Investigation of Expanded Human Adipose-derived Stem Cell Dosage and Timing for Improved Defecation Function.

BACKGROUND/AIM: Although certain treatment options exist for intestinal incontinence, none are curative. Adipose-derived stem cells (ADSCs) have emerged as promising therapeutic agents, but most preclinical studies of their effectiveness for anal function have used autologous or allogeneic ADSCs. In this study, the effectiveness, timing of administration, and required dosage of human ADSCs were investigated for clinical application. MATERIALS AND METHODS: A 10-mm balloon catheter was used to induce anal sphincter injury in immunodeficient mice in the following experimental groups (n=4 per group): ADSC (injected ADSCs after injury), PBS (injected phosphate-buffered saline after injury), and control (uninjured). The effects of different timing (immediately after injection and 30 days following injury) and number of human ADSCs administered was compared among groups based on defecation status and pathological evaluation. RESULTS: In terms of defecation status, groups receiving ≥1×104 human ADSCs after injection showed improvement. Pathological images showed that compared to the PBS group, the thinnest part of the sphincter was thicker for animals that received ≥1×104 human ADSCs, and fibrosis of the sphincter was notable in those treated with 1×103 human ADSCs or PBS. Furthermore, defecation status was improved by administration of human ADSCs, not only immediately after injury, but also at 30 days following injury. CONCLUSION: Human ADSC administration in a mouse model of anal sphincter injury was effective. Injection of ≥1×104 human ADSCs was the amount necessary to improve defecation status, an effect detected in both the acute and chronic phases.

Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice.

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel-Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf-/-, Adamts13-/-) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf-/- mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

Identification of a unique subset of tissue-resident memory CD4+ T cells in Crohn's disease.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Locally advanced rectal cancer receiving total neoadjuvant therapy combined with nivolumab: a case report and literature review.

BACKGROUND: The standard treatment for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, it has been suggested that intensification of neoadjuvant treatment with polychemotherapy in addition to CRT instead of as an adjuvant chemotherapy is better tolerated and associated with a higher pathological complete response (pCR) rate. This concept is known as total neoadjuvant therapy (TNT). Recently, the addition of immunotherapy to preoperative CRT has been reported to be useful in LARC patients with mismatch-repair-deficiency and high levels of microsatellite instability (MSI-H), but there are no reports showing the therapeutic effect of nivolumab in combination with TNT. CASE PRESENTATION: A 23-year-old man had frequent diarrhea. Preoperative examination revealed two adenocarcinomas in the rectum. His maternal grandmother had a rectal cancer patient who developed the disease at age 70s. The larger tumor was located at the peritoneal reflection, and its anterior border close to the prostate (<1 mm); there were eight enlarged pararectal lymph nodes. Considering the size and depth of the tumor, it was judged that radical resection with sufficient margins would be difficult. Therefore, it was decided that TNT would be performed. At first, CAPOX (capecitabine and L-OHP) was administered, followed by preoperative CRT (RT:50.4 Gy and capecitabine). During this period, genetic testing diagnosed this patient as MSI-H, so additional nivolumab was administered after CRT. Colonoscopy revealed that the larger tumor was no longer detectable, so robot-assisted intersphincteric resection and bilateral lateral lymph node dissection was performed. The diagnosis of pCR was made for the larger tumor and partial response was achieved for the smaller tumor, and no lymph node metastasis was found. Major complications were not observed and the patient was discharged on the 14th day after surgery. He was followed up without adjuvant chemotherapy and is alive and recurrence-free after 9 months. CONCLUSION: A case of LARC with MSI-H was treated with TNT with nivolumab, resulting in pCR and complete radical resection. This result suggests that nivolumab in addition to TNT can be an option as a preoperative strategy for LARC with MSI-H.

Long Distance Between the Superior Mesenteric Artery Root and Bottom of the External Anal Sphincter Is a Risk Factor for Stoma Outlet Obstruction After Total Proctocolectomy and Ileal-Pouch Anal Anastomosis for Ulcerative Colitis.

Background: Stoma outlet obstruction (SOO) is much more common after total proctocolectomy (TPC) and ileal-pouch anal anastomosis (IPAA) for ulcerative colitis (UC) compared to after rectal surgery for cancer. Few prior reports have evaluated anatomical risk factors for SOO. In this study we aimed to clarify the risk factors for SOO after IPAA, focusing on the anatomical perspective. Methods: This study included 68 UC patients who underwent IPAA with diverting ileostomy. These cases were analyzed based on clinicopathological factors and computed tomography (CT)-based anatomical factors. Results: SOO was identified in 18 patients (26.5%). We compared this SOO group with the non-SOO group. The two groups significantly differed in sex distribution, and patients in the SOO group tended to have a longer postoperative hospital stay. Regarding surgery-related factors, patients who underwent two-stage surgery and experienced high-output syndrome tended to develop SOO. Analysis of anatomical risk factors revealed that SOO was more common in patients with a longer distance between the root of their superior mesenteric artery and the bottom of the external anal sphincter (rSMA-bEAS). This tendency remained significant even with adjustment for patient height. In multivariate analyses, adjusted rSMA-bEAS (>191.0 mm/m) and male sex were independent risk factors associated with SOO. Conclusion: A long rSMA-bEAS distance suggests that the mesentery is likely to be under tension. In such cases, surgeons should endeavor to avoid tension in the mesentery as much as possible.

Usefulness of An Anal Sphincter Injury Mouse Model by Means of a Balloon Catheter and a New Method of Evaluating Anal Sphincter Function.

Background: The incidence of fecal incontinence is ~2%, and the associated symptoms significantly impact daily life. New treatment methods including electrical stimulation and regenerative therapy using stem cells for fecal incontinence have been reported. We explored the usefulness of an anal sphincter injury mouse model by means of a balloon catheter and focused on the defecation status of mice as a novel method for evaluating anal function. We examined the utility of the mouse model of anal sphincter injury and the efficacy of electrical stimulation as a treatment modality using this model. Methods: A 10-mm balloon catheter was used to create an anal sphincter injury model in mice. Sphincter function was evaluated in the noninjured (n = 4), injured (n = 4), noninjured electrical stimulation (n = 4), and injured electrical stimulation (n = 4) groups. Defecation status (defecation frequency in 24 h and fecal weight per stool) and pathological evaluation were used for comparison. Results: The defecation frequency increased and the fecal weight per stool decreased significantly in the anal sphincter injury model. Pathological evaluation revealed that anal sphincter tears occurred the day after the injury. Meanwhile, the defecation frequency improved on d 7, and the fecal weight per stool gradually normalized to that of the control group and exhibited significant sphincter muscle hypertrophy in the electrical stimulation group. Conclusion: Anal sphincter injury using a balloon catheter in mice allowed us to create a uniform model. The evaluation of defecation status in mice is a useful method for comparatively evaluating anal function.

The prediction of postoperative anorectal dysfunction after low anterior resection for lower rectal cancer by measuring the volume of defecation-related muscles.

PURPOSE: Approximately 90% of patients are thought to develop bowel dysfunction after low anterior resection (LAR). Although some prognostic factors have been reported, the volumes of defecation-related muscles have not been examined. This retrospective study investigated the association between the preoperative volume of defecation-related muscles and major LARS. METHODS: Forty-six patients who underwent LAR for rectal cancer between 2013 and 2020 in our institution were analyzed. They had no local residual tumor or local recurrence at the time of the study and no problems with their defecation function pre-operatively. Defecation-related muscle volume measurements were made before surgery, and the patients answered a low anterior resection syndrome (LARS) score questionnaire after surgery. The muscle volume was adjusted by the patient's height squared. RESULTS: Twenty-seven patients (58.7%) developed major LARS. In the univariate analysis, sex, lateral lymph node dissection, and diverting ileostomy as well as muscle volume of the external anal sphincter, pubococcygeal + iliococcygeus muscle, and puborectal muscle were associated with major LARS. In a multivariate analysis, pubococcygeal + iliococcygeus muscle (< 5.96 ml/m2) was the only factor (p = 0.02). CONCLUSIONS: Measuring the volume of the defecation-related muscles may aid in predicting major LARS.

Defecation Function After Laparo-Assisted Restorative Proctocolectomy with Ileal Pouch Anal Anastomosis for Ulcerative Colitis.

Background: Defecation status is an important determinant of quality of life. Previous studies showed that postoperative defecation disorders occurred after open surgery for ulcerative colitis (UC), but few have investigated defecation status after laparo-assisted surgery. The added precision and magnification provided with laparo-assisted surgery should lead to less damage to the anal sphincter muscle. This study investigated defecation function after a laparo-assisted restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA). We also clarified factors that worsened defecation status. Methods: This retrospective study included 57 patients who underwent laparo-assisted RPC with IPAA for UC from January 2000 to May 2019. At 1 year after surgery, functional outcomes were evaluated with the Kirwan classification and Wexner score. Risk factors for poor defecation status were investigated with multiple regression. Results: At 1 year after surgery, the median Kirwan classification score was 2 and the median Wexner score was 8. Defecation disorder was observed in 19 (33.3%) patients, according to the Kirwan classification, and 15 (26.3%) patients, according to the Wexner score. Hand-sewn IPAA was associated with defecation disorder (P = .04), evaluated with the Kirwan classification. Hand-sewn IPAA (P = .01), older age (P = .03), high body mass index (P = .04), and the surgical indication (cancer/dysplasia; P = .03) were significantly associated with defecation disorder, evaluated with the Wexner score. The multivariable analysis showed that hand-sewn IPAA was an independent risk factor (P = .049; odds ratio: 4.99; 95% confidence interval: 1.0-28.39). Conclusions: We found that hand-sewn IPAA was a risk factor for defecation disorders after laparo-assisted RPC for UC.

An oncologic emergency case of massive dedifferentiated liposarcoma of the small bowel mesentery.

We report the case of a 71-year-old man who complained of abdominal distension, pedal edema, respiratory discomfort, and weight gain. Computed tomography revealed a giant, poorly enhancing tumor occupying the entire abdomen, with abdominal ascites. The tumor was causing hydronephrosis, compression of the inferior vena cava, and elevation of the diaphragm. The patient exhibited deterioration of performance status (PS3 on the ECOG scale) and required oxygen; therefore, emergency surgery was performed. Operative findings included bloody abdominal ascites and peritoneal dissemination. The large tumor arose from the small bowel mesentery, and infiltrated into the cecum and sigmoid colon. Tumor excision with ileocecal resection and sigmoidectomy was performed. Histopathological examination revealed dedifferentiated liposarcoma. The patient was discharged on postoperative day 22, but pre-discharge CT revealed a recurrent liposarcoma in the retroperitoneum. Therefore, chemotherapy was initiated and the treatment has been continued for over 6 months after surgery. Due to the rarity of this disease, there is no consensus regarding treatment strategies for DDLPS with peritoneal dissemination or in patients with a poor general condition, especially in the setting of oncologic emergency. In this case, multimodal treatment was used to successfully manage this life-threatening state and obtain satisfactory therapeutic results.

Neutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: a retrospective study.

PURPOSE: Trifluridine/tipiracil (FTD/TPI) improves the overall survival (OS) of metastatic colorectal cancer (mCRC) patients. Additionally, FTD/TPI plus bevacizumab (BEV) has demonstrated promising efficacy for mCRC patients who are refractory to standard chemotherapy. Chemotherapy-induced neutropenia (CIN) has been reported to be an indicator of efficacy for FTD/TPI. This study investigated whether CIN was an indicator of efficacy for FTD/TPI plus BEV. METHODS: We reviewed chemo-refractory mCRC patients who were treated with FTD/TPI alone (monotherapy) or FTD/TPI plus BEV (combination) at our institution and compared the safety and efficacy of the two. Progression-free survival (PFS) and OS were analyzed using Kaplan-Meier curves. We also investigated correlations between CIN and outcomes. RESULTS: In total, 56 patients received FTD/TPI, among whom 24 and 32 were treated with monotherapy and combination therapy, respectively. The median PFS was 1.8 and 4.7 months for the monotherapy and combination arms, respectively (hazard ratio [HR]: 0.28; 95% confidence interval [CI]: 0.15-0.51; P < 0.001). The median OS was 6.3 and 11.7 months for the monotherapy and combination arms, respectively (HR 0.25; 95% CI 0.13-0.48; P < 0.001). CIN (Grade 3 or worse) developed in five (20.8%) and 17 (53.1%) patients from the monotherapy and combination arms, respectively (P = 0.030). Patients with CIN in the combination arm had improved PFS and OS compared with non-CIN patients (P = 0.033 and P = 0.045, respectively). CONCLUSIONS: FTD/TPI plus BEV prolonged PFS and OS and had tolerable toxicity compared with FTD/TPI alone. CIN is an indicator of patients who will benefit from FTD/TPI plus BEV.

[A Case of Robot-Assisted Abdominoperineal Resection for Local Control for Lower Rectal Cancer with Synchronous Liver and Lung Metastases].

The patient was a 70s woman who was referred to our hospital with a complaint of bloody stool. Colonoscopy revealed type 2 tumor at a distance of 1 cm from the dentate line, without obstruction. The pathological diagnosis was adenocarcinoma. Enhanced CT revealed a tumor at the rectum below peritoneal reflection as well as swelling of the mesorectal lymph nodes. Multiple liver and lung metastases were also observed. The diagnosis was lower rectal cancer cT4aN2M1b(H2, PUL2), cStage Ⅳ. Chemotherapy was performed for disease control because of unresectable metastases. She received 7 courses of mFOLFOX plus bevacizumab. Further, as the metastatic lesion was inhibited, the primary lesion was excised for the purpose of symptom control. We judged that sphincter preservation was impossible because it was 1 cm away from the dentate line. She underwent robot-assisted abdominoperineal resection with D3 lymphadenectomy and sigmoid colostomy.

[A Case of Stage â £ Breast Cancer Treated with Mastectomy after Spontaneous Removal of a Cosmetic Breast Implant].

A 51-year-oldwoman came to our hospital complaining of a skin ulcer in the left breast. She hadpreviously undergone cosmetic breast augmentation by placement of a bag prosthesis under each mammary gland. She was diagnosed with Stage Ⅳ(T4bN1M1)breast cancer with multiple bone metastases. Following the diagnosis, 3 regimens of hormonal therapy were sequentially administered. The treatment was then switched to chemotherapy following confirmation of tumor progression in the left breast tumor. After 3 cycles of paclitaxel andbevacizumab as the second-line of chemotherapy, the size of the left breast tumor was remarkably reduced. Mastectomy with axillary lymph node sampling and removal of the implant were scheduled for local control. However, due to gradual exposure of the implant under the left breast, it was spontaneously removedfrom the original position when the patient was waiting for the surgery. Therefore, only mastectomy with axillary lymph node sampling was performed, followed by 45 Gy/25 times of postmastectomy and locoregional lymph node irradiation. Six months after the surgery, the patient is alive with no signs of local recurrence.

[A Resected Case of Hepatocellular Carcinoma Recurrence with Bile Duct Tumor Thrombus after RFA].

Hepatocellular carcinoma with bile duct invasion is rare, with a reported incidence of 3.4%. A 71-year-old man with hepatocellular carcinoma underwent radiofrequency ablation(RFA)(S6, S7, S8)and required readmission 22 months after the RFA for hepatocellular carcinoma recurrence detected by gadoxetic acid-enhanced magnetic resonance imaging. Enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography revealed a tumor thrombus in a biliary branch and left adrenal gland metastases. We performed a right lobectomy and left adrenalectomy. The biliary thrombus was easily removed. Postoperative histopathological examination of the resected specimen showed a moderately differentiated hepatocellular carcinoma invading the biliary tract and the absence of viable cells in the liver tumor. The patient has shown no recurrence 6 months after the hepatectomy.

[Long-Term Survival in a Patient with Stage â £ Gastric Cancer Successfully Treated with Multidisplinary Treatment].

A man in his 60s who had epigastric pain was referred to our hospital and diagnosed with advanced type 3 gastric cancer with multiple liver metastases, cT4acN2cN1(H1), cStage Ⅳ(HER2 3+). He underwent chemotherapy using capecitabine, cisplatin(CDDP), and trastuzumab(T-mab)(XPT). After 7 courses of XPT and 23 courses of XT, liver metastases disappeared, and we decided to perform open distal gastrectomy, D2+ #18 lymphadenectomy, and Billroth Ⅰ reconstruction as a conversion surgery. Despite adjuvant chemotherapy with S-1 plus T-mab, multiple lymph nodes recurrence occurred 3 months after the surgery. He was found to be in complete remission as assessed by CT after 5 courses of second-line CPT-11 treatment, which was discontinued after 17 courses. The patient is alive without recurrence at 57 months after the initial treatment and 22 months after the last treatment.

[A Case of Leiomyosarcoma of the Sigmoidal Mesocolon].

Leiomyosarcoma of the mesocolon is a very rare disease. Previously, there was no recommendation for chemotherapy or radiotherapy for leiomyosarcoma of the mesocolon, and only surgical resection reportedly offers a chance for cure. However, the reported cases of leiomyosarcoma of the mesocolon were not distinguished from those of gastrointestinal stromal tumor (GIST), which is the same mesenchymal tumor; thus, there is a possibility that they include cases that should be diagnosed as GIST. We report a case of leiomyosarcoma of the sigmoidal mesocolon.

[Sustained Complete Response of Hepatocellular Carcinoma with Multiple Intrahepatic Metastases following the Discontinuation of Sorafenib].

Sorafenib is an oral multi-targeted tyrosine kinase inhibitor used in cases of unresectable advanced HCC that significantly improves progression-free and overall survival. Complete response(CR)is uncommon; however, if major or complete radiological response are obtained, the issue of the discontinuation of sorafenib remains unresolved. The present study reported a case of a 75-year-old man with non-hepatitis B and C virus-related cirrhosis and multiple recurrent HCCs followingresection. In December 2010, a CT scan revealed multiple intrahepatic recurrence after TACE. Laboratory testingshowed Child-Pugh class A cirrhosis and an alpha-fetoprotein level of over 20,000 ng/mL. Sorafenib(800mg/day)was started in December 2010. The subsequent dynamic CT performed at the 6th month of therapy showed a partial response accordingto RECIST criteria and a complete response accordingto mRECIST. The AFP had decreased to within normal levels. In May 2012, the sorafenib dose was reduced(200 mgtwice daily)due to side effects(skin reaction). In December 2013, treatment was stopped after confirmation of a CR associated with shrinkage of the HCC. The patient maintained this remission until June 2018, more than 54 months after the discontinuation of sorafenib therapy. The adverse events of sorafenib were reversible. Further reportingof similar cases should help in the design of treatment strategies after CR to sorafenib therapy.

[A Resected Case of Tumorigenic Pancreatic Endocrine Cell Hyperplasia].

A 51-year-old man with a gallstone was found to have a tumor in the tail of the pancreas during preoperative examination. We performed EUS-FNA and a pancreatic neuroendocrine tumor was suspected.Therefore, laparoscopic distal pancreatectomy and cholecystectomy were performed.Pathological examination and immunohistochemistry showed that the pancreatic endocrine cells were uniformly increased and were composed of normal Langerhans islets.Therefore, the patient was diagnosed with pancreatic endocrine cell hyperplasia.Typical pancreatic endocrine cell hyperplasia does not form a tumor and is asymptomatic.However, some cases are symptomatic; therefore, when hypoglycemia or pancreatic hormone elevation are found without a clear cause, it should be distinguished.Because pancreatic tumors are difficult to diagnose definitely by imaging inspection alone, needle biopsy is necessary.However, neuroendocrine tumor and neuroendocrine cell hyperplasia are difficult to differentiate by biopsy.

[A Case of Strangulating Intestinal Obstruction Caused by Coiling of Low-Grade Appendiceal Mucinous Neoplasm to Terminal Ileum].

The patient was a 67-year-old female without a history of surgery. She presented with an abdominal pain and vomiting, and was rushed to our hospital. The abdominal pain was severe, but no peritoneal irritation sign was observed. Abdominal CT scan revealed a strangulating intestinal obstruction and accumulation of ascitic fluid. Emergency surgery was performed for diagnosis and treatment. The intraoperative finding showed serous ascitic fluid and strangulating intestinal obstruction caused by appendiceal tumor coiling around the terminal ileum, which had become ischemic with thinning of its wall. Ileocecal resection with removal of lymph nodes(D3)was performed. The postoperative course was uneventful, and the patient was discharged 13 days after the surgery. Pathological examination of the appendiceal tumor revealed a low-grade appendiceal mucinous neoplasm(LAMN)with no metastasis to the lymph nodes. We had a rare case of strangulating intestinal obstruction caused by coiling of LAMN to the terminal ileum.

[Problems of Home-Visiting Speech-Language-Hearing Therapists in Dysphagia Management].

There are fewer reports by speech-language-hearing therapists than those by physical therapists or occupational therapists for visiting rehabilitation. Therefore, we examined the present situation with emphasis on professional roles of speech-language- hearing therapists working in visiting rehabilitation, patient tendency, and dysphagia rehabilitation. A questionnaire survey and interview survey were conducted on 6 speech-language-hearing therapists working in visiting rehabilitation. In the questionnaire, personal attributes, subject area, details of dysphagia rehabilitation, professional duties, and tendency of patient in charge were collected. In the interview survey, we asked about trends and request status, evaluation and training protocol for patients with dysphagia, activities related to pneumonia prevention, and future directions in the field. Results show that many linguistichearing experts worked with dysphagia patients, indicating that the needs for respiratory rehabilitation and dysphagia rehabilitation are high. In this survey, the environment surrounding visiting speech-language-hearing therapists and patients with dysphagia was clarified.

[A Case of Rectal Cancer with Multiple Endocrine Neoplasia Type 2].

A 63-year-old man with multiple endocrine neoplasia type 2(MEN2)was admitted to the hospital because of positive fecal occult blood tests. Colonoscopy revealed a 50mm type 2 tumor at the rectum, which was diagnosed as an adenocarcinoma based on histology. Since there was no apparent distant metastasis, laparoscopy-assisted low anterior resection with regional lymph node dissection was performed. The final diagnosis was pT3, pN0, pM0, pStage II . Almost all patients with MEN2 have RET mutations, and they are resistant to EGFR inhibitors. Those who have thyroid cancer with RET mutations are often given a RET kinase inhibitor. In this case, if the patient develops recurrent rectal cancer, it warrants checking for RET mutations and using a multi-kinase inhibitor.