Search

Primary brain calcification (PBC), also known as idiopathic basal ganglia calcification (IBGC), primary familial brain calcification (PFBC) and so on, is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. The causative gene of familial PBC is SLC20A2, which encodes the phosphate transporter PiT-2. Despite this knowledge, the molecular mechanism underlying SLC20A2-associated PBC remains unclear. In the present study, we investigated whether haploinsufficiency or a dominant-negative mechanism reduced Pi uptake in two PiT-2 variants (T115 M and R467X). We demonstrated that the presence of T115 M or R467X had no dominant-negative effect on Pi transport activity of wild-type (WT). In addition, the subcellular localization of R467X completely differed from that of WT, indicating that there is no interaction between R467X and WT. Conversely, T115 M and WT showed almost the same localization. Therefore, we examined the interaction between T115 M and WT using the bioluminescence resonance energy transfer (BRET) method. Although WT and T115 M interact with each other, T115 M does not inhibit WT's Pi transport activity. These results suggest that the role of SLC20A2 in the pathogenesis of PBC may involve decreased intracellular Pi uptake by a haploinsufficiency mechanism rather than a dominant-negative mechanism; agents promoting PiT-2 dimerization may be promising potential therapeutic agents for PBC.

Surgery for T1b gastric cancer requires suprapancreatic nodes (SPA nodes) and perigastric nodes (PG nodes), however, SPA nodal dissection can cause pancreatic complications. If endoscopic treatment followed by additional surgery is planned, it may be possible to predict SPA nodal metastasis by analyzing the pathological information of the primary tumor in addition to the clinical findings.Patients who underwent D1+ or D2 and who were pathologically diagnosed with pT1b were retrospectively analyzed. The stations were divided into the nodes located at the perigastric area (PG nodes; #1-7) and the nodes located at the suprapancreatic area (SPA nodes; #8a-12a). The patients were classified into those with and without metastasis to the SPA nodes. Clinicopathological factors were investigated for their possible association with metastasis to the SPA nodes.A total of 2017 patients were examined in this study. Metastasis to the SPA nodes was observed in 80 patients (4%). In a multivariate analysis, undifferentiated histology, lower third, and lymphovascular invasion were independent risk factors for metastasis to the SPA nodes. The risk of metastasis to the SPA nodes waslt;2% in upper/middle tumors of differentiated type with no lymphovascular invasion and in lower tumors of undifferentiated type with no lymphovascular invasion. On the other hand, the risk of metastasis to the SPA nodes wasgt;10% in lower tumors of undifferentiated type with lymphovascular invasion.SPA nodal metastasis can be predicted when endoscopic treatment is initially planned. SPA nodal dissection should not be uniformly selected for T1b gastric cancer.

Background; Emphysema is a common phenotype of chronic obstructive pulmonary disease (COPD). Although resection of emphysematous tissue can improve lung mechanics, it is invasive and fraught with adverse effects. Meanwhile, radiofrequency (RF) treatment is an extracorporeal method that leads to tissue destruction and remodeling, resulting in “volume reduction” and overall improvement in lung compliance of emphysematous lungs. Whether these changes lead to improved exercise tolerance is unknown. Here, we investigated the effectiveness of RF treatment to improve the exercise capacity of mice with emphysema.Methods;Fifty-two mice (7 weeks of age) were used in this experiment. A bilateral emphysema model was created by intratracheally instilling porcine pancreatic elastase (PPE) (1.5U/100g body weight). RF treatment (0.5W/ g body weight) was performed extracorporeally 14 days later and mice were sacrificed after another 21 days. The exercise capacity of mice was measured using a treadmill. Treadmill runs were performed just before PPE instillation (baseline), before RF treatment and before sacrifice. Following sacrifice, lung compliance and mean linear intercept (Lm) were measured and fibrosis was assessed using a modified Ashcroft score.Results; There were 3 experimental groups: controls (instilled with saline, n=12), emphysema (instilled with porcine pancreatic elastase, PPE, n=11) and emphysema + treatment (instilled with PPE and given RF, n=9). At endpoint, the maximum velocity of the emphysema + treatment group was significantly higher than that of the emphysema group, indicating improved exercise tolerance (86.29% of baseline vs 61.69% of baseline, p=0.011). Histological analysis revealed a significant reduction in emphysema as denoted by Lm between the two groups (median 29.60 µm vs 35.68 µm, p=0.033). The emphysema + treatment group also demonstrated a higher prevalence of lung fibrosis (≧Grade 3) compared with the emphysema group (11.7% vs 5.4%, p

Mai Tsutsui,1 Firoozeh Gerayeli,1 Don D Sin1,2 1Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada; 2Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, CanadaCorrespondence: Don D SinCentre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, CanadaTel +1 604 806 8818Fax +1 604 806 9274Email don.sin@hli.ubc.caAbstract: Pulmonary rehabilitation (PR) is effective in reducing symptoms and improving health status, and exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). The coronavirus disease 19 (COVID-19) pandemic has greatly impacted PR programs and their delivery to patients. Owing to fears of viral transmission and resultant outbreaks of COVID-19, institution-based PR programs have been forced to significantly reduce enrolment or in some cases completely shut down during the pandemic. As a majority of COPD patients are elderly and have multiple co-morbidities including cardiovascular disease and diabetes, they are notably susceptible to severe complications of COVID-19. As such, patients have been advised to stay at home and avoid social contact to the maximum extent possible. This has increased patients’ vulnerability to physical deconditioning, depression, and social isolation. To address this major gap in care, some traditional hospital or clinic-centered PR programs have converted some or all of their learning contents to home-based telerehabilitation during the pandemic. There are, however, some significant barriers to this approach that have impeded its implementation in the community. These include variable access and use of technology (by patients), a lack of standardization of methods and tools for evaluation of the program, and inadequate training and resources for health professionals in optimally delivering telerehabilitation to patients. There is a pressing need for high-quality studies on these modalities of PR to enable the successful implementation of PR at home and via teleconferencing technologies. Here, we highlight the importance of telerehabilitation of patients with COPD in the post-COVID world and discuss various strategies for clinical implementation.Keywords: pulmonary rehabilitation, COVID-19, telerehabilitation, COPD

Introduction Although partial cystectomy has been performed by laparoscopy in patients with benign disease, there have only been a few reports regarding the laparoscopic partial resection of urinary bladder–adherent colorectal cancer. This study was conducted to evaluate the short-term surgical outcomes of laparoscopic partial resection of urinary bladder–adherent colorectal cancer. Case presentation Between April 2014 and February 2017, 6 patients with colorectal cancers that were adherent to the urinary bladder underwent laparoscopic colorectal cancer resection combined with partial cystectomy. Their surgical outcomes were reviewed retrospectively. The primary colorectal cancer was located in the sigmoid colon in 5 patients and the upper rectum in 1 patient. None of the patients required conversion to open surgery. The median duration of surgery was 411 minutes, and the median amount of intraoperative blood loss was 284 mL. In the patients with sigmoid colon cancer, the bladder was primarily closed under direct visualization via the small lower abdominal incision used to remove the tumor. In the patient with upper rectal cancer, the bladder was primarily closed laparoscopically. None of the patients demonstrated urinary leakage on retrograde cystography or anastomotic leakage, and there were no cases of perioperative mortality or morbidity. None of the patients developed recurrence of cancer at the median follow-up of 21 months. Conclusion Laparoscopic partial resection of urinary bladder–adherent colorectal cancer produces good short-term outcomes without increasing morbidity. Performing bladder closure under direct visualization via a small lower abdominal incision might be useful in selected patients.

Fluoropyrimidine has been commonly used not only in unresectable cases of metastatic colorectal cancer, but also in adjuvant therapy. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down more than 80% of standard doses of 5-fluorouracil (5-FU) and capecitabine, an oral prodrug of 5-FU. The lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity which may lead to life-threatening side effects. There have been several published case reports about DPD deficiency in patients with colorectal cancer in Western countries. However, case reports of DPD deficiency in Japanese patients with colorectal cancer are rare because measuring DPD activity is not covered by public medical insurance in Japan, and it is not examined in our daily clinical practice currently. Therefore, we think that it is important to accumulate such case reports for further understanding. This report describes the case of a Japanese patient with colon cancer who experienced severe side effects while taking capecitabine, due to DPD deficiency. A 68-year-old man with ascending colon cancer underwent curative laparoscopic right hemicolectomy. Because final pathologic staging was Stage IIIa, standard adjuvant chemotherapy with capecitabine (3600 mg/body/day, days 1–14, every 3 weeks) was started on postoperative day 50. After 2 weeks, he started to experience Grade 3 diarrhea and was admitted to the hospital on postoperative day 66. On day 70, the patient had Grade 4 febrile neutropenia. Antibiotics and granulocyte-colony-stimulating factor were administered until his blood tests recovered to the normal degree. After 1 week of diarrhea, antidiarrheal agents were administered, and the patient gradually recovered. During the occurrence of diarrhea, specimen cultures were negative for infection. He was discharged on day 21 of the hospital stay. DPD deficiency was suspected, and 2 weeks later the DPD activity of the peripheral blood mononucleocytes was examined. The result was 10.3 U/mg protein which was remarkedly low (reference range 22.6–183.6 U/mg protein), and DPD deficiency was diagnosed. We always must consider the possibility of DPD deficiency in patients who experience severe side effects while taking capecitabine.

Comprehensive gene screening with transposons is a novel procedure for the systematic identification of resistant genes. The present study aimed to use this technique to identify candidate radioresistant genes in esophageal squamous cell carcinoma. A transposon is a base sequence that can translocate to another location in the genome at random. By inserting the cytomegalovirus promotor as a transcriptional activator in the transposon, the following gene in the new location becomes overexpressed and the gene located at the transposon insertion site is downregulated. Consequently, various transposon-tagged cells, which have differentially overexpressed or downregulated genes using the transposon method can be obtained. Following the irradiation of transposon-tagged cells, candidate radioresistant genes can be selected in order to detect the location of the transposon in the cells that have survived. A total of 11 genes were detected as candidate radioresistant genes. Cytochrome c oxidase 1 (MT-CO1), an enzyme involved in apoptosis through the activation of the caspase cascade, was one of the candidate genes identified. The relative expression level of MT-CO1 was 0.12 in MT-CO1-downregulated cells which was significantly lower compared with the expression level in parent TE4 cells (P

Fluoropyrimidine has been commonly used not only in unresectable cases of metastatic colorectal cancer, but also in adjuvant therapy. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down more than 80% of standard doses of 5-fluorouracil (5-FU) and capecitabine, an oral prodrug of 5-FU. The lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity which may lead to life-threatening side effects. There have been several published case reports about DPD deficiency in patients with colorectal cancer in Western countries. However, case reports of DPD deficiency in Japanese patients with colorectal cancer are rare because measuring DPD activity is not covered by public medical insurance in Japan, and it is not examined in our daily clinical practice currently. Therefore, we think that it is important to accumulate such case reports for further understanding. This report describes the case of a Japanese patient with colon cancer who experienced severe side effects while taking capecitabine, due to DPD deficiency. A 68-year-old man with ascending colon cancer underwent curative laparoscopic right hemicolectomy. Because final pathologic staging was Stage IIIa, standard adjuvant chemotherapy with capecitabine (3600 mg/body/day, days 1–14, every 3 weeks) was started on postoperative day 50. After 2 weeks, he started to experience Grade 3 diarrhea and was admitted to the hospital on postoperative day 66. On day 70, the patient had Grade 4 febrile neutropenia. Antibiotics and granulocyte-colony-stimulating factor were administered until his blood tests recovered to the normal degree. After 1 week of diarrhea, antidiarrheal agents were administered, and the patient gradually recovered. During the occurrence of diarrhea, specimen cultures were negative for infection. He was discharged on day 21 of the hospital stay. DPD deficiency was suspected, and 2 weeks later the DPD activity of the peripheral blood mononucleocytes was examined. The result was 10.3 U/mg protein which was remarkedly low (reference range 22.6–183.6 U/mg protein), and DPD deficiency was diagnosed. We always must consider the possibility of DPD deficiency in patients who experience severe side effects while taking capecitabine.

COPD is characterised by the destruction of lung tissue resulting in alveolar tissue destruction, enlargement of alveolar spaces, poor gas exchange and airway collapse due to the loss of elastic recoil [1]. Lung volume reduction surgery (LVRS) is effective in reducing long term morbidity and mortality of patients with severe emphysema who have a predominance of upper lobe disease and are able to tolerate the surgical procedure [2, 3]. However, the financial cost and the peri-operative morbidity and mortality of the procedure have limited its application in clinical practice [4, 5]. Here, we investigated the possibility of using external radiofrequency (RF) as a novel extracorporeal treatment for emphysema in a rat model of unilateral emphysema. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Wada reports grants from IKOMED, grants from MITACS, during the conduct of the study. Conflict of interest: Dr. Jaw reports grants from Mitacs (joint application with iKomed), during the conduct of the study. Conflict of interest: Dr. Tsuruta reports grants from IKOMED, grants from MITACS, during the conduct of the study. Conflict of interest: Dr. Moritani reports grants from IKOMED, grants from MITACS, during the conduct of the study. Conflict of interest: Dr. Tsutsui reports grants from IKOMED, grants from MITACS, during the conduct of the study. Conflict of interest: Dr. Tam has nothing to disclose. Conflict of interest: Dr. Vasilescu has nothing to disclose. Conflict of interest: Dr. CHEUNG reports grants from Ikomed, grants from Mitac, during the conduct of the study. Conflict of interest: Dr. Yamasaki reports grants from IKOMED, grants from MITACS, during the conduct of the study. Conflict of interest: Dr. Lichtenstein reports In addition, Dr. Lichtenstein has a patent Method for selectively heating tissue issued to Ikomed Technologies Inc and Founder and Investor in Ikomed Technologies Inc.. Conflict of interest: Dr. Machan reports he is an Investor in Ikomed Technologies. Conflict of interest: Dr. Gelbart reports In addition, Dr. Gelbart has a patent 8444635 licensed to Ikomed. Conflict of interest: Dr. Man has nothing to disclose. Conflict of interest: Dr. Sin reports grants from IKOMED, during the conduct of the study; grants from Merck, personal fees from Sanofi-Aventis, personal fees from Regeneron, grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Novartis, outside the submitted work.

Introduction The optimal surgical management strategy for isolated para-aortic lymph node (PALN) metastases from colorectal cancer (CRC) remains unclear. However, the complication rates for open approaches remain high. In this study, the outcomes of laparoscopic para-aortic lymphadenectomy in patients with clinically suspected PALN metastasis were evaluated. Methods Between April 2013 and April 2018, we performed laparoscopic primary resection and para-aortic lymphadenectomy in 11 patients with advanced colorectal cancer and clinically suspected PALN metastasis. This study was a single-center, retrospective, case series analysis, and the surgical outcomes were reviewed. Results There were no cases of perioperative mortality, and conversion to open surgery was necessary in only one patient (9%) because of invasion into a rib. One patient (9%) required a blood transfusion. Postoperative complications occurred in three patients, and the morbidity rate was 27% (3/11). Pathologically, PALN metastasis was confirmed in five patients (45%), all of whom received postoperative chemotherapy. The median survival time for all patients was 25 months, and one patient died of recurrence at 25 months after the initial surgery. Two other patients were alive with recurrence after 47 and 36 months, and two patients were alive without recurrence after 17 and 2 months. Conclusion Laparoscopic para-aortic lymphadenectomy for advanced colorectal cancer with clinically suspected PALN is technically feasible and may be beneficial in selected patients. It is necessary to investigate the feasibility of this procedure in a future case series, and information regarding true oncologic outcome will require long-term follow-up.

Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified.

Aim Many studies have evaluated the risk factors for anastomotic leakage after laparoscopic anterior resection. In this study in order to increase the tightness of anastomoses and prevent bleeding from their staple lines, a linear stapler with pre-attached bioabsorbable polyglycolic acid (PGA) felt was used for rectal transection, and the short-term surgical outcomes were evaluated. Patients and methods A prospective registry of 62 patients with rectosigmoidal or rectal carcinoma who initially underwent laparoscopic anterior resection using PGA felt for rectal transection was reviewed. Results The overall frequency of anastomotic leakage was 1.6% (1/62), and none of the patients developed postoperative staple line bleeding or other adverse events related to the use of PGA felt. Conclusion The frequency of anastomotic leakage was relatively low, and therefore the use of a linear stapler with pre-attached bioabsorbable PGA felt might reduce the risk of adverse events related to anastomosis, especially anastomotic leakage.

It is a great honor to comment on the article entitled “Prognostic impact of hypochloremia in patients with stage I to III colorectal cancer after radical resection” by Qingguo Li and his colleagues in the Diseases of Colon and Rectum (1).

Comprehensive gene screening with transposons is a novel procedure for the systematic identification of resistant genes. The present study aimed to use this technique to identify candidate radioresistant genes in esophageal squamous cell carcinoma. A transposon is a base sequence that can translocate to another location in the genome at random. By inserting the cytomegalovirus promotor as a transcriptional activator in the transposon, the following gene in the new location becomes overexpressed and the gene located at the transposon insertion site is downregulated. Consequently, various transposon-tagged cells, which have differentially overexpressed or downregulated genes using the transposon method can be obtained. Following the irradiation of transposon-tagged cells, candidate radioresistant genes can be selected in order to detect the location of the transposon in the cells that have survived. A total of 11 genes were detected as candidate radioresistant genes. Cytochrome c oxidase 1 (MT-CO1), an enzyme involved in apoptosis through the activation of the caspase cascade, was one of the candidate genes identified. The relative expression level of MT-CO1 was 0.12 in MT-CO1-downregulated cells which was significantly lower compared with the expression level in parent TE4 cells (P

A 63-year-old man who underwent insertion of a lumboperitoneal shunt developed gait disturbance. He had undergone surgery for gastric cancer 7 years and for ileus 5 years previously. Head computed tomography (CT) revealed enlargement of the ventricles. Abdominal CT revealed a cyst in the abdominal region and the distal segment of the peritoneal shunt tube located within the cyst. Laparotomy revealed the cyst located between the small intestine, colon, and peritoneum. The anterior wall of the cyst was excised. The distal segment of the peritoneal shunt tube was replaced in the rectovesical pouch. Histological examination showed that the cyst wall consisted of inner fibrous tissue and outer fat tissue without epithelial lining, and invasion of lymphocytes. The diagnosis was pseudocyst. Only 29 cases of abdominal cerebrospinal fluid (CSF) pseudocysts have been reported in adults. Although the mechanism underlying the formation of abdominal pseudocyst remains to be clarified, several predisposing factors for cyst formation have been reported including changes in absorption of CSF due to inflammation or infection, peritoneal adhesions due to previous abdominal surgery, and increase in the protein content of the CSF. In our case, the medical history and histological features of the cyst wall indicated that formation of the abdominal pseudocyst was associated with previous surgery or inflammatory reaction.

A 29-year-old man with a type 4 tumor, in the lower third of the stomach, and carcinomatous ascites was diagnosed by aspiration cytology of the ascitic fluid. Curative resection was considered impossible, and S1 (120 mg/d) and cisplatin (90 mg/d) were given for 21 days in 1 course. The cancer lesion showed marked remission (partial response), and the ascites completely disappeared after the fourth course. Twenty-five days after completion of the S1 treatment, laparoscopy-assisted total gastrectomy was performed. Histopathological examination showed no remnant cancer cells in the resected specimen and no lymph node metastases. The tumor was replaced with fibrosis having a granulomatous change. The patient's postoperative course was uneventful. The patient was continued with S1 monotherapy after surgery, and no signs of recurrence or metastases have been seen on any examination 12 months after the surgery.

症例は49歳，男性．門脈浸潤を伴う膵頭部癌に対し，亜全胃温存十二指腸切除術+門脈合併切除を施行した．術後2日目より飲水，経腸栄養，6日目に食事開始したが，10日目より膵背側の留置ドレーンから3,500ml/day以上の乳糜腹水を認めるようになった．無～低脂肪の食事，絶食で経過観察するも明らかな腹水の減少は認められなかった．術後30日目より酢酸オクトレオチド300μg/day皮下注を開始したところ，翌日より排液量が著明に減少し，40日目に排液が0mlとなった．40日目に投与を中止し，41日目より食事を再開，42日目にドレーン抜去後，45日目に退院となった．術後乳糜腹水の発生には乳糜槽付近のリンパ節郭清や血管の合併切除，再建が深く関連していると言われる．全身状態の悪化を防ぐためにも，難治性術後乳糜腹水に酢酸オクトレオチド投与は効果的であると考えられる．

Background: Esophageal cancer has a poor prognosis due to early metastasis and direct invasion. Multimodal therapies including surgery, chemotherapy, and radiotherapy are necessary for advanced esophageal cancer. Although chemo or radiosensitivity is closely related to prognosis, it is currently impossible to predict the therapeutic effect of therapies. Patients with resistance to chemo or radiotherapy cannot derive benefit from the therapy but suffer side effects. Therefore, detecting resistant genes and mechanisms is essential for tailoring treatment to improve the prognosis. Drug and radiation resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes and radio-resistant genes. Methods: A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku Esophagus (TE)] with cisplatin (CDDP) or radiation. We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and Next-Generation sequencing was used to identify the over-expressed/down-regulated sequences as candidate genes for CDDP resistance or radiation resistance, Results: We established 4 cell lines of transposon-tagged cells, TE 4, 5, 9, and 15. We treated the 2 relatively viable cell lines, TE4 and TE15, with CDDP or irradiation. We identified 37 candidate genes from 8 resistant colonies for CDDP. Eight genes were over-expressed whilst 29 were down-regulated. Eleven genes were detected as candidate radioresistant genes. Conclusions: The new gene screening technique was useful for detecting candidate of drug-resistant genes and radio-resistant genes in esophageal squamous cell carcinoma. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. Eleven genes were detected as candidate radioresistant genes in the two cell lines derived from ESCC cells.The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes and radio-resistant genes to be identified. Citation Format: Hirofumi Kawakubo, Kazumasa Fukuda, Yu Kigasawa, Tomoko Takesue, Mai Tsutsui, Tsunehiro Takahashi, Rieko Nakamura, Norihito Wada, Hiroya Takeuchi, Yuko Kitagawa. The novel and comprehensive screening of genes resistant to an anticancer drug and radiation in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2117.

Background: Early diagnosis and early treatment are the best ways to improve cancer patient prognoses and keep quality of life of the patients after treatment. We developed ELPS (endoscopic laryngo-pharyngeal surgery) as an endoscopic treatment for superficial pharyngeal carcinoma. ELPS was performed on 278 patients of superficial carcinoma of the pharynx. However 18 lesions have lymphatic invasion, and lymphatic metastasis have occurred in 10 patients after ELPS. HOXB9, a member of the HOX genes, has been reported to be overexpressed in some neoplastic tissues. The class I HOXB gene family consists of 39 members with a shared and highly conserved 61-amino acid homeodomain motif. These genes are significant regulators of development, and their roles in neoplastic transformation and tumor progression have been recognized. Some studies have suggested that HOXB9 expression promotes cellular invasiveness, metastatic ability, and tumor vascularization in the surrounding tissue by inducing EMT. These findings imply that HoxB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to lymphatic invasion of superficial carcinoma. The objective of this study is to analyze whether HOXB9 expression associates with lymphatic invasion and causes in lymph node metastasis of superficial pharyngeal carcinoma. METHODS: A total of 36 superficial pharyngeal carcinoma patients who underwent endoscopic surgery were examined. Immunohistochemical staining was performed to evaluate the expression of HoxB9, and the association of lymphatic invasion and lymph node metastasis with HoxB9 expression was analyzed. RESULTS: Of the 36 superficial pharyngeal carcinoma specimens, depth of tumor invasion is epithelial layer (EP) in 19 tumors and submucosal layer (SEP) in 17 tumors. Thirteen of 19 (68.4%) EP tumors showed HoxB9 expression, and 10 of 17 (58.8%) SEP tumor showed HOXB9 expression. There is no significant correlation of HOXB9 expression and depth of tumor invasion. Six of the 36 tumors have lymphatic invasion. All tumors having lymphatic invasion showed positive HoxB9 expression, whereas 17 of 30 having no lymphatic invasion showed HoxB9 expression. HoxB9 positive tumors tend to have lymphatic invasion (p=0.07). Five of the 36 patients have lymphatic metastasis. Four of 5 patients (80%) who have lymph node metastasis showed positive HoxB9 expression, whereas 19 of 31 (61.3%) who have no lymph node metastasis showed HoxB9 expression. HOXB9 positive tumors tend to have lymphatic invasion. Conclusions: Our results suggest that HOXB9 can play a significant role in lymphatic invasion of superficial pharyngeal carcinoma and can be a novel molecular maker for the lymphatic metastasis. Citation Format: Hirofumi Kawakubo, Mai Tsutsui, Rieko Nakamura, Tsunehiro Takahashi, Norihito Wada, Yoshiro Saikawa, Tai Omori, Hiroya Takeuchi, Yuko Kitagawa. HOXB9 expression associate with lymphatic invasion in superficial pharyngeal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 50. doi:10.1158/1538-7445.AM2014-50

121 Background: Although the prognosis of early gastric cancer is favorable, the treatment for advanced cases still have difficulty in achieving satisfactory results. Thus, more effective multimodality treatment should be established. Chemoradiotherapy has become a standard treatment for gastric cancer especially as an adjuvant therapy while radiotherapy has been expected as one of the modalities against highly advanced gastric cancer. Methods: Patients with advanced gastric cancer who were treated with chemotherapy of S-1 and cisplatin plus radiation were analyzed retrospectively. Concurrent radiation therapy (5 days/week) at 2 Gy/day was started with chemotherapy and repeated daily on days 1–5, 8–12, 15–19 and 22–26. Irradiation was planned using a computed tomography (CT) simulator for two rectangular portals with a pair of 45-degree wedge filters and was targeted at the primary tumor and surrounding lesions, including lymph nodes. Results: A total 109 patients were treated with chemoradiotherapy between 2002 and 2013 at our institute. The median age was 64 years. Histological type included 45 differentiated and undifferentiated 64 subtypes. The TNM stage before the treatment was diagnosed as IIIA: 11; IIIB: 10; IIIC: 14; IV: 74. Of the 98 evaluable patients, 69 patients had partial responses while no patients had a complete response, resulting in an overall response rate of 70%. Progressive disease (PD) occurred in 2 patients (4%). The most frequent adverse events more than grade 3 were hematologic toxicities, including leukocytopenia (47%), neutropenia (25%), and thrombocytopenia (24%). Non-hematologic toxicities such as general fatigue, renal-related events, and gastrointestinal toxicities were manageable with no treatment-related death. The median survival time was 537 days. Conclusions: While there were disadvantages of radiotherapy including the difficulty of confirming the area of irradiation due to peristaltic movement, risk of perforation and ulceration, recent technological advancement of radiation therapy has enabled pinpoint accuracy in treatment of primary gastric lesions and regional lymph nodes. There has been much anticipation that chemoradiotherapy will be a part of multidisciplinary treatment for advanced cancer.