Evaluation of the prognostic impact of pathologic tumor regression grade on patients with colorectal cancer after preoperative chemoradiotherapy.

BACKGROUND: The prognostic value of the pathological response to preoperative chemoradiotherapy (CRT) in rectal cancer (RC) remains unknown. OBJECTIVES: We aimed to assess the predictive value of the response to CRT that was derived from an evaluation of the histological findings (whole-section vs. representative-section sampling) and attempted to determine an objective cut-off value for the tumor regression grade (TRG). METHODS: We examined the association of the TRG with the outcomes (recurrence-free survival [RFS] and overall survival [OS]) of 78 patients with RC. Patients with RC treated with preoperative CRT were divided into development (30 cases) and validation (48 cases) cohorts. The TRG was classified as grades I (Ia, Ib), II, and III. The cut-off value was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: The TRG determined from whole-section sampling versus representative-section sampling was more strongly correlated with patient survival. We found that in both cohorts, patients with a cut-off value of <73% had a poor prognosis. Finally, the cut-off value was found to be an independent predictive factor in both univariate and multivariate analysis. CONCLUSIONS: The TRG that was used to evaluate patients with RC who underwent preoperative CRT was an independent prognostic factor for outcome.

Evaluation of the advantage of surgeons certified by the endoscopic surgical skill qualification system participating in laparoscopic low anterior rectal resection.

Background: A technical qualification system was developed in 2004 by the Japan Society for Endoscopic Surgery. An analysis of the EnSSURE study on 3188 stage II-III rectal cancer patients, which was performed by including the participation of qualified surgeons as assistants and advisers without restricting their participation as operators, revealed that the participation of technically qualified surgeons in surgery improved the technical and oncological safety of laparoscopic rectal resection. Aim: This secondary retrospective analysis of the EnSSURE study examined the advantage of qualified surgeons participating in laparoscopic low anterior resection (LAR). Methods: The outcomes of low anterior resection were compared between groups with and without the participation of surgeons qualified by the Endoscopic Surgical Skill Qualification System (Q and non-Q groups, respectively). We used propensity score matching to generate paired cohorts at a one-to-one ratio. The postoperative complication rate, short-term results (hemorrhage volume, operative time, number of dissected lymph nodes, open conversion rate, intraoperative complication rate, and R0 resection rate), and long-term results (disease-free survival rate, local recurrence rate, and overall survival rate) were evaluated. Results: The frequencies of postoperative complications, anastomotic bleeding, and intraperitoneal abscess were significantly lower, the operative time was significantly shorter, the postoperative hospital stay was significantly shorter, and the number of dissected lymph nodes was higher in the Q group. No significant differences were observed in disease-free survival, local recurrence, or overall survival rate rates between the groups. Conclusion: The participation of qualified surgeons in LAR is technically advantageous.

Radiological Cutoff Values for Diagnosis of Lymph Node Metastasis in Colorectal Cancer With Multilevel Analysis.

Background/Aim: A cutoff value for lymph node diameter in colorectal cancer lymph node metastases has not been established. This prospective study aimed to investigate the direct association between swollen lymph nodes identified on preoperative computed tomography (CT) and pathological findings and proposed a cutoff value. Patients and Methods: We enrolled patients scheduled to undergo curative surgery with lymph node dissection for colorectal adenocarcinoma who underwent preoperative contrast-enhanced CT and had swollen lymph nodes ≥7 mm in diameter. Two gastrointestinal surgeons intraoperatively identified the target lymph nodes to assess the association between lymph node diameter and pathological findings. The diagnostic performance for lymph node metastasis was determined using multi-level logistic modelling. Results: A total of 109 patients were enrolled, and 225 swollen lymph nodes were pathologically evaluated. Using a cutoff value of ≥9 mm for the short diameter, the positive and negative predictive values, sensitivity, and specificity were 100.0% (99.6%-100.0%), 99.9% (99.1%-100.0%), 62.0% (45.6%-76.0%), and 84.9% (67.0%-94.0%), respectively. Conclusion: The cutoff value for improving the positive predictive value for the preoperative lymph node metastasis diagnosis in colorectal cancer patients should be at least 9 mm in diameter.

Clinical Indicators to Determine the Timing of Surgery for Adhesive Small Bowel Obstruction.

BACKGROUND: Decompression of the intestine with a long tube or nasogastric tube is the first-choice treatment for adhesive small bowel obstruction (ASBO). Scheduling surgery while weighing the risks of surgery against conservative care is a crucial factor in clinical decision-making. Whenever feasible, unnecessary surgeries should be avoided, and it is essential to provide clinical markers for this. This study aimed to obtain evidence regarding the optimal timing of ASBO and when conservative treatment options are not successful. METHODS: The data of patients diagnosed with ASBO and receiving long tube insertion for more than 7 days were reviewed. We investigated transit ileal drainage volume and recurrence. The primary outcomes were the change in the drainage volume from the long tube over time and the percentage of patients who required surgery. We evaluated some cutoff values to determine the indication for surgery based on the insertion duration and volume of long tube drainage. RESULTS: Ninety-nine patients were enrolled in this study. Fifty-one patients showed improvement with conservative treatment, whereas 48 ultimately required surgery. When a daily drainage volume of ≥500 mL was considered an indication for surgery, 13-37 cases (25%-72%) would be judged unnecessary within 6 days of long tube insertion, while 5 cases (9.8%) would be judged unnecessary on day 7. DISCUSSION: Unnecessary surgical interventions for ASBO might be avoided by assessing the drainage volume on day 7 after inserting a long tube.

Delayed Perforation of Colorectal Endoscopic Submucosal Dissection Treated by Endoscopic Ultrasound-Guided Drainage.

We report a case of a 70-year-old male with delayed perforation in the cecum treated by endoscopic ultrasonography-guided drainage for a pelvic abscess. The lesion was a 50-mm laterally spreading tumor, and endoscopic submucosal dissection (ESD) was performed. No perforation was detected during the operation, and en bloc resection was achieved. He had fever and abdominal pain on postoperative day (POD) 2. Computed tomography (CT) revealed the intra-abdominal free air, leading to a diagnosis of delayed perforation after ESD. Vital signs were stable, the perforation was considered minor, and endoscopic closure was attempted. The colonoscopy under fluoroscopy showed no perforation in the ulcer and no leakage of the contrast medium. He was managed conservatively with antibiotics and nothing per os. Symptoms improved; however, a follow-up CT on POD 13 revealed a 65-mm pelvic abscess, and endoscopic ultrasound (EUS)-guided drainage was successfully performed. The follow-up CT on POD 23 showed the reduction of abscess, and the drainage tubes were removed. Emergent surgical treatment is crucial in delayed perforation because it has a poor prognosis, and reports of conservative therapy for colonic ESD with delayed perforation are few. The present case was managed with antibiotics and EUS-guided drainage. Thus, EUS-guided drainage can be a treatment option for delayed perforation after colorectal ESD, if the abscess is localized.

Delayed Perforation after Endoscopic Detachable Snare Ligation for Colonic Diverticular Hemorrhage.

A 74-year-old man was admitted to our hospital with severe hematochezia. Abdominal enhanced computed tomography (CT) demonstrated extravasation of contrast material from the descending colon. Colonoscopy revealed recent bleeding in the descending colon diverticulum. Bleeding was stopped using detachable snare ligation. Eight days later, the patient developed abdominalgia, and CT revealed free air caused by delayed perforation. The patient underwent emergency surgery. Perforation at the ligation site was detected using intraoperative colonoscopy. This report is the first to describe a case of delayed perforation after endoscopic detachable snare ligation for colonic diverticular hemorrhage.

Clinical outcomes and factors involved in the local control of proton beam therapy for oligometastatic liver tumors in patients with colorectal cancer.

BACKGROUND AND PURPOSE: There are no existing reports on proton beam therapy (PBT) for local control (LC) of liver metastasis of colorectal cancer (LMCRC). We calculated the LC rate of PBT for LMCRC and explored the influence of each factor on the LC rate. MATERIALS AND METHODS: Cases in which PBT was performed at our center between 2009 and 2018 were retrospectively selected from the database. Patients with LMCRC without extrahepatic lesions and no more than three liver metastases were included. Effectiveness was assessed based on LC, overall survival (OS), and progression-free survival (PFS) rates. Adverse events (AEs) are described. Factors that may be related to LC were also investigated. RESULTS: This study included 23 men and 18 women, with a median age of 66 (range 24-87) years. A total of 63 lesions were included in the study. The most frequent dose was 72.6 Gy (relative biological effectiveness)/22 fractions. The median follow-up period was 27.6 months. The 3­year LC, OS, and PFS rates were 54.9%, 61.6%, and 16.7%, respectively. Our multivariate analysis identified the distance between the tumor and the gastrointestinal (GI) tract as a factor associated with LC (P = 0.02). No grade ≥ 3 AEs were observed. None of the patients experienced liver failure during the acute or late phase. CONCLUSION: Care must be taken with tumors that have reduced planning target volume coverage owing to organs at risk restrictions, especially in tumors near the GI tract.

The additional diagnostic impact of positron emission tomography-computed tomography for lymph node metastasis from colorectal cancer: A prospective lymph node level analysis.

BACKGROUND: We conducted a prospective study to determine the diagnostic performance of positron emission tomography-computed tomography (PET-CT) for lymph node metastasis in colorectal cancer patients. METHODS: We enrolled patients scheduled to receive curative surgery with lymph node dissection for colorectal adenocarcinoma who underwent contrast-enhanced abdominopelvic CT and PET-CT before surgery and who had primary lesions of cT2 or deeper. A radiologist determined the fluorodeoxyglucose uptake and the standardized uptake value (SUV) and metabolic volume (MV) to diagnose metastasis in cases with enlarged lymph nodes (≥7 mm long in minor diameter) on contrast-enhanced CT. Two gastrointestinal surgeons intraoperatively identified target lymph nodes to assess the association between images and pathological findings. The diagnostic performance (i.e., sensitivity, specificity, and positive and negative predictive values) for lymph node metastasis was determined using multilevel logistic modeling. RESULTS: A total of 205 colorectal cancer patients were enrolled from February 2018 to April 2020 and 194 patients were analyzed in this study. The sensitivity, specificity, and positive and negative predictive values of PET-CT were 15.3% (13.4%-17.5%), 100.0% (99.0%-100.0%), 100.0% (51.2%-100.0%), and 98.7% (98.5%-99.0%), respectively. CONCLUSION: PET-CT is a useful modality for determining the presence of metastasis in swollen lymph nodes on contrast-enhanced CT in colorectal cancer patients.

Comparison of ethanol concentrations after drinking in patients who underwent total gastrectomy versus healthy controls.

BACKGROUND: The safety of drinking in patients who have undergone total gastrectomy for gastric cancer has not been established. We conducted a clinical trial to investigate the trend in alcohol absorption in actual patients. METHODS: Patients who received total gastrectomy with lymph-node dissection and Roux-en-Y reconstruction six or more months ago were enrolled. Participants drank 1 unit (20 g) of ethanol within 1 h starting at least 1 h after a meal. The blood alcohol concentration (BAC) was then estimated by a measurement of the breath alcohol concentration. The peak and trend in the BAC in patients was compared with that in healthy volunteers who were matched with patients for the alcohol-sensitive genotype. RESULTS: Ten patients and 10 healthy people were enrolled in the BAC evaluation. The peak BAC (%) was 0.158 in patients after total gastrectomy versus 0.110 in control (P < 0.001). The mean half-life of BAC was 58.0 min in the patient group and 94.0 min in the control group, although the mean time to complete drinking was significantly longer in the patient group than in the control group at 40.8 versus 21.9 min (P = 0.009). CONCLUSION: Drinking alcohol is likely to carry a risk of increasing the BAC in patients who have undergone total gastrectomy.

The effects of intensive oral care before surgery for gastric cancer patients.

OBJECTIVES: Oral function management has been recognized as important strategy for preventing postoperative complications. In this historical cohort study, we focused on the patients who planed gastrectomy, and investigated the appropriate duration and frequency of preoperative oral care to prevent complications after surgery. METHODS: Patients who planed surgery for gastric cancer between 2012 and 2018 were enrolled. We defined intensive oral care (IOC) as initial intervention at least three weeks before surgery and follow-up intervention within a week before surgery. As the primary outcome, the incidence of postoperative infectious complications was compared between the IOC and non-intensive oral care groups. RESULTS: A total of 576 patients were enrolled, including 66 with IOC. The incidence of infectious complications was 2/66 (3.0%) in the IOC group and 64/510 (12.5%) in the non-intensive oral care group. After adjusting for confounding factors, patients with IOC exposure had a lower chance of developing postoperative infectious complications (odds ratio; 0.217, 0.051-0.927). CONCLUSIONS: Intensive oral care can help prevent postoperative infectious complications after gastrectomy. These findings suggest that appropriate preoperative oral care includes at least two interventions: three weeks or more before and within one week before surgery.

The bacterial association with oral cavity and intra-abdominal abscess after gastrectomy.

BACKGROUND: Perioperative oral management has been reported to be effective for preventing postoperative infectious complications. In addition, severe periodontal disease was identified as the significant risk factor for complications after gastrointestinal surgery. We investigated the bacteriological association between the periodontal pocket, stomach mucosa and drainage fluid to determine whether oral bacteria directly cause intra-abdominal infection after gastrectomy. METHODS: Patients who were scheduled to undergo surgery for gastric cancer were prospectively enrolled. We evaluated the similarity of bacterial strains in periodontal pocket, stomach mucosa and fluid from drainage tube. Gingival crevicular fluid and dental plaque were collected from the periodontal pocket and cultured to detect bacteria. Specimens from the resected stomach were collected and used for bacterial culturing. Drainage fluid from the abdominal cavity was also cultured. RESULTS: All of 52 patients were enrolled. In the periodontal pocket, α-Streptococcus spp., Neisseria sp., and Prevotella sp. were mainly detected. Bacterial cultures in the stomach mucosa were positive in 26 cases. In 20 cases (76.9%), the detected strains were the same as those in the periodontal pocket. Six patients had the postoperative intra-abdominal infection after gastrectomy, and the same bacterial strains was detected in both of drainage fluid and periodontal pocket in two patients with severe periodontal disease. CONCLUSIONS: We found the bacteriological association that same strain detected in periodontal pocket, stomach and in intra-abdominal drainage fluid after gastrectomy in patients with periodontal disease.

The effectiveness of proton beam therapy for liver metastatic recurrence in gastric cancer patients.

OBJECTIVE: The purpose of this cross-sectional study was to evaluate the efficacy and safety of proton beam therapy for liver metastatic recurrence in gastric cancer patients. METHODS: Consecutive patients who underwent proton beam therapy from 2010 to 2015 were isolated from our institutional database. Patients with extrahepatic metastatic lesions were excluded. Seven patients were enrolled. The median diameter of target lesions was 31 mm (13-68 mm). The most frequent dosage was 72.6 Gy equivalent in 22 fractions. The effectiveness was assessed based on the local control, overall survival and progression-free survival rates. The local control, overall survival and progression-free survival rates were calculated using the Kaplan-Meier method. Adverse events were described according to the patients' medical records. RESULTS: The median follow-up period was 41.7 months (20.7-66.3 months). The 3-year local control, overall survival and progression-free survival rates were 85.7, 68.6 and 43%, respectively. All patients completed proton beam therapy without interruption. No grade ≥3 adverse events were observed. CONCLUSIONS: Proton beam therapy might be a treatment option for patients with liver metastasis of gastric cancer.

The long-term outcomes in adolescent and young adult patients with colorectal cancer -A multicenter large-scale cohort study.

Introduction: The prognosis of adolescent and young adult (AYA) patients with colorectal cancer (CRC) is still unclear. The aim of this study was to investigate the clinical features and prognosis in AYA patients compared with middle- aged patients. Methods: Participants were identified from a clinical database of the multicenter cohort in Japan. The AYA group was defined as those <40 years of age, whereas the middle-aged group was defined in 10-year ranges around the median age of all patients. The primary outcome was the overall survival (OS), and the secondary outcome was the recurrence-free survival (RFS). Results: A total of 502 patients were enrolled as the AYA group, and 7222 patients between 65 and 74 years of age were identified as the middle-aged group. The OS of colon cancer in stages II and III was significantly better in the AYA group (p = 0.033, 0.006, respectively) than in the middle-aged groups. There were no significant differences in the OS of rectal cancer in stages II and III between the two groups. Conclusion: The prognosis of AYA patients with CRC was the same or better than that in middle-aged patients.

Clinical impact of periodontal disease on postoperative complications in gastrointestinal cancer patients.

BACKGROUND: The effectiveness of perioperative oral management in gastrointestinal surgery remains unclear. To elucidate the clinical significance of oral care, we investigated the relationship between the oral environment and postoperative infectious complications (POICs) in patients undergoing gastrointestinal surgery. METHODS: This was a single-institute and historical cohort study of 341 patients. The participants were isolated from consecutive patients undergoing planned radical resection for gastrointestinal carcinoma from January 2016 to June 2017. Dentists assessed the oral environment for periodontal disease, hygiene status, dry mouth, fur on tongue, and tooth stumps. All patients received scaling and tooth brushing instructions. A stepwise logistic regression analysis was conducted to identify risk factors for POICs among the different oral statuses. RESULTS: The surgical procedures performed were gastrectomy in 123 (36.1%), colorectal resection in 185 (54.2%), and pancreatoduodenectomy or others in 38 (11.1%). POICs occurred in 48 patients (14.1%), including deep organ space infection in 20, surgical site infection in 11, anastomotic leakage in 5, urinary tract infection in 4, pneumonia in 2, and others in 6. After adjusting for confounding factors, periodontal disease was isolated as an independent risk factor for POICs (odds ratio 2.091, p = 0.037, 95% confidence interval 1.045-4.183). Other variables of oral environment such as hygiene status, dry mouth, fur on tongue, and tooth stumps did not have a significant impact on POICs. CONCLUSIONS: Periodontal disease is a risk factor for infectious complications after gastrointestinal surgery.

[Four Patients Who Underwent Proton Beam Therapy after Debulking Surgery and Omental Wrapping of the Residual Tumor as a Spacer for Unresectable Local Recurrence of Rectal Cancer].

We report 4 patients who underwent proton beam therapy after debulking surgery for unresectable local recurrence of rectal cancer. Case 1: A 55-year-old man underwent radiotherapy and systemic chemotherapy for local recurrence; however, the lesion exhibited evident regrowth. Combination therapy of debulking surgery, omental wrapping of the residual tumor as a spacer, and postoperative proton beam therapy was performed. He died of lung metastasis after 24 months. Case 2: A 79- year-old woman who underwent surgical resections and radiotherapy twice in a previous hospital was referred to our hospital. Similar to that in case 1, proton beam therapy after debulking surgery and omental wrapping was performed. She died of lymph node metastasis after 31 months. Case 3: A 75-year-old man was diagnosed with unresectable local recurrence of rectal cancer. He underwent combination therapy and is doing well without any recurrence for 43 months. Case 4: A 57-yearold woman was also diagnosed with unresectable local recurrence. She underwent the same combination therapy after systemic chemotherapy. She died of lymph node metastasis after 11 months.

[Indication for Radiotherapy for Breast Cancer Metastasis to the Skull Base Accompanied by Cranial Nerve Palsies].

Distant metastasis to the skull base region frequently manifests various cranial nerve symptoms and reduces patients' quality of life(QOL). We report a 62-year-old woman with skull base metastasis of breast cancer, whose condition clinically improved following palliative radiotherapy. The patient presented to our hospital with hoarseness. CT screening revealed a tumor in the right breast, axial lymph node swelling, and osteoblastic change at multiple sites. A core needle biopsy of the breast tumor revealed invasive lobular carcinoma. She also had nausea, anorexia, vertigo, lower left angle of the mouth, apraxia of lid closing, and dysphagia owing to several cranial nerve palsies. MRI T1- and T2-weighted images showed a diffuse low-signal intensity of the skull base region, and the patient was diagnosed as having breast cancer with symptomatic skull base metastases. Her cranial nerve symptoms improved after 1 week of palliative irradiation to the skull base. We conclude that, even among terminal-stage patients, palliative radiotherapy to the skull base region is an effective treatment option to improve patients' QOL.

Neuroendocrine tumor of the extrahepatic bile duct: A case report.

INTRODUCTION: Neuroendocrine tumors (NETs) of the extrahepatic bile ducts are extremely rare neoplasms arising from endocrine cells and have variable malignant potential. They most commonly occur in young females and usually present with painless jaundice. PRESENTATION OF CASE: Here we present the case of an asymptomatic 57-year-old woman with NET of the common bile duct that was incidentally discovered on abdominal ultrasound during a medical examination. She was admitted to our hospital with a diagnosis of hepatic hilar tumor. Computed tomography revealed the tumor surrounding the hepatic hilum and duodenum. Magnetic resonance cholangiopancreatography revealed a filling defect of the common bile duct with morphology suggestive of external compression. Endoscopic ultrasound confirmed a submucosal tumor of the duodenal bulb measuring 30×20mm in size. The patient qualified for surgery with a preoperative diagnosis of submucosal tumor of the duodenal bulb. Intraoperative examination revealed that the tumor location involved the common bile duct and/or cystic duct with no signs of invasion to other organs or metastatic lymph nodes. Excision of the biliary ducts and tumor was followed by Roux-en-Y anastomosis. Histological results showed NET grade 1. DISCUSSION: Preoperative diagnosis of NETs is difficult because of their rarity. A definitive diagnosis is usually established intraoperatively or after histopathological evaluation. CONCLUSION: For these tumors, surgical resection is currently the only treatment modality for achieving a potentially curative effect and prolonged disease-free survival.

[A Case of Perianal Squamous Cell Carcinoma with Left Inguinal Lymph Node Metastasis That Showed a Complete Response More Than Five Years after Chemotherapy and Concomitant Proton Beam Therapy].

We report a case of perianal squamous cell carcinoma and left inguinal lymph node metastasis that showed a complete response more than 5 years after chemotherapy and concomitant proton beam therapy. A 34-year-old woman was referred to our hospital for an anal tumor and a left inguinal tumor. A digital rectal examination revealed a tumor in the anterior wall of the anal canal. In addition, the left inguinal lymph nodes were swollen, leading us to suspect metastases. Biopsy specimens confirmed poorly differentiated squamous cell carcinoma. We made a diagnosis of squamous cell carcinoma T4bN2M0, Stage III b. The patient was treated with chemotherapy consisting of 5-FU(700mg/m / 2/day; continuous intravenous administra- tion)on days 1-5, and CDDP(70mg/m / 2/day)on day 1, along with concomitant proton beam therapy. A total of 45 Gy of X-ray irradiation was administered to the primary lesion, pelvis, and groin area. Furthermore, 24.2 Gy of proton beam therapy was administered to the primary lesion, and 28.6 Gy to the left inguinal lymph nodes. The patient tolerated this treatment with no severe adverse effects. The tumor disappeared completely 1 month after this treatment, and biopsy specimens confirmed the absence of any viable cancer cells. The patient has been alive with no sign of recurrence for 5 years.

[An Autopsy Case of Pulmonary Tumor Thrombotic Microangiopathy That Progressed Slowly during Chemotherapy for Advanced Gastric Cancer].

A man in his 50s presented to our hospital for anemia and was diagnosed with advanced gastric cancer with para-aortic lymph node metastases. He underwent gastrojejunostomy and received postoperative chemotherapy. Despite stable disease with chemotherapy, he complained of cough and respiratory discomfort and was subsequently admitted with progressive respiratory distress. Pulmonary hypertension and right-sided heart failure developed, and he died of sudden cardiopulmonary arrest 9 days after admission. An autopsy revealed widespread tumor metastasis, and he was diagnosed with pulmonary tumor thrombotic microangiopathy(PTTM)associated with gastric cancer. Although PTTM is a rare clinicopathological entity that causes severe pulmonary hypertension, it should be considered in the differential diagnosis of acute dyspnea in patients with carcinoma, regardless of clinical improvement.

[A Case of an Abdominal Desmoplastic Small Round Cell Tumor with Metastasis in the Medulla Oblongata].

A desmoplastic small round cell tumor(DSRCT)is a very rare malignant tumor that mainly occurs in the intra-abdominal cavity in young adults.This neoplasm has an extremely poor prognosis, with a clinical course characterized by rapid progression and metastasis.We present a 31-year-old man who presented with chief complaints of dysphagia, ataxic gait, and hoarseness.He first underwent surgical resection of a tumor in the medulla oblongata; however, the lesion was suspected to be a metastatic neoplasm.Following a thorough medical examination, the patient was diagnosed with retroperitoneal DSRCT with multiple metastatic lesions.He received multidisciplinary treatment including debulking surgery for the primary lesion; radiotherapy for metastatic lesions in the brain, abdomen, and cervical lymph nodes; hepatic artery embolization for liver metastasis; and systemic chemotherapy.The patient died of progressive disease 17 months after the initial diagnosis.