Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus.

BACKGROUND: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). METHODS: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). RESULTS: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. CONCLUSION: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.

Effects of meropenem supply restriction: A multicenter retrospective study.

BACKGROUND: In Japan, the supply of one generic meropenem product was restricted from August 2022 to March 2023. OBJECTIVE: To determine the effects of meropenem (MEPM) restriction. METHODS: We conducted a multicenter retrospective study comparing antimicrobial use, bacteremia mortality, and drug-resistant bacteria detected before the restriction of MEPM (control period), from September 2021 to February 2022, and after the restriction of MEPM (MEPM supply restriction period), from September 2022 to February 2023, in five institutions. RESULTS: The number of carbapenem days of therapy (DOTs) were decreased in all five institutions. Fourth-generation cephalosporin DOTs increased in all facilities, and piperacillin/tazobactam DOTs increased in four facilities. The 30-day and 90-day mortality rates were significantly higher during the MEPM supply restriction period than those during the control period. Moreover, survival time was significantly shorter during the MEPM supply restriction period than that during the control period. Multivariable analysis revealed that MEPM supply restriction, age >80 years, Pitt Bacteremia Score ≥4, platelet count <10 × 104/µL, serum albumin level <2.5 g/dL, and methicillin-resistant Staphylococcus aureus bloodstream infection were independent risk factors for 30-day mortality. The detection rates of carbapenem-resistant Pseudomonas aeruginosa and Enterobacteriaceae did not differ significantly between the two periods. CONCLUSIONS: MEPM supply restriction decreased the use of carbapenems and increased the use of other broad-spectrum antimicrobial agents, which worsened the prognosis of bacteremia. Overall, carbapenems are important drugs for the treatment of infectious diseases and are difficult to replace in unforeseen situations such as drug supply outages.

Interrupted mosaic speech revisited: Gain and loss in intelligibility by stretchinga).

Our previous investigation on the effect of stretching spectrotemporally degraded and temporally interrupted speech stimuli showed remarkable intelligibility gains [Udea, Takeichi, and Wakamiya (2022). J. Acoust. Soc. Am. 152(2), 970-980]. In this previous study, however, gap durations and temporal resolution were confounded. In the current investigation, we therefore observed the intelligibility of so-called mosaic speech while dissociating the effects of interruption and temporal resolution. The intelligibility of mosaic speech (20 frequency bands and 20 ms segment duration) declined from 95% to 78% and 33% by interrupting it with 20 and 80 ms gaps. Intelligibility improved, however, to 92% and 54% (14% and 21% gains for 20 and 80 ms gaps, respectively) by stretching mosaic segments to fill silent gaps (n = 21). By contrast, the intelligibility was impoverished to a minimum of 9% (7% loss) when stretching stimuli interrupted with 160 ms gaps. Explanations based on auditory grouping, modulation unmasking, or phonemic restoration may account for the intelligibility improvement by stretching, but not for the loss. The probability summation model accounted for "U"-shaped intelligibility curves and the gain and loss of intelligibility, suggesting that perceptual unit length and speech rate may affect the intelligibility of spectrotemporally degraded speech stimuli.

[A Case of Perforated Low-Grade Appendiceal Mucinous Neoplasm Diagnosed During Appendectomy].

A 46-year-old female presented persistent right lower abdominal pain for 4 days. Computed tomography revealed an enlarged appendix with a surrounding low-attenuation mass. The patient was diagnosed with appendiceal abscess-forming appendicitis and initially treated with antibiotics. However, owing to the manifestation of nausea as a side effect, laparoscopic appendectomy was performed 3 days after the initial consultation. Intraoperative examination revealed mucinous material on the surface of the appendix and within the abdominal cavity, leading to the decision to perform an appendectomy with partial cecum resection and excision of the omentum with mucinous deposits. Pathological examination confirmed the diagnosis of a perforating low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei. The patient was subsequently referred to a specialized center for ongoing management, and at 9 months postoperatively, surveillance is being conducted. Low-grade appendiceal mucinous neoplasms can progress to pseudomyxoma peritonei through perforation; however, an optimal treatment approach has not yet been established. In particular, patients in advanced stages of the disease often require challenging management decisions. This case is reported along with a review of the literature to provide further guidance.

[Dedifferentiated Liposarcoma Originated from Small Bowel Mesentery Resected under Laparoscopic Surgery-A Case Report].

A 74-year-old woman with severe anemia was presented to our hospital to investigate the cause of the disease. Under investigation, submucosal tumor in the small intestine was suspected. We performed the laparoscopic surgery for resection. The pathological diagnosis was dedifferentiated liposarcoma originated from the small bowel mesentery.

Outcomes of solitary postoperative recurrence of esophageal squamous cell carcinoma diagnosed with FDG-PET/CT and treated with definitive radiation therapy.

BACKGROUND: Surgical resection of esophageal cancer is frequently performed to achieve a complete cure. However, the postoperative recurrence rate is 36.8-42.5%, leading to poor prognosis. Radiation therapy has been used to treat recurrences; solitary recurrence has been proposed as a prognostic factor for radiation therapy, though its significance is unclear. 18F-fluorodeoxyglucose positron emission tomography is a highly accurate diagnostic modality for esophageal cancer. This retrospective study aimed to analyze the outcomes of solitary postoperative recurrences of esophageal squamous cell carcinoma diagnosed with 18F-fluorodeoxyglucose positron emission tomography and treated with definitive radiation therapy. METHODS: We examined 27 patients who underwent definitive radiation therapy for single or multiple postoperative recurrences of esophageal squamous cell carcinoma between May 2015 and April 2021. 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed within 3 months before the commencement of radiation therapy. Kaplan-Meier, univariate, and multivariate analyses were performed to examine the overall survival and identify potential prognostic factors. RESULTS: The 1-, 2-, and 3-year overall survival rates were 85.2%, 62.6%, and 47.3%, respectively, and solitary recurrence was the only significant factor associated with overall survival (P = 0.003). The 1-, 2-, and 3-year overall survival rates in patients with solitary recurrence were 91.7%, 80.2%, and 80.2%, respectively, and in patients with multiple recurrences they were 80.0%, 50.3%, and 25.1%, respectively. Multivariate analysis also showed solitary recurrence as a significant factor for overall survival. CONCLUSIONS: When diagnosed with 18F-fluorodeoxyglucose positron emission tomography/computed tomography, solitary recurrence appears to have a more favorable prognosis than multiple recurrences.

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles.

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives.

BACKGROUND: Very few papers covering the anticancer activity of azulenes have been reported, as compared with those of antibacterial and anti-inflammatory activity. This led us to investigate the antitumor potential of fifteen 4,6,8-trimethyl azulene amide derivatives against oral malignant cells. METHODS: 4,6,8-Trimethyl azulene amide derivatives were newly synthesized. Anticancer activity was evaluated by tumor-specificity against four human oral squamous cell carcinoma (OSCC) cell lines over three normal oral cells. Neurotoxicity was evaluated by cytotoxicity against three neuronal cell lines over normal oral cells. Apoptosis induction was evaluated by Western blot and cell cycle analyses. RESULTS: Among fifteen derivatives, compounds 7, 9, and 15 showed the highest anticancer activity, and relatively lower neurotoxicity than doxorubicin, 5-fluorouracil (5-FU), and melphalan. They induced the accumulation of a comparable amount of a subG1 population, but slightly lower extent of caspase activation, as compared with actinomycin D, used as an apoptosis inducer. The quantitative structure-activity relationship analysis suggests the significant correlation of tumor-specificity with a 3D shape of molecules, and possible involvement of inflammation and hormone receptor response pathways. CONCLUSIONS: Compounds 7 and 15 can be potential candidates of a lead compound for developing novel anticancer drugs.

[A Case of Intra-Abdominal Desmoid Tumor after Laparoscopic Resection of Colon Cancer].

An 84-year-old man underwent laparoscopic descending colon resection for colon cancer with stage Ⅰ. Follow-up computed tomography(CT), 18 months after surgery showed a soft tissue density nodular mass, 30 mm in size, in the small intestinal mesentery. The surgical resection of the tumor was performed after a thorough examination. Histopathological examination showed spindle-shaped fibroblasts and abundant collagen fibers. Immunohistochemical staining was negative for c-kit and CD34 and positive for α-SMA and ß-catenin. From the above, this tumor was diagnosed as intra-abdominal desmoid tumor.

[A Case of Cecal Burkitt's Lymphoma with Intussusception].

We report a case of ileocecal intussusception due to Burkitt's lymphoma(BL). A 14-year-old boy was admitted to our hospital for abdominal pain and diarrhea. He was diagnosed an intussusception by the ultrasonography and the CT scan. Laparoscopic ileocecal resection was performed. A diagnosis of BL was made on basis of pathological examination. He was transferred for the chemotherapy on postoperative day 8. We conclude that, if the intussusception associated with malignant lymphoma is assumed from the preoperative findings, we have to keep minimal surgical invasion and start postoperative chemotherapy immediately.

[Telomerase-Specific Oncolytic Adenovirus Expressing p53 Gene Stimulating CD8+ Memory T Cells in Pancreatic Cancer].

Pancreatic cancer has poor prognosis despite the various developed multimodal treatment strategies. Currently, neoadjuvant chemotherapy and immunotherapy have attracted substantial attention as effective treatment strategies. However, amplifying immune response with existing treatments is difficult. We developed telomerase-specific oncolytic adenoviruses (OAs), including OBP-301 that is currently tested in a clinical trial of combined anti-PD-1 antibody and p53-armed OBP- 301 variant(OBP-702). OAs have immune-modulation functions and induce CD8+ T cells into tumors by releasing immunogenic cell death markers, such as extracellular adenosine triphosphate. Here, we investigated the effectiveness of OBP- 702 in pancreatic cancer treatments, focusing on the influence on CD8+ memory T cells.

Neoadjuvant chemotherapy for locally advanced esophageal cancer comparing cisplatin and 5-fluorouracil versus docetaxel plus cisplatin and 5-fluorouracil: a propensity score matching analysis.

BACKGROUND: The standard treatment for locally advanced esophageal cancer is preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), followed by surgery. Although docetaxel plus cisplatin and 5-fluorouracil (DCF) has been reported to have favorable outcomes, no study has compared its therapeutic efficacy to that of standard treatment. This study aimed to compare the therapeutic effects of CF and DCF in the real world by matching patient background factors using propensity scores. METHODS: We retrospectively reviewed the data of 237 patients with esophageal squamous cell carcinoma who underwent esophagectomy between January 2008 and December 2018. Patients were divided into two groups based on the preoperative chemotherapy regimens of CF (79 patients) or DCF (158 patients), and 49 matched pairs were finally analyzed using propensity score matching. Short- and long-term outcomes were compared between groups. RESULTS: After matching, although no significant differences in survival were observed among the groups, patients receiving DCF showed a significantly high histological response (P < 0.001). Subgroup analyses demonstrated that DCF therapy had better overall survival (P = 0.046) and relapse-free survival (P = 0.010) among pathological T3 and T4 cases. Whereas, adverse effects of chemotherapy were more frequent in the DCF group. CONCLUSIONS: Patients receiving DCF had higher pathological response and better survival than those receiving CF, especially in pathological T3 and T4 cases matched using propensity scores. Thus, the DCF regimen might be an effective treatment for locally advanced esophageal cancer. However, the adverse side effects of chemotherapy remain high and should be handled appropriately.

Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines through Formal [4+2] Cycloaddition of Acyclic α,ß-Unsaturated Amides and Imides with N,N-Dialkylanilines.

1,2,3,4-Tetrahydroquinolines should be applicable to the development of new pharmaceutical agents. A facile synthesis of 1,2,3,4-tetrahydroquinolines that is achieved by a photoinduced formal [4+2] cycloaddition reaction of acyclic α,ß-unsaturated amides and imides with N,N-dialkylanilines under visible-light irradiation, in which a new IrIII complex photosensitizer, a thiourea, and an oxidant act cooperatively in promoting the reaction, is reported. The photoreaction enables the synthesis of a wide variety of 1,2,3,4-tetrahydroquinolines, while controlling the trans/cis diastereoselectivity (>99:1) and constructing contiguous stereogenic centers. A chemoselective cleavage of an acyclic imide auxiliary is demonstrated.

Initial introduction of robot-assisted, minimally invasive esophagectomy using the microanatomy-based concept in the upper mediastinum.

BACKGROUND: We have recently standardized upper mediastinal lymph node dissection (UMLND) using a microanatomy-based concept in thoracoscopic esophagectomy in the prone position (TEPP), and introduced robot-assisted minimally invasive esophagectomy (RAMIE) using the same concept as in TEPP while aiming at solo surgery. The purpose of this study was to investigate the outcomes of RAMIE using the microanatomy-based concept in the initial introduction phase. METHODS: We have performed more than 500 TEPP procedures as minimally invasive esophagectomy (MIE). After performing about 400 cases of MIE, we established a microanatomy-based standardization of UMLND. In October 2018, we introduced RAMIE, and have performed 75 procedures in 20 months. Two groups were analyzed: a group after microanatomy-based standardization in TEPP (100 cases after completing 400 cases of TEPP) and a RAMIE group (75 cases). Finally, 51 paired cases were matched using a propensity score. Furthermore, the change in postoperative short-term outcome for RAMIE in the initial introduction phase was analyzed. RESULTS: Although there were no significant differences between the two groups in the number of upper mediastinal lymph nodes dissected, there was a significant decrease (P = 0.036) in intraoperative blood loss volume with RAMIE, representing a definite benefit for patients. The thoracoscopic operative time for RAMIE decreased by almost 100 min following less than 50 cases of experience, reaching the same level as that for recent TEPP, but with only one-tenth the operator experience. There were no significant differences in the total postoperative morbidity rate including the recurrent laryngeal nerve palsy rate. CONCLUSION: RAMIE has been introduced safely and smoothly using the microanatomy-based concept established in TEPP.

Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody.

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

[A Case of Radiation Recall Dermatitis That Was Difficult to Distinguish from Inflammatory Breast Recurrence].

The case involved a 51-year-old woman who was diagnosed with Stage Ⅰ right breast cancer(cT1, N0, M0). Partial resection of the right breast and sentinel lymph node biopsy were performed. The histological type was found to be Stage Ⅰ triple-negative medullary carcinoma with pT1c, pN0(sn), and M0. A pituitary tumor was diagnosed after discharge. After removal of the pituitary tumor, whole-breast irradiation was performed. Subsequently, chemotherapy was started. Approximately 5 months after surgery, redness and swelling of the right breast were observed. Inflammatory breast cancer recurrence could not be ruled out by imaging, and skin biopsy was performed. No malignant findings were observed, and the symptoms were considered to indicate radiation recall dermatitis caused by chemotherapy. When chemotherapy was discontinued, the redness of the right breast improved.

[A Case of Local Recurrence 20 Years after Surgery of Ascending Colon Cancer].

The case was a 67-year-old male, who underwent right hemicolectomy+D3 LN resection for ascending colon cancer at the age of 47, and pathological diagnosis was tub1>tub2, T3, N0, M0, ly1, v1, Stage Ⅱa. 20 years after the first surgery, he visited our hospital for intermittent abdominal pain and abdominal fullness. CT scan showed stenosis and wall thickening at the anastomosis of the ileum and colon. When combining the detail examination by upper and lower gastrointestinal endoscopy and PET-CT scan, the tumor was clinically diagnosed asynchronous colon cancer, duodenal invasion. Partial resection of transverse colon and duodenal combined resection was performed. The pathological diagnosis was local recurrence of previous ascending colon cancer. Postoperative adjuvant chemotherapy was performed, but it was discontinued due to poor appetite. Currently, it has not recurred 7 months after the surgery. Recurrences more than 5 years after resection of colorectal cancer are rare, and reports of local recurrence are even rare. A long-term prognosis may be expected for early detection and treatment. Even if more than 5 years passed since the surgery, examination and treatment should be performed with recurrence in mind.

[Examination of Breast Cancer in the Super-Elderly Individuals(85 Years Old and Above)at Our Hospital].

The rate of aging in Japan has currently exceeded 28.1%. Moreover, it is expected that the rate of aging will continue to increase in the future. Under these circumstances, the opportunities to treat breast cancer in the super-elderly individuals are elevating. Here, we summarized and examined the cases who were 85 years or above in age and diagnosed with breast cancer at our hospital during the last 10 years. There were 29 cases(30 breasts), who were all female, with an average age of 89.6 years. Dementia coexisted in 17 cases, and an enlarged mass was the trigger for the discovery in most cases. For breast cancer in super-elderly females, it is necessary to treat it in the right proportion. Moreover, it is considered that the treatment policy should be decided considering the presence or absence of dementia and comorbidities. Also, the treatment regime should be decided upon full consultation with the surroundings, such as family members and long-term care facilities.

[Stage â £ HER2-Positive Breast Cancer That Showed Complete Response for Over One Year after Discontinuation of Anti-HER2 Therapy-A Case Report].

A 75-year-old woman with a left breast mass on breast cancer screening was referred to our hospital for detailed evaluation. Further examination revealed left breast cancer with metastases to the left axilla, left parasternal region, left supraclavicular fossa, mediastinum, and left hilar lymph nodes, as well as multiple lung metastases. Histopathological evaluation of a needle biopsy specimen revealed invasive ductal carcinoma(scirrhous type), and she was diagnosed with Stage Ⅳ human epidermal growth factor receptor 2(HER2)-positive breast cancer. Following diagnosis, treatment was initiated with trastuzumab, pertuzumab, and docetaxel; however, she developed hypersensitivity to docetaxel and received only trastuzumab and pertuzumab after the second course. We observed a complete response after 3 courses, and treatment was discontinued after 13 courses. She underwent regular evaluation after treatment discontinuation, and a complete response was maintained for 1 year and 6 months. We conclude that combination therapy comprising trastuzumab and pertuzumab was effective for Stage Ⅳ HER2-positive breast cancer and that a complete response could be maintained even after treatment discontinuation.

[Early Detection of and Initial Response to Oxaliplatin-Related Hypersensitivity Reactions].

Oxaliplatin(L-OHP)-related hypersensitivity reactions(HSRs)may be fatal due to bronchospasm, dyspnea, and hypotension. Therefore, management of HSRs is extremely important, and a prompt and appropriate response is required when HSRs develop. To clarify the importance of early detection and an appropriate initial response to HSRs, we retrospectively investigated the expression of HSRs and subsequent response in patients using L-OHP from April 2016 to December 2017 at the outpatient chemotherapy center of Nagasaki Medical Center. HSRs were observed in 14/155 cases(one case of Grade 1 HSRs and 13 cases of Grade 2 HSRs). No significant risk factors were identified in individuals with and without HSRs. HSRs devel- oped following a median of 7.9(2-11)courses of chemotherapy and a median 687.8(75.4-960.2)mg/m2 cumulative dose. Half of the patients were able to recognize the hypersensitivity early by themselves. Furthermore, nurses were able to implement an appropriate initial response. Early detection and an appropriate early response to HSRs can possibly prevent the severity of symptoms.