancer with careful observation allowed for a definitive radical resection. This method was an effective treatment for lung nodules with pancreatic cancer.

Downregulation of neuropilin-1 on macrophages modulates antibody-mediated tumoricidal activity.

Neuropilin-1 (NRP-1)-expressing macrophages are engaged in antitumor immune functions via various mechanisms. In this study, we investigated the role of NRP-1 on macrophages in antibody-mediated tumoricidal activity. Treatment of macrophages with NRP-1 knockdown or an anti-NRP-1-neutralizing antibody significantly suppressed antibody-dependent cellular cytotoxicity and modulated cytokine secretion from macrophages in vitro. Furthermore, in vivo studies using a humanized mouse model bearing human epidermal growth factor receptor-2 (HER2)-positive breast cancer xenografts showed that antibody-mediated antitumor activity and tumor infiltration of CD4+ T lymphocytes were significantly downregulated when peripheral blood mononuclear cells in which NRP-1 was knocked down were co-administered with an anti-HER2 antibody. These results revealed that NRP-1 expressed on macrophages plays an important role in antibody-mediated antitumor immunity. Taken together, the induction of NRP-1 on macrophages may be a therapeutic indicator for antibody treatments that exert antibody-dependent cellular cytotoxicity activity, although further studies are needed in order to support this hypothesis.

Analysis of the microvascular morphology and hemodynamics of breast cancer in mice using SPring-8 synchrotron radiation microangiography.

Tumor vasculature is characterized by morphological and functional abnormalities. However, analysis of the dynamics in blood flow is still challenging because of limited spatial and temporal resolution. Synchrotron radiation (SR) microangiography above the K-edge of the iodine contrast agent can provide high-contrast imaging of microvessels in time orders of milliseconds. In this study, mice bearing the human breast cancer cell lines MDAMB231 and NOTCH4 overexpression in MDAMB231 (MDAMB231NOTCH4+) and normal mice were assessed using SR microangiography. NOTCH is transmembrane protein that has crucial roles for vasculogenesis, angiogenesis and tumorigenesis, and NOTCH4 is considered to be a cause of high-flow arteriovenous shunting. A subgroup of mice received intravenous eribulin treatment, which is known to improve intratumor core circulation (MDAMB231_eribulin). Microvessel branches from approximately 200 µm to less than 20 µm in diameter were observed within the same visual field. The mean transition time (MTT) was measured as a dynamic parameter and quantitative analysis was performed. MTT in MDAMB231 was longer than that in normal tissue, and MDAMB231NOTCH4+ showed shorter MTT [5.0 ± 1.4 s, 3.6 ± 1.0 s and 3.6 ± 1.1 s (mean ± standard deviation), respectively]. After treatment, average MTT was correlated to tumor volume (r = 0.999) in MDAMB231_eribulin, while in contrast there was no correlation in MDAMB231 (r = -0.026). These changes in MTT profile are considered to be driven by the modulation of intratumoral circulation dynamics. These results demonstrate that a SR microangiography approach enables quantitative analysis of morphological and dynamic characteristics of tumor vasculature in vivo. Further studies will reveal new findings concerning vessel function in tumors.

Regulation of trunk neural crest delamination by δEF1 and Sip1 in the chicken embryo.

The vertebrate Zfhx1 transcription factor family comprises δEF1 and Sip1, which bind to CACCT-containing sequences and act as transcriptional repressors. It has been a longstanding question whether these transcription factors share the same regulatory functions in vivo. It has been shown that neural crest (NC) delamination depends on the Sip1 activity at the cranial level in mouse and chicken embryos, and it remained unclear how NC delamination is regulated at the trunk level. We observed that the expression of δEF1 and Sip1 overlaps in many tissues in chicken embryos, including NC cells at the trunk level. To clarify the above questions, we separately knocked down δEF1 and Sip1 or in combination in NC cells by electroporation of vectors expressing short hairpin RNAs (shRNAs) against respective mRNAs on the dorsal side of neural tubes that generate NC cells. In all cases, the migrating NC cell population was significantly reduced, paralleled by the decreased expression of δEF1 or Sip1 targeted by shRNAs. Expression of Sox10, the major transcription factor that regulates NC development, was also decreased by the shRNAs against δEF1 or Sip1. We conclude that the trunk NC delamination is regulated by both δEF1 and Sip1 in an analogous manner, and that these transcription factors can share equivalent regulatory functions in embryonic tissues.

[A Case of Angiomyolipoma Occurring in the Mesentery of the Transverse Colon and Treated Using Laparoscopic Excision].

A 65-year-old woman had received chemotherapy for malignant lymphoma since 2011. After the 8th course, computed tomography revealed the disappearance of lymph node metastasis, except for 22mm of the mass located on the tail side of the antrum. MRI showed a low intensity mass on the T1 and T2-weighted images. FDG-PET did not show abnormal uptake in the tumor. EUS-FNA did not reveal a definitive diagnosis. We performed a laparotomy for diagnosis and treatment. Intraoperative findings showed that the tumor occurred in the mesentery of the transverse colon. The pathological diagnosis was angiomyolipoma. The patient has been free from recurrent disease for 2 years and 6 months. Angiomyolipoma originating in the transverse mesentery region is rare and, due to various percentage of tissue factors, there are no fixed view of image findings. Furthermore, a large tissue volume is need for histological diagnosis. Laparotomy is useful for diagnosis and therapy for angiomyolipoma occurring in the mesentery of the transverse colon.

[A Case of Ovarian Cancer with Lymph Node Metastasis in the Lesser Curvature of the Stomach Resected Using Laparoscopic Surgery].

A 67-year-old woman, who was diagnosed with ovarian cancer with multiple metastases, underwent abdominal total hysterectomy, bilateral salpingo-oophorectomy, para-aortic lymph node dissection(b2), omental subtotal hysterectomy, and lower anterior rectal resection after receiving a combination of PTX plus CBDCA chemotherapy. Macroscopically, complete resection was achieved and histopathological examination of the resectedspecimen showedpoorly differentiatedserous adenocarcinoma. After surgery, additional chemotherapy was administered. However, increasing only lesser curvature of stomach lymph node, we performed laparoscopic lymph node resection as debulking surgery. It is often said that macroscopic complete resection of ovarian cancer improves the prognosis. In particular, we hope that this patient will survive longer with a sustainable quality of life as a result of laparoscopic stomach- andnerve -sparing surgery.

[A Case of Myxofibrosarcoma of the Retroperitoneum].

Myxofibrosarcoma(MFS)is one of the most common sarcomas in the extremities of elderly patients.We report a rare case of MFS originating in the retroperitoneum.A 65-year-old man presented to our hospital with an intraabdominal tumor, which was identified by abdominal CT during an investigation of an abdominal protuberance.Contrast -enhanced CT and MRI revealed a 18×12 cm mass in the left retroperitoneum.The patient underwent retroperitoneum tumor resection.Operative findings showed that there was an indistinct area between the left side of the tumor and the abdominal wall.There was no residual tumor macroscopically after the operation.The histopathological diagnosis was MFS arising from the retroperitoneum. Four months later, local recurrence and para-aortic lymph node metastasis were diagnosed.We performed tumor resection; however, the recurrent tumor had invaded the iliopsoas and iliac muscles.Additionally, there was peritoneal dissemination around the tumor.Five months after the initial surgery, a recurrence on the back was identified.He died 7 months after the first operation.According to previous reports, patients who undergo an operation with pathologically negative margins achieve better surgical outcomes.Therefore, it is important to perform expanded resection with enough surgical margin as possible.

[A Case of Small Bowel Cancer Treated with Laparoscopic Surgery].

We report a case of small intestinal adenocarcinoma treated with laparoscopic surgery. A 70-year-old woman had abdominal pain and epigastralgia. There were no abnormal findings on upper and lower endoscopy. The symptoms continued for 4 months after endoscopy, so she presented to our hospital. After CT examination, small bowel cancer with ileus was suspected. An ileus tube was inserted to relieve the bowel pressure and she was diagnosed with ileum cancer by enteroscopy. Laparoscopic surgery was performed and the pathological stage was determined as pStage Ⅲa. She was treated with oral chemotherapy (UFT plus LV) and had no recurrence 6 months after surgery.

[Usefulness of Metallic Stent for Left-Sided Obstructive Colon Cancer].

The aim of this study was to compare the efficacy of self-expandable metallic stent (SEMS) and transanal tube as preoperative treatments for left-sided obstructive colon cancer. Forty-three patients (the SEMS group: 28 cases, the tube group: 15 cases) were included in this study. Clinicopathological data (age, sex, tumor location, depth, histological type, stage) were comparable between the 2 groups. In addition, there was no difference in intestinal decompression rate between the SEMS group and the tube group (technical success rate: 100% vs 86.7%, clinical success rate: 92.8% vs 73.3%, complication rate: 7.1% vs 0%). A significantly higher number of patients in the SEMS group underwent laparoscopic surgery because of difference of historical background. However, no significant difference was observed between the 2 groups in postoperative outcome(complication rate, hospital stay duration). SEMS insertion had several benefits compared to transanal tube placement, such as the resumption of oral intake because of rapid resolution of obstruction and easier management because SEMSs do not require washing. SEMS insertion could be a safe and effective bridge to subsequent surgery in patients with left-sided obstructive colon cancer.

[A Case of Radical Resection of Rectal Cancer with Multiple Liver and Lung Metastases after Preoperative Chemotherapy].

We report a case of radical resection of rectal cancer with multiple liver and lung metastases after preoperative chemotherapy. A 54-year-old woman presented with abdominal pain and loss of body weight due to rectal cancer with multiple liver and lung metastases. Therefore, the patient received 14 courses of bevacizumab+mFOLFOX6, and 7 courses of panitumumab+FOLFIRI. After the chemotherapy, the size of the distant metastases reduced by 62% on computed tomography, according to RECIST. Due to the reduction in size, a conversion surgery was attempted. First, an abdominal operation with laparoscopy was performed, and 2 months later an operation to resect the lung metastases via thoracoscopy was performed. Currently, 3 months after surgery, the patient is alive, without recurrence.

Intracellular calcium elevation during plateau potentials mediated by extrasynaptic NMDA receptor activation in rat hippocampal CA1 pyramidal neurons is primarily due to calcium entry through voltage-gated calcium channels.

We reported previously that plateau potentials mediated by extrasynaptic N-methyl-d-aspartate receptors (NMDARs) can be induced either by synaptic stimulation in the presence of glutamate transporter antagonist or by iontophoresis of NMDA in rat hippocampal CA1 pyramidal neurons. To examine whether the plateau potentials are accompanied by an elevation of intracellular Ca2+ and to determine the source of Ca2+ elevation, we performed Ca2+ imaging during the plateau potential. Neurons were loaded with Ca2+ indicator fluo-4, and the plateau potentials were generated either synaptically in the presence of glutamate transporter antagonist or by iontophoretically applying NMDA. We have found that a transient elevation in intracellular Ca2+ accompanies the plateau potential. The synaptically induced plateau potential and the Ca2+ elevation were blocked by 5,7-dichlorokynurenic acid (5,7-dCK), an antagonist for the glycine-binding sites of NMDAR. A mixture of Cd2+ and tetrodotoxin did not block NMDA-induced plateau potentials, but completely abolished the accompanying Ca2+ elevation in both the presence and absence of Mg2+ ions in the bathing solution. The NMDA-induced plateau potential was blocked by further adding 5,7-dCK. Our results show that the NMDAR-mediated plateau potential is accompanied by elevation of intracellular Ca2+ that is primarily caused by the influx of Ca2+ through voltage-gated Ca2+ channels.

[A case of advanced gastric cancer with liver metastasis involving curative surgery after neoadjuvant chemotherapy].

A 77-year-old-woman, whose chief complaint was anemia, was referred to our hospital and diagnosed with advanced gastric cancer with liver metastasis and lymph node metastasis.Gastrointestinal endoscopy showed a tumor on the lesser curvature of the gastric corpus.Histologically, biopsy specimens indicated adenocarcinoma with genetic amplification of human epidermal growth factor receptor type 2.Computed tomography and magnetic resonance imaging showed lymph node metastasis and liver metastasis.The patient received a total gastrectomy and a partial liver resection after combination chemotherapy consisting of capecitabine, cisplatin, and trastuzumab.Histopathological examination of a resected specimen showed a minute residual cancer nest at the subserosa of the stomach and lymph node metastasis, but no liver metastasis. This combined modality therapy can be considered an effective treatment for gastric cancer with liver metastasis, and we hope that it will be established as a standard therapy.