Efficacy of Intravesical Instillation Therapy with Low-Dose Tokyo-172 Bacillus Calmette-Guérin to Prevent Recurrence of Non-Muscle-Invasive Bladder Cancer and Treat Carcinoma in situ: A Multi-Institutional Retrospective Study.

INTRODUCTION: There are various doses, durations, and strains of bacillus Calmette-Guérin (BCG) intravesical instillation therapy, but optimal treatment has not yet been established. We retrospectively investigated the efficacy and safety of low-dose BCG therapy for non-muscle-invasive bladder cancer (NMIBC) and carcinoma in situ (CIS) in a multicenter study. METHODS: From 1991 to 2019, 323 patients who received BCG therapy to prevent recurrence of NMIBC were analyzed as group A. Similarly, 147 patients who received BCG therapy for the treatment of CIS were analyzed as group B. Patients received low- or full-dose Tokyo-172 strain or full-dose Connaught strain, and the three strains were compared. Survival curves were estimated by the Kaplan-Meier method, and independent risk factors for intravesical recurrence were examined by multivariate logistic regression. RESULTS: Recurrence-free survival (RFS) in group A was significantly better for the Connaught strain than the low-dose Tokyo-172 strain (p = 0.026), but not between the low- and full-dose Tokyo-172 strains (p = 0.443). RFS of group B, cancer-specific survival, and progression-free survival in both groups did not show statistically significant differences. Logistic analysis of group A showed that for intravesical recurrence, only pT1 was a significant risk factor, and there were no differences between the BCG strain and dose and no significant factors in group B. There were also no differences in the completion rate in both groups, but adverse events such as urinary frequency and feeling of residual urine were significantly lower with the low-dose Tokyo-172 strain. CONCLUSION: There was no difference in efficacy between the low- and full-dose Tokyo-172 strains, but to minimize adverse events, the low-dose Tokyo-172 strain may be worth considering.

Patients with Non-Muscle-Invasive Bladder Cancer Previously Treated with Nephroureterectomy Have a High Risk of Recurrence after Bacillus Calmette-Guérin Intravesical Instillation Therapy.

BACKGROUND: There is a high incidence of intravesical recurrence after transurethral resection of bladder tumor for non-muscle-invasive bladder cancer (NMIBC). Intravesical instillation of bacillus Calmette-Guérin (BCG) is widely used to prevent recurrence and progression. There are two types of NMIBC: primary NMIBC and subsequent NMIBC after radical nephroureterectomy (RNU). We compared the clinical outcomes of BCG intravesical instillation therapy between the two types of NMIBC. PATIENTS AND METHODS: This study included a total of 357 patients, who received BCG intravesical instillation therapy to prevent recurrence of NMIBC (pTa/pT1) between 1991 and 2019. Among them, 34 patients had subsequent NMIBC after RNU, and the remaining 323 patients had primary NMIBC. This retrospective study analyzed 68 patients extracted by propensity score matching. Survival curves were estimated using the Kaplan-Meier method, and independent prognostic factors for survival were examined by the Cox proportional hazards model. RESULTS: The 3-year recurrence-free survival (RFS) rates in patients with primary NMIBC and subsequent NMIBC after RNU were 70.7% and 54.8%, respectively (p = 0.036). However, there were no significant differences between the two groups in progression-free survival and cancer-specific survival. Multivariate analysis of RFS showed that only a previous history of upper tract urothelial carcinoma was an independent prognostic and predictive factor. CONCLUSION: Patients with subsequent NMIBC after RNU treated with BCG intravesical instillation therapy have a higher risk of recurrence than those with primary NMIBC. Thus, stringent follow-up is necessary for patients with subsequent NMIBC after RNU.

Noninferior oncological outcomes in adults aged 80 years or older compared with younger patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma.

AIM: Radical nephroureterectomy (RNU) is the gold standard treatment for upper tract urothelial carcinoma (UTUC), but the usefulness of this surgery for older patients is rarely discussed. The prognosis following RNU for patients ≥80 years old remains controversial. We retrospectively investigated the prognosis of UTUC in patients ≥80 years old who underwent RNU. METHODS: Between January 1990 and December 2015, 451 patients with UTUC underwent RNU at six hospitals affiliated with Kitasato University (Kanagawa, Japan), eight patients who underwent neoadjuvant chemotherapy and two patients with metastases before surgery were excluded. Patients were divided into three groups according to their age at the time of RNU: ≤64 years (n = 135), 65-79 years (n = 254), and ≥80 years (n = 52). Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) curves were estimated using Kaplan-Meier analysis for all patients and each pT stage. Independent prognostic factors for survival were examined via multivariate analysis. RESULTS: RFS and CSS did not significantly differ between the three groups, but OS was significantly poorer in patients ≥80 years old. Stratification by pT stage (≤pT1, ≥pT2, and ≥pT3) yielded the same results. In the multivariate analysis for OS, an age of ≥80 years was a significant independent risk factor (hazard ratio: 3.01, p = .01), but RFS and CSS did not significantly differ. CONCLUSION: Oncological outcomes showed the same anticancer effects in patients ≥80 years old who underwent RNU for UTUC compared with those of younger patients. Our study suggests that surgical treatment is a beneficial option for older patients who can tolerate radical surgery.

Theoretical investigation of active listening behavior based on the echolocation of CF-FM bats.

Bats perceive the three-dimensional environment by emitting ultrasound pulses from their nose or mouth and receiving echoes through both ears. To determine the position of a target object, it is necessary to know the distance and direction of the target. Certain bat species that use a combined signal of long constant frequency and short frequency modulated ultrasounds synchronize their pinnae movement with pulse emission, and this behavior has been regarded as helpful for localizing the elevation angle of a reflective sound source. However, the significance of bats' ear motions remains unclear. In this study, we construct a model of an active listening system including the motion of the ears, and conduct mathematical investigations to clarify the importance of ear motion in direction detection of the reflective sound source. In the simulations, direction detection under rigid ear movements with interaural level differences was mathematically investigated by assuming that bats accomplish direction detection using the amplitude modulation in the echoes caused by ear movements. In particular, the ear motion conditions required for direction detection are theoretically investigated through exhaustive simulations of the pseudo-motion of the ears, rather than simulations of the actual ear motions of bats. The theory suggests that only certain ear motions, namely three-axis rotation, allow for accurate and robust direction detection. Our theoretical analysis also strongly supports the behavior whereby bats move their pinnae in the antiphase mode. In addition, we suggest that simple shaped hearing directionality and well-selected uncomplicated ear motions are sufficient to achieve precise and robust direction detection. Our findings and mathematical approach have the potential to be used in the design of active sensing systems in various engineering fields.

[A Case of Rectal Cancer Diagnosed Based on Brain Metastasis and Had a Long-Term Prognosis by Radical Resections].

The patient was a 57-year-old man who visited the department of neurosurgery for headache and lightheadedness. He was admitted with a diagnosis of brain tumor based on imaging findings. Severe brain dysfunction and mild ataxia were observed, and craniotomy tumor resection was performed 5 days after admission. He was diagnosed with brain metastasis of colorectal cancer based on histopathological examination and endoscopic findings, and was therefore referred to our department. No extracranial metastases were observed, laparoscopic-assisted low anterior resection was performed 1 month after the craniotomy. The final diagnosis was rectal cancer(Ra), pT3N0M1a(BRA), Stage Ⅳa. Three months after the craniotomy, subsequent MRI examination revealed a new metastatic lesion inferior to the tumor excision cavity, and gamma knife radiosurgery was performed. However, because an increasing tendency was noted, craniotomy was performed again 7 months after the first craniotomy. Following operative treatment, follow up has been performed without adjuvant chemotherapy or prophylactic irradiation, the patient has survived without recurrence at 34 months postoperatively. Here, we report a valuable rare case of solitary brain metastasis of colorectal cancer in which prognosis could be expected by radical resections.

Analysis of echolocation behavior of bats in "echo space" using acoustic simulation.

BACKGROUND: Echolocating bats use echo information to perceive space, control their behavior, and adjust flight navigation strategies in various environments. However, the echolocation behavior of bats, including echo information, has not been thoroughly investigated as it is technically difficult to measure all the echoes that reach the bats during flight, even with the conventional telemetry microphones currently in use. Therefore, we attempted to reproduce the echoes received at the location of bats during flight by combining acoustic simulation and behavioral experiments with acoustic measurements. By using acoustic simulation, echoes can be reproduced as temporal waveforms (including diffracted waves and multiple reflections), and detailed echo analysis is possible even in complex obstacle environments. RESULTS: We visualized the spatiotemporal changes in the echo incidence points detected by bats during flight, which enabled us to investigate the "echo space" revealed through echolocation for the first time. We then hypothesized that by observing the differences in the "echo space" before and after spatial learning, the bats' attentional position would change. To test this hypothesis, we examined how the distribution of visualized echoes concentrated at the obstacle edges after the bats became more familiar with their environment. The echo incidence points appeared near the edge even when the pulse direction was not toward the edge. Furthermore, it was found that the echo direction correlated with the turn rate of the bat's flight path, revealing for the first time the relationship between the echo direction and the bat's flight path. CONCLUSIONS: We were able to clarify for the first time how echoes space affects echolocation behavior in bats by combining acoustic simulations and behavioral experiments.

[Relationship between Degree of Obstruction of Colorectal Cancer and Nutritional and Immune Status].

This study examined the impact of the degree of occlusion in colorectal cancer during the perioperative period. The subjects included 207 patients who underwent elective colorectal cancer resection. The degree of obstruction at the first medical examination was evaluated using the ColoRectal Obstruction Scoring System(CROSS). We classified the subjects into two groups(CROSS score 0-2, CROSS score 3-4)and assessed their associations with clinicopathological factors, nutritional immune status, and postoperative course. Compared to the CROSS score 3-4 group, the CROSS score 0-2 group(42 subjects [20.3%])had a higher proportion of subjects with ≥2 lesions, T4, Stage classification Ⅳ, CEA >5.0 ng/mL, prognostic nutritional index( PNI)≤40, controlling nutritional status( CONUT) score ≥2, modified Glasgow prognostic score (mGPS)2, weight loss rate>2.3, mini nutritional assessment-short form(MNA®-SF)score <12, neutrophil lymphocyte ratio(NLR) ≥4.0, postoperative complications, and postoperative hospital stay >16 days( p<0.05). Our findings suggest that the degree of occlusion in colorectal cancer is associated with clinicopathological and nutritional/immune factors and is reflected by the postoperative course.

Capecitabine Plus Bevacizumab as First-Line Therapy for Patients with Metastatic Colorectal Cancer and Poor Performance Status.

BACKGROUND: The benefit of chemotherapy for patients with metastatic colorectal cancer has not been established. METHODS: We retrospectively evaluated the effectiveness of chemotherapy with capecitabine and bevacizumab for patients with a performance status (PS) of 3. RESULTS: Seven patients were included; median age was 82 years (range, 65-91 years). Response was not ascertained; however, the disease control rate was 83.3%. Median PFS and OS were 10.0 and 25.8 months, respectively. Hand-foot syndrome was the most common toxicity observed (3 patients; 42.9%). Grade 3 toxicity was observed in 1 patient with proteinuria and 1 with hypertension. CONCLUSION: Chemotherapy using capecitabine and bevacizumab appeared to improve OFS and OS for patients with poor PS. However, care must be taken not to impose unnecessary burdens on patients with poor PS.

Laparoscopic Surgery Reduces Risk of Postoperative Complications and Non Cancer-related Survival in Patients Over 80 Years Old With Colorectal Cancer.

Background: The short- and long-term results from several reports suggest that laparoscopic surgery (LAP) for elderly patients is expected to reduce the risk of complications due to its minimal invasiveness, However, little is known about the effect of LAP on long-term prognosis aside from cancer. Patients and Methods: Eighty-five cases over 80 years old with colorectal cancer whose primary lesions were resected consecutively were enrolled. Risk factors for complications were searched using categorized clinicopathological factors. The factors for death unrelated to cancer were analyzed in patients by excluding cancer-related death. Results: Incidence of all complications, those of Clavien-Dindo grade 2 or more, and surgical site infection were significantly lower in LAP-treated patients (p=0.0343, p=0.0015 and p=0.0015, respectively). By multivariate analysis, LAP (odds ratio=0.19, 95% confidence intervaI=0.05-0.75, p=0.0177) and no pulmonary dysfunction (odds ratio=0.24, 95% confidence intervaI=0.06-0.96, p=0.0441) were significantly associated with reduced risk of complications of Clavien-Dindo grade 2 or more. LAP, no pulmonary dysfunction and Eastern Cooperative Oncology Group performance status of 0 or 1 were also significantly associated with reduced risk for death from non cancer-related causes. Additionally, LAP was significantly associated with improved survival excluding cancer-related death in patients with pulmonary dysfunction (p=0.0020) or with poor performance status (p=0.0412). Conclusion: These results suggest that fewer complications and non cancer-related deaths were achieved in very elderly patients with colorectal cancer when treated by LAP.

Expression of ATP-binding Cassette Transporter 11 (ABCC11) Protein in Colon Cancer.

AIM: To investigate the clinical significance of ATP-binding cassette transporter 11 (ABCC11) protein expression in colon cancer. MATERIALS AND METHODS: One hundred thirty nine patients with colon cancer resection between 2009 and 2011 were enrolled. The relationship with immunohistochemical ABCC11 staining and clinicopathological factors was retrospectively analyzed. RESULTS: Median age was 70 years including 67 males and 72 females. The patients with Stage 0, 1, 2, 3a and 4 were 4, 20, 43, 35, 7 and 30, respectively. The patients with curability (Cur) A, B and C were 109, 11 and 19, respectively. Positive expression of ABCC11 was observed in 31 patients (22.3%). There were no significant differences regarding age, gender, location, serum tumor markers, T category, lymphatic invasion and stage in relation to ABCC11 protein expression. Cases with node metastasis and venous invasion as well as unresectable cases were significantly more often found negative for ABCC11 protein (p=0.0246, 0.0285 and 0.0422, respectively). Concerning the 3 year disease free survival (DFS) and the 5 year overall survival (OS) in Stage 2/3 and in Stage 3 with adjuvant chemotherapy, no significant differences were found. However, OS in ABCC11 negative cases was 81.1%, which was significantly lower compared to positive cases, where OS was 96.2%. CONCLUSION: There was significant correlation with ABCC11 expression and lymph node metastasis, venous invasion and curability. The prognosis in ABCC11 negative cases was poor because of increased cases without curative resection.

Modulation of acoustic navigation behaviour by spatial learning in the echolocating bat Rhinolophus ferrumequinum nippon.

Using echolocation, bats receive acoustic information on their surroundings, which is assumed to help them sophisticatedly navigate complex environments. In this study, to understand spatial learning and acoustic sensing in bats, we investigated how flight and echolocation control changed in Rhinolophus ferrumequinum nippon as they learnt about their surroundings in an obstacle course that they flew through repeatedly. In these experiments, two testing environments (acoustically permeable and acoustically reflective) were prepared using chains and acrylic boards as obstacles to evaluate the interactive effects of spatial learning and flight environments. We found that bats reduced the meandering width of their flights and pulse emissions, and also seemed to reduce their shifts in pulse direction as they learnt more about their environments in both conditions. Throughout all our experiments, the bats with slower flight speeds tended to emit more pulses, which suggests that the number of pulse emissions reflects the echolocation tactics of each bat. The maximum flight speed was especially increased in the acoustically permeable condition, with frequent emissions of multiple pulses (≧triplets) in the early stages of flight, suggesting that bats adjust their flight plan based on how much of their surroundings they are able to sense in advance.

[Assessment of Curative Resection in Patients with Multiple Relapses of Colorectal Cancer].

We assessed the therapeutic effect of curative resection in patients with multiple relapses of colorectal cancer using the time to surgical failure(TSF)as an index. We included 24 patients who experienced recurrence after curative resection of primary colorectal cancer at our department between 1993 and 2015. Curative resection for multiple relapses was possible in these patients. The sites of recurrence included the liver, lungs, peritoneum, lymph nodes, localized, and brain in 9, 8, 3, 3, 2, and 1 patients, respectively. The relapse occurred in 2 organs in 2 patients. The TSF after curative resection of recurrent lesions was 25.6 months, with a 5-year TSF-free rate of 40.2%. The clinicopathological factors associated with poor prognosis were age B65 years at the time of recurrence, absence of distal metastasis at primary onset, and only 2 curative resections for relapses. However, there was no difference in prognosis because of the number of twice recurrent lesions. Therefore, curative resection should be proactively performed as long as feasible in colorectal cancer patients with multiple lesions or multiple relapses.

[A Case of Unresectable Ascending Colon Cancer Treated with a Newly Devised Bypass Method].

A 74-year-old man underwent a medical examination for anemia and had a positive fecal occult blood test. Ascending colon cancer was detected by colonoscopy. Since it was unresectable, a bypass operation was performed to prevent digestive symptoms prior to chemotherapy. The bypass was performed by cutting the ileum and attaching the oral side to the transverse colon with side to side anastomosis. The other end of the terminal ileum was anastomosed to the transverse colon on the oral side of the prior anastomosis, making a pretzel shaped bypass. There were no postoperative complications and the patient was treated with chemotherapy from postoperative day 23.

[A Case of Lung Metastases from Rectal Cancer Treated for Quite Long with FOLFIRI plus Ramucirumab as a Late Line of Therapy].

We herein report a case of lung metastases from rectal cancer treated with FOLFIRI plus ramucirumab(Ram)therapy after salvage for a long time. A 44-year-old woman underwent low anterior resection for rectal cancer. Fifteen months after the surgery, mFOLFOX6 plus bevacizumab(BV)therapy was initiated for left obturator lymph node metastases. Although the target lesion shrunk, left lung metastasis was found 36 months after the surgery. Partial resection of the lung metastasis was performed, and carbon-ion radiotherapy for pelvic recurrence was administered. Following these treatments, mFOLFOX6 plus BV therapy was administered again for multiple lung metastases 42 months after the surgery. FOLFIRI plus BV therapy, TAS- 102 plus BV therapy, and regorafenib were then administered because of the disease progression. Although the best supportive care was provided after disease progression, FOLFIRI plus Ram therapy was initiated owing to the patient's wish. Although Grade 3 hematological toxicity was observed, severe digestive symptoms were not noted. Long-term administration(approximately 1 year, 21 courses)of the drugs was possible with withdrawal. The patient died due to disease progression 66 months after recurrence. We experienced a case in which FOLFIRI plus Ram therapy after salvage line could be administered for a quite long time. It has been suggested that anti-VEGF drugs with different targets may improve the prognosis even as a late line of therapy if it is tolerable.

[Impact of Postoperative Inflammatory Status on Colorectal Cancer Prognosis].

To clarify the prognostic impact of postoperative inflammatory status, serum CRP levels on POD3 after radical resection (POD3 CRP)were evaluated as an indicator of inflammatory response after surgery in patients with colorectal cancer. Of the colorectal cancer patients who underwent radical resection at our department between 2000 and 2015, 916 patients with Stage Ⅰto Ⅳdisease were included in the analyses. The patients were divided into 2 groups according to high and low POD3 CRP levels. The POD3 CRP levels of the patients were analyzed for the 75th percentile that was 12.16mg/dL(range, 0.06- 33.78). The cancer-specific 5-year survival rate was 80.6%in patients in the high group and 90.5%in those in the low group, indicating poor prognosis in patients with high values. POD3 CRP levels were an independent prognostic factor in the multivariate analysis. It was suggested that the degree of inflammation after surgery influences the postoperative prognosis after radical resection for colorectal cancer.

[Efficacy of Negative Pressure Wound Therapy for Post-Operative Wound Dehiscence after Resection of a Metastatic AbdominalWal lTumor from Cecal Cancer during Chemotherapy with Bevacizumab].

A 74-year-old man with recurrence of cecal cancer received systemic chemotherapy(CapeOX plus bevacizumab). After the administration of 9 courses, he reported sudden appearance of bloody bowel discharge. Endoscopic examination could not locate the bleeding point. A CT scan indicated that the small intestine was affected by the recurrence of cancer. Therefore, resection of the small intestine was performed after 6 weeks of drug withdrawal. Although direct closure with fascia incision was performed for the repair of wound dehiscence after surgery, re-dehiscence occurred because of paralytic ileus. Wound lavage and nutritional intervention were performed, followed by negative pressure wound therapy. Excellent wound healing was achieved by this therapeutic approach for 3 months.

STEFTR: A Hybrid Versatile Method for State Estimation and Feature Extraction From the Trajectory of Animal Behavior.

Animal behavior is the final and integrated output of brain activity. Thus, recording and analyzing behavior is critical to understand the underlying brain function. While recording animal behavior has become easier than ever with the development of compact and inexpensive devices, detailed behavioral data analysis requires sufficient prior knowledge and/or high content data such as video images of animal postures, which makes it difficult for most of the animal behavioral data to be efficiently analyzed. Here, we report a versatile method using a hybrid supervised/unsupervised machine learning approach for behavioral state estimation and feature extraction (STEFTR) only from low-content animal trajectory data. To demonstrate the effectiveness of the proposed method, we analyzed trajectory data of worms, fruit flies, rats, and bats in the laboratories, and penguins and flying seabirds in the wild, which were recorded with various methods and span a wide range of spatiotemporal scales-from mm to 1,000 km in space and from sub-seconds to days in time. We successfully estimated several states during behavior and comprehensively extracted characteristic features from a behavioral state and/or a specific experimental condition. Physiological and genetic experiments in worms revealed that the extracted behavioral features reflected specific neural or gene activities. Thus, our method provides a versatile and unbiased way to extract behavioral features from simple trajectory data to understand brain function.

[A Case of Rectal Neuroendocrine Carcinoma That Developed Two Years after Curative Resection for Sigmoid Colon Cancer].

We report a rare case ofrectal neuroendocrine carcinoma(NEC)following sigmoidectomy of sigmoid colon cancer. NEC of the rectum is a rare disease. It has an extremely poor prognosis and a high potential for malignancy with hematogenous and lymph node metastases. A 90-year-old man who had carcinoma ofthe sigmoid colon 2 years ago was found to have rectal NEC based on endoscopy findings. He underwent the Hartmann operation. Histological and immunohistochemical analyses showed NEC. Four months after the surgery, he developed local recurrence with lymph node metastasis. He was not administered chemotherapy because ofhis old age. Although the patient needed strict outpatient care, he remained symptom-free 4 months after the Hartmann operation.

[Assessment of Less Invasiveness Based on Serum CRP Level on Postoperative Day Three in Laparoscopic Surgery for Colorectal Cancer].

To evaluate the less invasiveness of laparoscopic surgery for colorectal cancer, we compared open and laparoscopic surgery for sigmoid or recto-sigmoid cancer operations undergoing the same procedures. One hundred forty-three patients curatively resected with D3 dissection were enrolled. All cases underwent the following procedure; high ligation of the inferior mesenteric artery(IMA)with median approach and double stapling technique(DST)for anastomosis. The clinicopathological factors were examined in 70 cases of open surgery(OC)and 73 cases of laparoscopic surgery(LAC). The mean age of all cases was 66(38-88)years, including 83 men and 60 women. The mean operation time was 189(82-413)minutes and the mean blood loss was 45(5-1,025)mL. Postoperative complications were reported in 45 cases including 10 cases with surgical site infection(SSI)and 10 cases with remote infection(RI). There was no difference in sex, BMI, PS, and ASA between the 2 groups; however, the patients were significantly older and the tumor maximum diameter significantly larger in the OC group. There was no significant difference in operation time but the blood loss was significantly lower in the LAC group. There were no differences in postoperative complications, first gait, WBC, and body temperature on postoperative day(POD)3, but the first flatus was earlier and the CRP level was significantly lower on POD 3 in the LAC group. There was no difference in the CRP level on POD 3 in the age, tumor diameter, and blood loss which showed a difference in the both group. Laparoscopic surgery was considered less invasive than open surgery because the serum CRP level was lower in the LAC group.

[A Case of Low-Grade Appendiceal Mucinous Neoplasm with Cecum Cancer].

The case was a 76-year-old man. He visited our hospital for a positive fecal occult blood test finding at a medical examination. A colonoscopy revealed a macroscopic, 30 mm, type-1 lesion in the cecum. We performed laparoscope-assisted ileocolic resection and D3 dissection, with a diagnosis of cecum cancer. In postoperative histopathological examination, the tumor in the cecum was diagnosed as a well-differentiated tubular adenocarcinoma. In addition, a low-grade appendiceal mucinous neoplasm(LAMN)was observed on the distal side of the appendix. The patient has survived for 9 months after surgery without recurrence. We report this case with a review of the literature.