C-Reactive Protein/Albumin Ratio Is an Independent Risk Factor for Recurrence and Survival Following Curative Resection of Stage I-III Colorectal Cancer in Older Patients.

BACKGROUND: The number of older patients with cancer has increased, and colorectal cancer is expected to be affected by this trend. This study aimed to compare prognostic factors, including nutritional and inflammation-based indices, between patients aged ≥ 70 and < 70 years following curative resection of stage I-III colorectal cancer. PATIENTS AND METHODS: This study included 560 patients with stage I-III colorectal cancer who underwent curative resection between May 2010 and June 2018. A retrospective analysis was performed to identify prognosis-associated variables in patients aged ≥ 70 and < 70 years. RESULTS: Preoperative low body mass index, high C-reactive protein/albumin ratio, and comorbidities were mainly associated with poor prognosis in patients aged ≥ 70 years. Tumor factors were associated with a poor prognosis in patients aged < 70 years. The C-reactive protein/albumin ratio was independently associated with poor overall survival and recurrence-free survival in those aged ≥ 70 years. The time-dependent area under the curve for the C-reactive protein/albumin ratio was superior to those of other nutritional and inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years. CONCLUSIONS: Tumor factors were associated with a poor prognosis in patients aged < 70 years. In addition to lymph node metastasis, preoperative statuses were associated with poor prognosis in patients aged ≥ 70 years. Specifically, the preoperative C-reactive protein/albumin ratio was independently associated with long-term prognosis in patients aged ≥ 70 years with stage I-III colorectal cancer after curative resection.

Weekday Surgery Associated With Short-Term Outcomes in Patients With Colorectal Cancers.

INTRODUCTION: The "weekday effect" on elective surgery remains controversial. We aimed to examine the association between the day of surgery and short-term outcomes after elective surgery for stage I-III colorectal cancer (CRC). METHODS: We performed a multicenter retrospective analysis of 2574 patients who underwent primary colorectal resection for CRC between January 2017 and December 2019 at 15 institutions belonging to the Hiroshima Surgical Study Group of Clinical Oncology. Patients were divided into two groups according to the day of surgery: Friday and non-Friday (Monday to Thursday). After propensity score matching (PSM), we compared 30-day mortality and postoperative outcomes. RESULTS: Out of the total, 368 patients underwent surgery on Fridays, and the remaining 2206 underwent surgery on non-Fridays. The overall mortality rate was 0.04% (n = 1). In 1685 patients with colon cancer, the proportion of American Society of Anesthesiologists scores was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM of patient, tumor, and operative characteristics, operative time was slightly more prolonged and blood loss was slightly greater in the Friday group; however, these differences were not clinically meaningful. In the 889 patients with rectal cancer, the proportion of patients with abnormal respiratory patterns was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM, the Friday group had a higher incidence of morbidity (≥ Clavien-Dindo 3a), higher incidence of digestive complications, and prolonged postoperative hospital stay. CONCLUSIONS: The results may be useful in determining the day of the week for CRC surgery, which requires more advanced techniques and higher skills.

Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.

BACKGROUND: The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. METHODS: This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. RESULTS: A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). CONCLUSIONS: Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.

Long-Term Follow-up Data of a Multi-Institutional Phase-2 Study of S-1/oxaliplatin and Bevacizumab Therapy in Patients with Advanced Colorectal Cancer: The HiSCO-02 Study.

Oral fluoropyrimidines (FUs) have certain advantages over intravenous FUs, such as longer intervals between outpatient visits, no requirement for central venous port (CVP) implantation, and lower incidence of neutropenia. We previously reported the efficacy of S-1/oxaliplatin (SOX) with bevacizumab therapy as a first-line treatment for advanced colorectal cancer (CRC) in a prospective phase-II multi-institutional clinical trial (HiSCO-02 study). However, our prognostic data at the time lacked a sufficient observation period. Herein, we analyze the longer-term follow-up data, focusing on the status of eventual CVP implantation via an open-label, non-randomized, multicenter study. This study enrolled 55 patients (mean age, 64 years), of whom 43 died (41 of primary cancer). The median overall survival was 22.7 months (95% CI: 20.1-34.7 months). Post-treatment regimens after failure of first-line treatment were initiated in 43 patients; CPT11-based regimens were selected in most cases, and other oral FU combinations in nine. CVP was implanted in 35 patients prior to first-line treatment; eleven of the remaining 20 patients did not require CVP implantation. In conclusion, we report here the final prognostic update of the Phase II clinical trial examining the efficacy of SOX plus bevacizumab therapy, the results of which confirm the clinical efficacy of this regimen.

Effect of abdominal aortic calcification on the prognosis and recurrence of colorectal cancer stages II-III: A retrospective cohort study.

PURPOSE: Abdominal aortic calcification (AAC) is a well-known risk marker for cardiovascular disease. However, its clinical effect on patients who underwent radical surgery for colorectal cancer (CRC) stages II-III is unclear. This study aimed to analyze the associations between AAC and prognosis of patients with stage II-III CRC. METHODS: To evaluate the effect of AAC on clinical outcomes, prognosis, and metastatic patterns of CRC, we analyzed 362 patients who underwent radical surgery for stage II-III CRC between 2010 and 2018. RESULTS: The high AAC group had significantly worse overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In the multivariate Cox regression analyses, a high AAC was an independent risk factor for poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.23-4.59; p = 0.01), poor CSS (HR, 5.22; 95% CI, 1.74-15.6; p < 0.01), and poor RFS (HR, 1.83; 95% CI, 1.19-2.83; p < 0.01). A high AAC was not associated with a risk of lung metastasis or local or peritoneal recurrence, but a risk for liver metastasis of CRC. CONCLUSION: A high AAC showed a strong relationship with poor OS, CSS, and RFS after curative resection for stage II-III CRC. A high AAC was also associated with a risk for liver metastasis, which may worsen the prognosis in stage II-III CRC. AAC could be a new clinical tool for predicting the prognosis for patients in stage II-III CRC.

Association between social background and implementation of postoperative adjuvant chemotherapy for older patients undergoing curative resection of colorectal cancers, sub-analysis of the HiSCO-04 study.

PURPOSE: Adjuvant chemotherapy is recommended following colorectal cancer resection based on risk of recurrence. In older patients, treatment decisions should consider recurrence rates and tolerability, as well as functional prognosis, residual disease, and social factors. This study aims to investigate factors, including social background, influencing implementation of postoperative adjuvant chemotherapy in older patients undergoing curative resection for colorectal cancer. METHODS: This multi-institutional prospective cohort study included 15 institutions belonging to the Hiroshima Surgical study group for Clinical Oncology. We analyzed 159 older patients aged ≥ 80 years, who underwent curative resection for stage III colorectal cancer between December 2013 and June 2018, as sub-analysis of the HiSCO-04 study. RESULTS: In total, 62 (39.0%) patients underwent postoperative adjuvant chemotherapy. Four factors were significantly associated with its implementation: performance status < 2, Charlson Comorbidity Index < 2, prognostic nutritional index ≥ 40, and presence of a spouse or siblings as lifestyle supporters. No significant difference was found in the backgrounds between complete and incomplete postoperative adjuvant chemotherapy patients. CONCLUSION: Performance status, Charlson Comorbidity Index, nutritional status, and presence of a spouse or siblings as lifestyle supporters are possible factors influencing the implementation of postoperative adjuvant chemotherapy in older patients. To select appropriate treatment options, including postoperative adjuvant chemotherapy, it is essential to consider physical condition and comorbidities of older patients, thoroughly explain the situation to their families, and establish a support system to enhance understanding of the available treatment options.

Predictive factors associated with anastomotic leakage after resection of rectal cancer: a multicenter study with the Hiroshima Surgical study group of Clinical Oncology.

PURPOSE: Several factors have been reported as risk factors for anastomotic leakage after resection of rectal cancer. This study aimed to evaluate the risk factors for anastomotic leakage, including nutritional and immunological indices, following rectal cancer resection. METHODS: This study used a multicenter database of 803 patients from the Hiroshima Surgical study group of Clinical Oncology who underwent rectal resection with stapled anastomosis for rectal cancer between October 2016 and April 2020. RESULTS: In total, 64 patients (8.0%) developed postoperative anastomotic leakage. Five factors were significantly associated with the development of anastomotic leakage after rectal cancer resection with stapled anastomosis: male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection. The incidence of anastomotic leakage was correlated with the number of risk factors. The novel predictive formula based on odds ratios in the multivariate analysis was useful for identifying patients at high risk for anastomotic leakage. Diverting ileostomy reduced the ratio of anastomotic leakage ≥ grade III after rectal cancer resection. CONCLUSIONS: Male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection are possible risk factors for developing anastomotic leakage after rectal cancer resection with the stapled anastomosis. Patients at high risk of anastomotic leakage should be assessed for the potential benefits of diverting stoma.

Clinical efficacy of Daikenchuto (DKT: TJ-100) for gastrointestinal symptoms in patients with a history of colon and rectosigmoid cancer surgery: a randomized crossover study.

PURPOSE: This randomized crossover trial investigated the effects of Daikenchuto (DKT: TJ-100) on gastrointestinal symptoms of patients after colon and rectosigmoid cancer surgery. METHODS: Among patients who had completed surgery for colon cancer, including rectosigmoid cancer, over 6 months ago, 20 who complained of gastrointestinal symptoms were enrolled. Subjects were randomly assigned to two sequences: sequences: A and B. In period 1, sequence A subjects were orally administered DKT, whereas sequence B subjects were untreated for 28 days. After a 5-day interval, in period 2, sequences A and B were reversed. Quality-of-life markers (GSRS and VAS), the Sitzmark transit study, the orocecal transit time (lactulose hydrogen breath test) and Gas volume score were evaluated before and after each period with findings compared between the presence of absence of DKT administration. RESULTS: Between sequences, there were no significant differences in clinicopathological characters or any evaluations before randomization. There was no carryover effect in this crossover trial. The administration of DKT significantly ameliorated the GSRS in total, indigestion, and diarrhea, although the planned number of subjects for inclusion in this trial was not reached. CONCLUSIONS: DKT may ameliorate subjective symptoms for postoperative patients who complain of gastrointestinal symptoms.

Success rate of acquiring informed consent and barriers to participation in a randomized controlled trial of laparoscopic versus open surgery for non-curative stage IV colon cancer in Japan (JCOG1107).

BACKGROUND: Successful achievement of randomized controlled trials (RCTs) is dependent on the acquisition of informed consent (IC) from patients. The aim of this study was to prospectively calculate the proportion of participation in a surgical RCT and to identify the reasons for failed acquisition of IC. METHODS: A 50-insitution RCT was conducted to evaluate oncological outcomes of open and laparoscopic surgery for stage IV colon cancer (JCOG1107: UMIN-CTR 000000105). The success rate of obtaining IC was evaluated in eight periods between January 2013 and January 2021. In addition, reasons for failed acquisition of IC were identified from questionnaires. RESULTS: In total, 391 patients were informed of their eligibility for the trial, and 168 (42%) were randomly assigned to either the laparoscopic surgery group (n = 84) or open surgery group (n = 84). The success rate of IC acquisition ranged from 33 to 58% in three periods. The most common reasons for failed IC acquisition were the patients' preference for one approach of surgery based on recommendations from referring doctors and family members, and anxiety/unhappiness about randomization. CONCLUSIONS: The success rate of acquiring IC from patients for an RCT of laparoscopic versus open surgery for stage IV colon cancer was lower than the expected rate planned in the protocol. To obtain the planned rate, investigators should make efforts to inform patients and their families about the medical contributions a surgical RCT can make and recognize that the period in equipoise may be limited.

Spontaneous regression of transverse colon cancer with high-frequency microsatellite instability: a case report and literature review.

BACKGROUND: Spontaneous regression (SR) of colorectal cancer (CRC) is extremely rare, and only few cases have been reported. Although it is not yet clarified, a plausible mechanism for SR of CRC is an immunological event. CASE PRESENTATION: In this report, we present the case of SR of primary CRC in a 78-year-old man. Preoperative colonoscopy was performed, and a type 2 tumor measuring 30 mm in diameter in the transverse colon was detected. The biopsy revealed a poorly differentiated adenocarcinoma. Colectomy was performed 2 months after initial colonoscopy. During the surgery, only a 10-mm ulcer harboring a polypoid lesion measuring 8.5 mm was detected in the resected tissue; no other masses or carcinoma cells were seen on histological examination. Afterwards, the biopsy specimens were reanalyzed, and immunohistological analysis verified this as adenocarcinoma with stroma-infiltrating lymphocytes. Further analysis revealed a loss of two mismatch repair proteins, suggesting sporadic high-frequency microsatellite instability (MSI-H). CONCLUSION: According to previous literature, a common site of SR in CRC is the proximal colon, which is a feature of MSI-H CRC. However, our report showed a rare case of SR of CRC, which was in the transverse colon, with MSI-H present. This report indicates a relationship between immunological features of MSI-H and the occurrence of SR of CRC. A better understanding of this phenomenon and the mechanisms involved will have significant preventive and therapeutic implications for CRC, including anti-PD-1 immune checkpoint inhibitor therapy.

Is laparoscopic colorectal surgery with continuation of antiplatelet therapy safe without increasing bleeding complications?

PURPOSE: The number of patients on antiplatelet therapy (APT) who need surgery is increasing; however, it is unclear whether APT should be continued for abdominal surgery, particularly laparoscopic colorectal surgery. We investigated the safety of continuing APT for patients undergoing laparoscopic colorectal surgery. METHODS: We collected retrospective data from 529 patients who underwent laparoscopic colorectal surgery at Hiroshima University between January, 2013 and December, 2018. We analyzed information related to APT. Thirty-six pairs were matched by the propensity score method between patients on APT (APT+) and those not on APT (APT-). We compared the surgical outcomes of both groups. RESULTS: Among 463 patients eligible for the study, 48 were on APT for cerebrovascular or cardiovascular disease, and 36 continued to take aspirin. In the case-matched comparison, the amount of intraoperative blood loss in the APT+ group was not significantly higher than that in the APT- group, and the incidences of bleeding complications, thromboembolic complications, and other complications were not significantly different between the groups. CONCLUSION: In a case-matched comparison, continuation of aspirin during laparoscopic colorectal surgery did not increase perioperative complications. In laparoscopic colorectal surgery, continuation of aspirin is an acceptable strategy for patients with thromboembolic risk caused by interruption of APT.

Clinical Significance of Pharmacological Prophylaxis based on the Original Risk Classification of Venous Thromboembolism after Lower Abdominal Surgery.

Pharmacological prophylaxis was not routinely administrated following gastroenterological surgery because of concerns about bleeding complications. We tried to establish the original risk classification to determine the indication for pharmacological prophylaxis for selected patients at high risk of venous thromboembolism (VTE). One hundred and fifty-six consecutive patients who underwent lower abdominal elective surgery were divided into three groups (highest, high, and low risk groups) based on the original risk classification. Pharmacological prophylaxis was indicated for patients in the highest and high risk groups. We investigated safety and efficacy of the pharmacological prophylaxis based on this classification. Sixteen patients were classified in the highest, 50 in the high, and 90 in the low risk groups. Pharmacological prophylaxis was used for 59 cases (37.8%). There was no symptomatic pulmonary embolism or major bleeding complications. There were no significant differences in the occurrence of postoperative complications, analgesia use, and median postoperative pain scores for the three groups. In the highest and high risk groups administrated pharmacological prophylaxis, fibrin degradation products (FDP) and D-dimer did not change between postoperative day 1 and day 7. These data suggested the clinical significance of the pharmacological prophylaxis based on the original risk classification.

Initial experiences of robotic versus conventional laparoscopic surgery for colorectal cancer, focusing on short-term outcomes: a matched case-control study.

BACKGROUND: Robotic surgery is a new technique with the benefits of a three-dimensional view, the ability to use multi-degree-of-freedom forceps, the elimination of physiological tremors, and a stable camera view. The aim of this study was to evaluate the feasibility and short-term outcomes of robotic surgery for colorectal cancer as initial cases, compared with conventional laparoscopic surgery. METHODS: From July 2010 to June 2013, ten patients with left-sided colon and rectal cancer underwent robotic surgery, and 121 received conventional laparoscopic surgery. Both groups were balanced in terms of age, gender, American Society of Anesthesiologists (ASA) score, body mass index (BMI), operative history, TNM staging, and tumor location. Moreover, in order to improve objectivity and approximate a randomized controlled study, we used the propensity score matching method. The matching was successful because the ROC analysis showed a well-balanced curve (C = 0.535). RESULTS: Following propensity score matching, ten patients were included in the robotic surgery group and 20 patients were included in the conventional laparoscopic surgery group. There were no significant differences in the short-term clinicopathologic outcomes between the robotic surgery group and the conventional laparoscopic surgery group. However, the operative time was significantly longer in the robotic surgery group than in the conventional laparoscopic surgery group. CONCLUSIONS: There were no significant differences between the robotic surgery group and the conventional laparoscopic surgery group with respect to short-term clinicopathologic outcomes, with the exception of the operative time. Our early experience indicates that robotic surgery is a promising tool, particularly in patients with rectal cancer.

Up-front systemic chemotherapy is a feasible option compared to primary tumor resection followed by chemotherapy for colorectal cancer with unresectable synchronous metastases.

BACKGROUND: In stage IV colorectal cancer (CRC) with unresectable metastases, whether or not resection of the primary tumor should be indicated remains controversial. We aim to determine the impact of primary tumor resection on the survival of stage IV CRC patients with unresectable metastases. METHODS: We retrospectively investigated 103 CRC patients with stage IV colorectal cancer with metastases, treated at Hiroshima University Hospital between 2007 and 2013. Of these, those who had resectable primary tumor but unresectable metastases and received any chemotherapy were included in the study. We analyzed the overall survival (OS) and short-term outcomes between the patients who received up-front systemic chemotherapy (USC group) and those who received primary tumor resection followed by chemotherapy (PTR group). RESULTS: Of the 57 included patients, 15 underwent USC and 42 PTR. The median survival times were 13.4 and 23.9 months in the USC and PTR groups, respectively (P = 0.093), but multivariate analysis for the overall survival showed no significant difference between the two groups (hazard ratio, 1.30; 95% confidence interval (CI), 0.60 to 2.73, P = 0.495). In the USC group, the disease control rate of primary tumor was observed in 12 patients (80.0%), but emergency laparotomy was required for 1 patient. Morbidity in the PTR group was observed in 18 cases (42.9%). CONCLUSIONS: The overall survival did not differ significantly between the USC and PTR groups. USC may help avoid unnecessary resection and consequently the high morbidity rate associated with primary tumor resection for stage IV CRC with unresectable metastases.

Avoiding restorative proctocolectomy for colorectal cancer in patients with ulcerative colitis based on preoperative diagnosis involving p53 immunostaining: report of a case.

The standard operation for colitic cancer in ulcerative colitis (UC) is restorative proctocolectomy; however, sporadic colorectal cancer (CRC) can coincidentally arise in patients with UC and the optimal procedure remains controversial. Therefore, it is crucial to preoperatively determine whether the CRC in UC is a sporadic or colitic cancer. We report a case of avoiding proctocolectomy for sporadic CRC in a patient with UC based on preoperative diagnosis involving p53 immunostaining. A 73-year-old man with CRC in UC had undergone sigmoid colectomy with lymphadenectomy because of the submucosal deep invasion pathologically after endoscopic mucosal resection. The cancer was diagnosed sporadic cancer preoperatively not only based on the endoscopic, clinical, and histological patterns but also that the colon epithelium was unlikely to develop dysplasia as the circumference and unaffected UC mucosa did not detect p53 protein overexpression. Recent reports have shown that the immunohistochemical detection of p53 protein overexpression can be useful for a differential diagnosis and as a predictor of dysplasia and colitic cancer. The analysis of p53 mutation status based on immunostaining of p53 protein expression in the unaffected UC mucosa can be useful for the decision regarding a surgical procedure for CRC in patients with UC.

The modified Glasgow prognostic score for early mortality in patients with synchronous peritoneal carcinomatosis from colorectal cancer.

PURPOSE: Few studies have investigated the risk factors in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) who die within 3 months of undergoing surgical intervention and systemic chemotherapy. This study aimed to identify the risk factors associated with the post-treatment 3-month mortality rate. METHODS: Retrospectively collected data from Hiroshima University were analyzed for patients presenting with synchronous PC from CRC between 1992 and 2012. The clinical, histological and survival data were evaluated and correlated with the overall survival rate at 3 months after surgical intervention. RESULTS: In patients who underwent surgical intervention with systemic chemotherapy for synchronous PC from CRC (N = 65), a Kaplan-Meier analysis and the log-rank test revealed that systemic chemotherapy (P = 0.023) and the modified Glasgow Prognostic Score (mGPS) (P = 0.00001) were associated with the 3-month mortality rate. Multivariate analyses using these two factors revealed that the mGPS (0/1, 2) (odds ratio 8.087; 95 % CI 1.512-43.25; P = 0.015) was an independent risk factor for the 3-month mortality rate. CONCLUSION: The mGPS is an important independent predictor of the 3-month mortality rate in patients who undergo surgical intervention with systemic chemotherapy for synchronous PC from CRC. The mGPS could aid surgeons in choosing the appropriate treatment strategy and best care for patients.

High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer.

Colon cancer (CC) is a leading cause of cancer mortality. Novel biomarkers are needed to identify CC patients at high risk of recurrence and those who may benefit from therapeutic intervention. The aim of this study is to investigate if miR-21 expression from RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue sections is associated with prognosis and therapeutic outcome for patients with CC. The expression of miR-21 was measured by quantitative reverse transcriptase-polymerase chain reaction in a Japanese cohort (stage I-IV, n = 156) and a German cohort (stage II, n = 145). High miR-21 expression in tumors was associated with poor survival in both the stage II/III Japanese (p = 0.0008) and stage II German (p = 0.047) cohorts. These associations were independent of other clinical covariates in multivariable models. Receipt of adjuvant chemotherapy was not beneficial in patients with high miR-21 in either cohort. In the Japanese cohort, high miR-21 expression was significantly associated with poor therapeutic outcome (p = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21 (p = 0.001). These results suggest that miR-21 is a promising biomarker to identify patients with poor prognosis and can be accurately measured in FFPE tissues. The expression of miR-21 may also identify patients who will benefit from adjuvant chemotherapy.