A Case of Gallbladder Cancer with Trousseau Syndrome Successfully Treated Using Radical Resection.

Trousseau syndrome is characterized by cancer-associated systemic thrombosis. We describe the first case of a successfully treated gallbladder adenocarcinoma accompanied by Trousseau syndrome. A 66-year-old woman presented with right hemiplegia. Magnetic resonance imaging identified multiple cerebral infarctions. Her serum carbohydrate antigen 19-9 and D-dimer levels were markedly elevated, and a gallbladder tumor was detected via abdominal computed tomography. Venous ultrasonography of the lower limbs revealed a deep venous thrombus in the right peroneal vein. These findings suggested that the brain infarctions were likely caused by Trousseau syndrome associated with her gallbladder cancer. Radical resection of the gallbladder tumor was performed. The resected gallbladder was filled with mucus and was pathologically diagnosed as an adenocarcinoma. Her postoperative course was uneventful, and she received a one-year course of adjuvant therapy with oral S-1. No cancer recurrence or thrombosis was noted 26 months postoperatively. Despite concurrent Trousseau syndrome, a radical cure of the primary tumor and thrombosis could be achieved with the appropriate treatment.

A Case Report of Neoadjuvant Gemcitabine Plus Cisplatin for Locally Advanced Unresectable Ampulla of Vater Carcinoma.

INTRODUCTION: Ampulla of Vater carcinoma (AVC) with para-aortic node (PAN) metastasis is considered unresectable and is equivalent to distant metastasis, contributing to poor outcomes. CASE PRESENTATION: A 60-year-old man was referred to our hospital and was diagnosed with an unresectable ampulla of Vater carcinoma that had metastasized to the para-aortic nodes. The patient received a systemic chemotherapy regimen comprising a combination of gemcitabine and cisplatin. Following five cycles of treatment, imaging studies revealed a significant reduction in the primary tumor and para-aortic node metastasis, rendering detection difficult. Pancreatoduodenectomy with para-aortic node dissection was performed as a radical surgery. Upon pathological examination, no residual tumors were identified in the resected specimen, indicating that the systemic chemotherapy achieved a complete pathological response. The postoperative course of the patient was uneventful, and he was discharged on the 25th postoperative day. The patient was followed up as an outpatient and remained stable without any recurrence for two months after surgery. CONCLUSION: Neoadjuvant chemotherapy with gemcitabine and cisplatin was useful for downstaging the ampulla in patients with Vater carcinoma. This finding may help physicians manage patients with similar presentations.

Preoperative percent body fat in bioelectrical impedance analysis predicts pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: It is unclear which body composition affects postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy. In the present study, we evaluated the relationship between nutritional factors, body composition, and POPF. METHODS: This was a prospective observational cohort study. Patients who underwent pancreaticoduodenectomy between March 2018 and July 2021 were included in this study. Preoperative body composition was measured using a bioelectrical impedance analyzer. In addition, the predictive factors for POPF were analyzed using logistic regression model. RESULTS: The study included 143 patients. Among these patients, 31 had POPF (POPF group) and 112 did not (non-POPF group) after pancreaticoduodenectomy. For body composition, the percent body fat was significantly higher in the POPF group (26.90 vs 23.48, P = 0.022). Multivariate analysis revealed that alcohol consumption (odds ratio 2.95, P = 0.03), pancreatic duct < 3 mm (odds ratio 3.89, P < 0.01), and percent body fat (odds ratio 1.08, P = 0.01) were significantly independent predictive factors for POPF. When the patients were divided into three groups based on their percent body fat (< 25, 25-35, and ≥ 35), POPF occurred more frequently in the group with ≥ 35 percent body fat (47.1%) than in the < 25 group (15.5%) (P = 0.008). CONCLUSION: Predictive factors for POPF related to nutritional status, such as percent body fat, should be considered before proceeding to pancreaticoduodenectomy (ClinicalTrials.gov trial registration no. NCT5257434).

Favorable Outcome of Repeated Salvage Surgeries for Rare Metastasis to the Ligamentum Teres Hepatis and the Upper Abdominal Wall in a Stage IV Gastric Cancer Patient.

Gastric cancer with peritoneal metastases is typically a devastating diagnosis. Ligamentum teres hepatis (LTH) metastasis is an extremely rare presentation with only four known cases. Herein, we report salvage surgery of successive metastases to the abdominal wall and LTH in a patient originally presenting with advanced gastric cancer with peritoneal metastasis, leading to long-term survival. A 72-year-old man with advanced gastric cancer underwent curative-intent distal gastrectomy with D2 lymph node dissection for gastric outlet obstruction. During this procedure, three small peritoneal metastases were detected in the lesser omentum, the small mesentery, and the mesocolon; however, intraoperative abdominal lavage cytology was negative. We added cytoreductive surgery for peritoneal metastasis. The pathological diagnosis of the gastric cancer was tubular adenocarcinoma with pT4aN1pM1(PER/P1b)CY0 stage IV (Japanese classification of gastric carcinoma/JCGC 15th), or T4N1M1b stage IV (UICC 7th). Post-operative adjuvant chemotherapy with S-1 (TS-1)+cisplatin (CDDP) was administered for 8 months followed by S-1 monotherapy for 4 months. At 28 months after the initial surgery, a follow-up computed tomography (CT) detected a small mass beneath the upper abdominal wall. The ass showed mild avidity on 18F-fluorodeoxyglucose positron-emission (FDG-PET) CT. Salvage resection was performed for diagnosis and treatment, and pathological findings were consistent with primary gastric cancer metastasis. At 49 months after the initial gastrectomy, a new lesion was detected in the LTH with a similar level of avidity on FDG-PET CT as the abdominal wall metastatic lesion. We performed a second salvage surgery for the LTH tumor, which also showed pathology of gastric cancer metastasis. There has been no recurrence up to 1 year after the LTH surgery. With multidisciplinary treatment the patient has survived almost 5 years after the initial gastrectomy. Curative-intent gastrectomy with cytoreductive surgery followed by adjuvant chemotherapy for advanced gastric cancer with localized peritoneal metastasis might have had a survival benefit in our patient. Successive salvage surgeries for oligometastatic lesions in the abdominal wall and the LTH also yielded favorable outcomes.

Hydrophobicity of the Pentafluorosulfanyl Group in Side Chains of Polymethacrylates by Evaluation with Surface Free Energy and Neutron Reflectivity.

A hydrophobic surface or coating is required for surface protection, anti-fouling, adhesion, and other applications. For the achievements of hydrophobic properties, fluorine-based coatings, such as the introduction of trifluoromethyl or difluoromethylene groups, are conventionally employed. Recent developments in synthetic chemistry have indicated other organic fluoroalkyl groups that are suitable for achieving a more hydrophobic surface. In this study, we focused on the hydrophobic properties of the pentafluorosulfanyl (-SF5) group. We synthesized polymethacrylates with -SF5 groups or other functional groups (-CF3, -CH3, and -H) in their side chains and evaluated their hydrophobicity based on contact angles of water and ethylene glycol and the affinities of their films to water through neutron reflectivity measurements to demonstrate the superior hydrophobic properties of the -SF5 group. The water contact angle on the polymethacrylate film with -SF5 groups was larger, which suggested that the surface free energy was lower than that of the other polymethacrylate thin films with pendant side chains of -CF3, -CH3, and -H. In addition, the fitting analyses of the neutron reflectivity profiles of the thin polymer films in contact with air and water revealed the lowest affinity between water and the surface of polymethacrylate films with -SF5 groups among the films of the synthesized polymers. Thus, we demonstrated the potential of pentafluorosulfanyl groups as advanced hydrophobic groups.

Reconsideration of indications for third hepatectomy for colorectal liver metastases.

BACKGROUND: It is unclear which patients with recurrence after a second hepatectomy will benefit from a third hepatectomy. METHODS: Patients who underwent hepatectomy for colorectal liver metastasis (CRLM) between April 2005 and July 2021 were included. Factors affecting recurrence after each hepatectomy were analyzed. RESULTS: Sixty-four of the 167 patients who had recurrence after the first hepatectomy underwent a second hepatectomy. Then, 46 patients had recurrence and 18 patients did not have recurrence after the second hepatectomy. Sixteen patients who underwent a third hepatectomy had better overall survival (OS) than those who did not (52 vs. 31 months, p = 0.043). However, the multivariate analysis demonstrated that only tumor size (>5 cm) during the second hepatectomy (p = 0.022) and carbohydrate antigen 19-9 (CA 19-9) level (>50 U/ml) (p = 0.041) at recurrence after the second hepatectomy were poor prognostic factors for OS. CONCLUSION: While a third hepatectomy can be performed if it is technically and oncologically appropriate, tumor size >5 cm and CA 19-9 >50 U/ml should be considered in terms of long-term outcomes before proceeding to surgery.

Clinicopathological Features and Surgical Outcomes of Small Bowel Metastasis from Renal Cell Carcinoma.

Small bowel metastasis from renal cell carcinoma (RCC) is rare, and its clinicopathological characteristics are unclear; thus, we revisited the concept of this tumor and reviewed its diagnostic and treatment modalities. We filtered MEDLINE searches of articles published in English between 1950 and 2019, and identified 100 patients who had undergone treatment, including 1 patient from our clinic. We extracted patient characteristics, treatment, and prognostic data, resulting in clinicopathological data on 100 patients (83 men, 17 women). Mean age was 63 years (range, 16-86 years). Tumor sites were duodenum, jejunum, ileum, and multiple sites in 30, 37, 25, and 7 patients, respectively. The 1-, 3-, and 5-year overall survival rates after diagnosis were 53.0%, 36.0%, and 36.0%. Curative resection patients showed 62.1% 5-year survival after surgery, vs. 27.5% in noncurative surgical management cases. Good prognoses can be expected if these tumors are identified early for complete removal. Surgery is the only curative option. To determine the best management strategy and improve prognostic accuracy, we continue to collect and analyze epidemiological and pathological data. Although this condition is rare, surgery should be considered if curative resection is expected. Prognosis after curative resection is not poor, but recurrence is not unlikely.

A proposal to modify the 8th edition of the UICC staging system for pancreatic adenocarcinoma.

PURPOSE: The aim of this study was to validate and improve the 8th edition of the Union for International Cancer Control (UICC) staging system for pancreatic ductal adenocarcinoma (PDAC). METHODS: Prognostic impact of the pathological tumor (pT) and lymph node (pN) stages between the 7th and 8th editions were compared using a single-center cohort of 311 patients who underwent curative pancreatic resection for PDAC. RESULTS: Applying the 7th edition T staging system resulted in a clustering of pT3 cases (92.3%) and failed to show significant prognostic differences between the three pT stages. However, applying the 8th edition T staging system yielded a more even distribution and resulted in an excellent prognostic separation between the pT stages based on decreases in median survival (month [pT1: 69.4, pT2: 27.6, pT3: 16.7], p=0.001). In pN staging system, the 8th edition provided more precise prognostication in median survival (month [pN0: 41.7, pN1: 25.6, pN2: 14.4], p<0.001). Moreover, in the 8th edition pT2 category, patients with portal vein invasion (PVI) showed significantly worse survival than those without PVI (median survival months [without PVI: 38.2, with PVI: 17.1], p<0.001). CONCLUSIONS: The 8th edition provides a more even distribution among stages and better stage discriminations compared to the 7th edition. The 8th edition pT2 category should be subdivided according to PVI status of the patient to allow for more precise patient prognostication.

Laparoscopic Synchronous Resection for Descending Colon Cancer and Tailgut Cyst.

A 67-year-old woman underwent polypectomy for a tumor at the descending colon. Pathologically, the tumor was diagnosed as adenocarcinoma with an invasion of 2000 µm. Computed tomography showed a swollen paracolic lymph node and a mass lesion in the presacral space. Magnetic resonance imaging revealed a multio-cular cystic lesion. On diagnosis of descending colon cancer and tailgut cyst, she underwent synchronous lapa-roscopic resection. Histopathologically, the colon cancer was diagnosed as pT1bN1M0, pStage IIIa. The pre-sacral cystic lesion was diagnosed as a nonmalignant tailgut cyst with negative surgical margin. The patient is currently doing well without recurrence at 28 months.

[Successful Resection Using a Posterior Approach of a Tailgut Cyst in the Retrorectal Space].

We present the case of a Tailgut cyst occurring in the retrorectal space that was curatively resected using a posterior approach. A 40-year-old man presented to the Kochi Health Sciences Center with the chief complaint of perineal incongruity. Pelvic magnetic resonance imaging revealed a multilocular cystic lesion in the retrorectal space, with high signal intensity on T2-weighted imaging. After diagnosing a Tailgut cyst, we performed resection of the tumor using a posterior approach. The lesion was removed en bloc with the coccyx. Histopathologically, the lesion was diagnosed as a non-malignant Tailgut cyst, and the surgical margin was negative. The patient is currently doing well without recurrence at 20 months.

[Measurement of PODXL and SCGB1D2 for detecting intraductal papillary mucinous neoplasm].

We determined whether PODXL and SCGB1D2 expressions in whole blood could be useful as diagnostic biomarkers to determine the presence of intraductal papillary mucinous neoplasm (IPMN), as compared to serum CA19-9. A discovery-stage clinical study was performed on 12 patients with IPMN, including 6 intraductal papillary mucinous adenoma (IPMA) patients and 6 intraductal papillary mucinous carcinoma (IPMC) patients who had undergone treatment at the Department of Surgery at Kochi Health Sciences Center and the Department of Gastroenterology and Hepatology at Kochi Medical School Hospital from April 2015 to January 2016;13 controls who did not have pancreatic disease were also enrolled. Serum PODXL and SCGB1D2 levels were measured using ELISA. We found that the area under the receiver-operating characteristic curve (AUC) for IPMN (IPMA+IPMC) diagnosis in IPMN patients and control individuals was 0.89 (95% CI:0.76-1) for PODXL, 0.50 (95% CI:0.25-0.74) for SCGB1D2, and 0.81 (95% CI:0.62-1) for CA19-9. Multivariable logistic regression analysis showed that PODXL was independently able to distinguish IPMN patients from controls. PODXL may be a novel, non-invasive diagnostic biomarker for the detection of IPMN. The AUC for distinguishing IPMC patients from IPMA patients was 0.78 (95% CI:0.47-1) for PODXL, 0.83 (95% CI:0.58-1) for SCGB1D2, and 0.58 (95% CI:0.22-0.95) for CA19-9. Although it was quantitatively demonstrated that the detection of PODXL and SCGB1D2 in the serum may provide a novel, non-invasive approach for distinguishing IPMC patients from IPMA patients, the present findings are preliminary until more elaborate studies are able to clarify whether PODXL and SCGB1D2 are useful as diagnostic markers for IPMC detection.

Feasibility of preserving the remnant stomach during distal pancreatectomy after distal gastrectomy.

PURPOSE: The safety and feasibility of preserving the remnant stomach during distal pancreatectomy (DP) in patients who have undergone distal gastrectomy (DG) remains unclear. METHODS: A retrospective review of a prospectively maintained database was performed to identify patients who underwent DP. A propensity score-matched analysis was performed to match post-DG patients with control patients. RESULTS: Among the 226 patients included in this study, 9 DP patients who had a history of DG were studied (4.0%). These nine patients in the DG group were matched to 45 patients in the control group. There were no significant differences in the incidence of postoperative morbidities, including postoperative pancreatic fistula rate or stomach-related complications. The hemoglobin A1C (HbA1c) levels in the DG group after surgery decreased to the normal range. CONCLUSION: Our study suggested that the remnant stomach may be safely preserved when performing DP in patients with a history of DG with respect to short-term morbidities. However, there are some concerns about the long-term nutritional status in patients with a history of DG.

Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone.

The transcription factor Hes family basic helix-loop-helix transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like π-electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression. This screening identified a lead compound whose extensive chemical modification to improve potency yielded JI051, which inhibited HEK293 cell proliferation with an EC50 of 0.3 µm Unexpectedly, using immunomagnetic isolation and nanoscale LC-MS/MS, we found that JI051 does not bind TLE1 but instead interacts with prohibitin 2 (PHB2), a cancer-associated protein chaperone. We also found that JI051 stabilizes PHB2's interaction with Hes1 outside the nucleus, inducing G2/M cell-cycle arrest. Of note, JI051 dose-dependently reduced cell growth of the human pancreatic cancer cell line MIA PaCa-2, and JI130 treatment significantly reduced tumor volume in a murine pancreatic tumor xenograft model. These results suggest a previously unrecognized role for PHB2 in the regulation of Hes1 and may inform potential strategies for managing pancreatic cancer.

Clinicopathologic Features and Surgical Outcomes of Neuroendocrine Carcinoma of the Gallbladder.

Neuroendocrine carcinoma (NEC) of the gallbladder is highly aggressive and has a poor prognosis even after curative resection. The purpose of this study was to collate and analyze published data to clarify the surgical outcome of NEC of the gallbladder and the relationships between potential prognostic factors and survival after surgery. We surveyed worldwide literature from 1981 to 2018 and obtained clinicopathological data for 65 patients who had undergone surgical resection for NEC of the gallbladder. The relationships between potential prognostic factors and survival rates were examined by the Kaplan-Meier method and the log-rank test. The 1-, 3-, and 5-year disease-specific survival rates after surgery were 70.2%, 39.3%, and 29.5%, respectively. A multivariate analysis revealed that the factors that were independently associated with poor outcomes after surgery in patients with NEC of the gallbladder were older age, higher pathologic T stage, and positive lymph node metastasis. The major sites of recurrence were the liver, lung, lymph node, and local recurrence. The median time to the event for recurrence was 4.0 months. Even when curative resection was achieved, 36.9% of patients exhibited recurrence within 12 months after curative resection of gallbladder NEC. Although NEC of the gallbladder remains a rare disease worldwide, its poor prognosis, even after curative resection, demands further epidemiological and pathological studies that could lead to the development of new management strategies.

Effect of Neoadjuvant Chemotherapy in Patients with Colorectal Cancer Liver Metastases.

BACKGROUND: This study was performed to evaluate the relationships between potential prognostic factors and post-surgery survival in patients with colorectal cancer liver metastasis (CRLM). In particular, this study investigated the value of neoadjuvant chemotherapy as an independent predictor of cancer-specific survival. METHODS: The study participants included 147 patients who underwent resection for CRLM. Demographics, treatments, and relationships between potential prognostic factors and the survival rate were analyzed using a prospective database. RESULTS: The overall 1-, 3- and 5-year cancer-specific survival rates for post-surgery CRLM patients were 94.3%, 71.2%, and 53.5%, respectively. Multivariate analysis revealed that a positive surgical margin and extrahepatic metastasis were independent negative prognostic factors. The administration of neoadjuvant chemotherapy prior to liver surgery did not significantly improve post-surgery outcomes of patients with CRLM. In a subgroup analysis, the time to recurrence in the remnant liver after hepatectomy for CRLM was significantly less in the neoadjuvant group than in the upfront surgery group. CONCLUSIONS: Neoadjuvant chemotherapy was not predictive of cancer-specific survival. The achievement of macroscopically and microscopically negative resection remains the main aim of surgery.

A Novel Physiobiological Parameter-Based Grading System for Resectable Pancreatic Cancer.

BACKGROUND: Preoperative methods to estimate disease-specific survival (DSS) for resectable pancreatic cancer are limited. OBJECTIVE: The aim of this study was to develop and validate a pretreatment physiobiological prognostic model in patients with radiologically resectable pancreatic cancer. METHODS: A retrospective review of a prospectively maintained institutional database was undertaken to identify patients who underwent potentially curative resection for radiologically resectable pancreatic cancer. Demographics, treatments, and relationships between the potential prognostic factors and survival rate were analyzed, and prognostic nomograms were established. RESULTS: We identified 240 patients who fulfilled our eligible criteria. The 1-, 3-, and 5-year DSS rates after surgery were 77.8, 40.9, and 31.3%, respectively. On multivariate analysis, increased neutrophil/lymphocyte ratio [hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.17-2.17; p < 0.01], reduced Prognostic Nutritional Index (HR 2.08, 95% CI 1.68-3.20; p < 0.01), and elevated preoperative serum carbohydrate antigen 19-9 level (HR 2.12, 95% CI 1.55-2.88; p < 0.01) were associated with worse DSS. Although curative resection was the operative aim for all patients, 131 (54.6%) patients had recurrence within 12 months after curative resection of resectable pancreatic cancer. There was a significant correlation between recurrence pattern and physiobiological characteristics. CONCLUSION: We developed a new grading system for radiologically resectable pancreatic cancer. This system is simple and reliably predicts differences in survival after pancreatic resection.

Chemoradiotherapy for Initially Unresectable Locally Advanced Cholangiocarcinoma.

OBJECTIVE: Surgical resection is the only available treatment for achieving long-term survival in cholangiocarcinoma. The purpose of this study is to elucidate the utility of chemoradiotherapy for initially unresectable locally advanced cholangiocarcinoma. METHODS: Unresectable locally advanced cholangiocarcinoma was defined as those in which radical surgery could not be achieved even with aggressive surgical procedure. Fifteen candidates (7 intrahepatic cholangiocarcinomas and 8 hilar cholangiocarcinomas) underwent chemoradiotherapy. Fourteen of the 15 patients received oral S-1 chemotherapy. Radiotherapy was administered with 50 Gy for each patient. After chemoradiotherapy, the resectability of each cholangiocarcinoma was reexamined. RESULTS: Of the 15 patients with initially unresectable locally advanced cholangiocarcinoma, 11 (73.3%) were judged to have resectable cholangiocarcinoma after chemoradiotherapy, and received radical hepatectomy (R0 resection in 9 patients). Among the 11 patients who underwent surgical resection, 4 had recurrence-free survival and the median survival time (MST) was 37 months. The overall 1-, 2-, and 5-year survival rates were 80.8, 70.7 and 23.6%, respectively. Among the 4 patients who were unable to receive surgery, 3 died of the primary disease and the MST was 10 months. The overall 1- and 2-year survival rates were 37.5 and 0%, respectively. Patients who received radical surgery had significantly longer survival time than those who were unable to receive surgery (p = 0.027). CONCLUSIONS: Chemoradiotherapy allowed patients with initially unresectable locally advanced cholangiocarcinomas to be reclassified as surgical candidates in a substantial proportion. Chemoradiotherapy might be one of the treatment options for similarly advanced cholangiocarcinomas.

Correlation between the skeletal muscle index and surgical outcomes of pancreaticoduodenectomy.

PURPOSES: Sarcopenia is known to be associated with a worse prognosis following abdominal operations; however, the relationship between sarcopenia and the outcomes of pancreaticoduodenectomy remains unclear. MATERIALS: We measured body composition parameters, including total abdominal muscle area, using preoperative staging computed tomography (CT), in patients undergoing pancreaticoduodenectomy for periampullary cancer. The incidence of sarcopenia among these patients was evaluated and multivariable analysis was performed to identify independent predictors of postoperative pancreatic fistula. RESULTS: We identified 335 consecutive patients who were eligible for the study. Patients with sarcopenia had significantly poorer 5-year survival rates than those without sarcopenia (32.4 vs. 51.6%, respectively, P = 0.009). Interestingly, the incidence of Grade B/C pancreatic fistula was significantly lower in the sarcopenia group than in the non-sarcopenia group. Multivariate analysis identified high body mass index and soft pancreatic texture as independent predictors of postoperative pancreatic fistula. CONCLUSION: Sarcopenia may have an independent prognostic effect on the survival of patients with periampullary cancer. Preoperative nutritional intervention and rehabilitation may improve the postoperative outcomes of pancreaticoduodenectomy for periampullary cancer.

A Surgical Case of Inferior Mesenteric Arteriovenous Malformation.

The treatment option for inferior mesenteric arteriovenous malformations is under debate because of the number of cases. We, herein, report about a 35-year-old man with congenital inferior mesenteric artery malformation (AVM) presenting with mucous stool and severe abdominal pain. The radical operation, after building the diverting stoma, minimized the extent of the resection. This is the first reported case where surgical management was used to control severe symptoms induced by inferior mesenteric AVM.

TGFß regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate.

Clefting of the soft palate occurs as a congenital defect in humans and adversely affects the physiological function of the palate. However, the molecular and cellular mechanism of clefting of the soft palate remains unclear because few animal models exhibit an isolated cleft in the soft palate. Using three-dimensional microCT images and histological reconstruction, we found that loss of TGFß signaling in the palatal epithelium led to soft palate muscle defects in Tgfbr2(fl/fl);K14-Cre mice. Specifically, muscle mass was decreased in the soft palates of Tgfbr2 mutant mice, following defects in cell proliferation and differentiation. Gene expression of Dickkopf (Dkk1 and Dkk4), negative regulators of WNT-ß-catenin signaling, is upregulated in the soft palate of Tgfbr2(fl/fl);K14-Cre mice, and WNT-ß-catenin signaling is disrupted in the palatal mesenchyme. Importantly, blocking the function of DKK1 and DKK4 rescued the cell proliferation and differentiation defects in the soft palate of Tgfbr2(fl/fl);K14-Cre mice. Thus, our findings indicate that loss of TGFß signaling in epithelial cells compromises activation of WNT signaling and proper muscle development in the soft palate through tissue-tissue interactions, resulting in a cleft soft palate. This information has important implications for prevention and non-surgical correction of cleft soft palate.