Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC.

BACKGROUND: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. METHODS: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. RESULTS: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. CONCLUSIONS: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses. TRIAL REGISTRATION: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

BACKGROUND: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis. MATERIALS AND METHODS: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction. RESULTS: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction. CONCLUSION: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT02069093. IMPLICATIONS FOR PRACTICE: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.

Transplantation of dental pulp-derived cell sheets cultured on human amniotic membrane induced to differentiate into bone.

OBJECTIVE: The usefulness of the amniotic membrane as a cell culture substrate has led to its use in the development of dental pulp-derived cell sheets. We induced osteoblastic differentiation of dental pulp-derived cell sheets and conducted histological and immunological examinations in addition to imaging assessments for regeneration of bone defects. METHODS: Dental pulp cells were obtained by primary culture of the dental pulp tissue harvested from extracted wisdom teeth. These cells were maintained for three to four passages. Subsequently, the dental pulp cells were seeded onto an amniotic membrane to produce dental pulp-derived cell sheets. Following the induction of osteoblastic differentiation, the sheets were grafted into the subcutaneous tissue of the lower back and maxillary bone defect of a nude mouse. Histological and immunological examinations of both grafts were performed. RESULTS: Dental pulp-derived cell sheets cultured on an osteoblast differentiation-inducing medium demonstrated resemblance to dental pulp tissue and produced calcified tissue. Mineralization was maintained following grafting of the sheets. Regeneration of the maxillary bone defect was observed. CONCLUSION: Induction of osteoblastic differentiation of the dental pulp-derived cell sheets may be indicated for the regeneration of periodontal tissue.

Postoperative function following radical surgery in gastric and colorectal cancer patients over 80 years of age--an objection to "ageism".

PURPOSE: With rapid growth in the elderly population, the number of elderly cancer patients who should be offered life-prolonging radical surgery has been increasing. The aim of this report is to demonstrate the outcome of elective radical surgery for gastric or colorectal cancer patients 80 years of age or older, including the natural course of recovery of functional independence, in order to avoid the negative attitude held toward surgery that is due only to patients' high chronological age. METHODS: Physical condition, ADL, and QOL of 108 patients 80 years of age or older with gastric or colorectal cancer were evaluated preoperatively and at the 1st, 3rd, and 6th postoperative months. RESULTS: There were no operative deaths, and the morbidity rate was 27.9%. Only 6% of the patients showed a decrease in ADL at the 6th postoperative month. This decrease typically occurred following discharge from the hospital. Patient QOL showed recovery to an extent equal to or better than average preoperative scores. CONCLUSIONS: Of the patients who underwent elective surgery for gastric or colorectal cancer, only a few showed a protracted decline in ADL, and most exhibited better QOL after surgery. Surgical treatment should therefore be considered, whenever needed, for elderly patients 80 years of age or older with gastric or colorectal cancer.

Oral care and oral assessment guide in breast cancer patients receiving everolimus and exemestane: subanalysis of a randomized controlled trial (Oral Care-BC).

BACKGROUND: Oral mucositis is a clinically significant adverse event linked to cancer therapy; it reduces the quality of life of patients and may result in the discontinuation of treatment and a poorer prognosis. Based on level 3 evidence, the Mucositis Study Group of Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology recommend oral care for all patients receiving cancer chemotherapy and radiotherapy, although no data from large-scaled randomized controlled trials support the efficacy of oral care in preventing oral mucositis. Therefore, this randomized, controlled, multicenter, open-label, phase III study sought to determine whether professional oral care reduces oral mucositis in everolimus and exemestane-treated estrogen receptor-positive metastatic breast cancer patients. METHODS: Altogether, 169 patients were randomized into the professional oral care (n=82) and control (n=87) groups. The professional oral care group received oral health instruction, professional mechanical tooth and tongue cleaning, gargling with a benzethonium chloride mouthwash, and dexamethasone ointment when grade 1 mucositis manifested. The control group received oral health instruction and gargling. Eight weeks after the everolimus and exemestane administration, the oral status (Oral Assessment Guide criteria) and oral mucositis status (Common Terminology Criteria for Adverse Events functional and clinical examinations) were evaluated. RESULTS: The incidence of oral mucositis of any grade and grade 2 severe mucositis was significantly lower in the professional oral care group, based on the Common Terminology Criteria for Adverse Events functional and clinical examinations. The total Oral Assessment Guide score, total Oral Assessment Guide grade, and Oral Assessment Guide score of teeth/dentures and mucous membranes were significantly different between the two groups. The Oral Assessment Guide grade for swallow, lip, teeth/dentures, mucous membrane, tongue, and saliva significantly correlated to oral mucositis severity. CONCLUSIONS: Professional oral care may prevent oral mucositis and improve teeth/denture conditions in patients receiving everolimus and exemestane.

A case of intracystic papillary carcinoma accompanying widespread ductal carcinoma in situ.

A 39-year-old Japanese woman noticed a right breast tumor in July 2004. Mammography (MMG) demonstrated an oval tumor without calcification. Dynamic Magnetic Resonance Imaging (D-MRI) demonstrated a high-intensity mass on T2-weighted images, showing mild enhancement during the arterial phase and persistent enhancement during the arterial late phase. Core needle biopsy revealed papillary carcinoma suggestive of Intracystic Papillary Carcinoma (IPC). Auchincloss operation was performed following a partial mastectomy, as the surgical margin after partial mastectomy was positive for carcinoma. Histopathologic mapping of her right breast revealed wide and extensive intraductal spread of DCIS around the IPC. IPC was originally reported to be a localized non-invasive mammary carcinoma. But approximately, half of IPC cases are associated with invasive carcinoma or DCIS beyond the tumor. Careful selection of operative procedure is needed after localized non-invasive IPC or IPC associated with DCIS around the main tumor or invasive carcinoma is diagnosed.

Long-term survival of a patient with advanced gastric cancer with paraaortic lymph node metastasis who attained pathological complete response after S-1/CDDP chemotherapy: A case report.

INTRODUCTION: Gastric cancer with paraaortic lymph node (PAN) metastasis have unfavorable prognosis. There are no evidence-based preoperative chemotherapy regimens available. CASE PRESENTATION: A 62-year-old female was diagnosed with advanced gastric cancer and PAN metastasis. We attempted S-1/CDDP chemotherapy in six coursed and total gastrectomy as well as systematic dissection of regional lymph nodes and PAN. Histologically, no cancerous cells were detected in specimens. The patient has been disease-free for 5 years since the surgery. DISCUSSION: Long-term survival case of gastric cancer with PAN metastasis attaining pathologically complete response is extremely rare. It is possible that preoperative S1/CDDP with surgery might be a standard treatment strategy for gastric cancer with PANs. CONCLUSION: We report herein a rare case of gastric cancer with PAN metastases who achieved a 5-year survival after S-1/CDDP chemotherapy and surgery.

Poorly differentiated adenocarcinoma with signet-ring cells in duodenal papilla: a case report.

An 82-year-old woman with common bile duct (CBD) dilatation observed during routine ultrasonography was referred to our hospital. Preliminary blood tests revealed elevated levels of hepatobiliary enzymes. Computed tomography (CT) scan showed lower bile duct wall thickening and enhancement. Esophagogastroduodenoscopy revealed mildly swollen papilla of Vater, without ulceration. Endoscopic retrograde cholangiography demonstrated that the CBD was grossly dilated with a constriction in the lower part. The final diagnosis indicated poorly differentiated adenocarcinoma of duodenal papilla with signet-ring cells; pT3N0M0, stage IIA (Unio Internationalis Contra Cancrum, 7th edition), for which subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) was performed. This case is quite rare, and the surgery resulted in a desirable outcome. The patient has been disease-free for 5 years since the surgery.

Autologous transplantation of oral mucosal epithelial cell sheets cultured on an amniotic membrane substrate for intraoral mucosal defects.

The human amniotic membrane (AM) is a thin intrauterine placental membrane that is highly biocompatible and possesses anti-inflammatory and anti-scarring properties. Using AM, we developed a novel method for cultivating oral mucosal epithelial cell sheets. We investigated the autologous transplantation of oral mucosal epithelial cells cultured on AM in patients undergoing oral surgeries. We obtained specimens of AM from women undergoing cesarean sections. This study included five patients without any history of a medical disorder who underwent autologous cultured oral epithelial transplantation following oral surgical procedures. Using oral mucosal biopsy specimens obtained from these patients, we cultured oral epithelial cells on an AM carrier. We transplanted the resultant cell sheets onto the oral mucosal defects. Patients were followed-up for at least 12 months after transplantation. After 2-3 weeks of being cultured on AM, epithelial cells were well differentiated and had stratified into five to seven layers. Immunohistochemistry revealed that the cultured cells expressed highly specific mucosal epithelial cell markers and basement membrane proteins. After the surgical procedures, no infection, bleeding, rejection, or sheet detachment occurred at the reconstructed sites, at which new oral mucous membranes were evident. No recurrence was observed in the long-term follow-up, and the postoperative course was excellent. Our results suggest that AM-cultured oral mucosal epithelial cell sheets represent a useful biomaterial and feasible method for oral mucosal reconstruction. However, our primary clinical study only evaluated their effects on a limited number of small oral mucosal defects.

Evaluation of a dental pulp-derived cell sheet cultured on amniotic membrane substrate.

OBJECTIVE: Mesenchymal stem cells (MSC) are transplanted for periodontal tissue regeneration, and the periodontal ligament (PDL) is regenerated using a cultured cell sheet. This cultured cell sheet is prepared using PDL-derived cells, growth factors, and amniotic membrane (AM). Dental pulp (DP)-derived cells can be easily obtained from extracted wisdom teeth, proliferate rapidly, and are less susceptible to bacterial infection than PDL-derived cells. Thus, to prepare a novel cell sheet, DP-derived cells were cultured on AM as a culture substrate for immunohistochemical examination. METHODS: Wisdom teeth extracted from three adults were cut along the cement-enamel border. DP tissue was collected, minced, and primarily cultured. After three or four passage cultures, DP-derived cells were cultured on AM, followed by hematoxylin-eosin (H-E) and immunofluorescence staining. RESULTS: DP-derived cells cultured on AM formed a layered structure. Cells positive for vimentin, Ki-67, ZO-1, desmoplakin, CD29, 44, 105 or 146, STRO-1, collagen IV or VII or laminin 5 or α5 chain were localized. CONCLUSIONS: DP-derived cells proliferated on AM, while retaining the properties of DP, which allowed the cultured cell sheet to be prepared. In addition, the cultured cell sheet contained MSC, which suggests its potential application in periodontal tissue regeneration.

Prospective application of our novel prognostic index in the treatment of anaplastic thyroid carcinoma.

BACKGROUND: We have previously performed retrospective analysis of patients with anaplastic thyroid carcinoma (ATC) treated between April 1976 and March 1999, revealing acute symptoms, large tumor (>5 cm), distant metastasis, and leukocytosis ≥ 10,000/mm(3) as the most important prognostic factors. We devised a novel prognostic index (PI) as the total number of these 4 factors present, giving a PI of 0-4. METHODS: We have adopted this PI since April 1999. In principle, multimodal treatment has been encouraged for a PI of ≤ 1, whereas aggressive treatment has been avoided to maintain quality of life for a PI of ≥ 3. The validity of this therapeutic strategy was prospectively investigated in 74 patients with ATC. RESULTS: Six-month survival rates for PI ≤ 1 and PI ≥ 3 were 72% and 12%, respectively. Among patients with a PI of ≤ 1,11 (42%) underwent multimodal treatment and showed significantly better survival than previous cases. Survival rates did not differ between stages. For patients with a PI of ≥ 3, survival rates were equally dismal, regardless of stage. Numbers of patients who underwent tracheostomy or died from local disease were significantly decreased compared with previous cases. CONCLUSION: Our PI is valid for anticipating prognosis and aiding timely decisions on treatment policy for ATC patients.

Immunohistochemical study of oral epithelial sheets cultured on amniotic membrane for oral mucosal reconstruction.

We immunohistochemically evaluated whether oral epithelial cells grown on amniotic membrane (AM) would be an effective biomaterial for reconstructing oral mucosal defects. Oral mucosal epithelial cells from albino rabbits were grown for 2-3 weeks on an AM carrier in a co-culture with 3T3 fibroblasts. The rabbits' oral mucosal defects were reconstructed by autologous transplantation of the oral epithelial sheets. The oral epithelial sheets and reconstructed tissues were then examined histologically and immunohistochemically. After 2-3 weeks of culture, the rabbit oral mucosal epithelial cells developed 5-7 layers of stratification on the AM. Immunohistochemistry revealed that they expressed keratins 4/13, integrin alpha 6, alpha 5 chain and collagen type III, but not keratins 1/10. The transplanted sheets attached to the mucosal defects, and AM fragments disappeared from the transplant area. Immunohistochemical patterns revealed properties of the mucous membrane and basement membrane components in the reconstructed epithelia. The results of this experiment showed that the AM-cultured oral epithelial sheets resulted in mucosa-like differentiation, and adhered to the mucosal defects. Therefore, AM-cultured oral epithelial sheets might be a useful biomaterial for oral mucosal reconstruction.

A patient with gallbladder cancer with paraaortic lymph node and hepatic metastases who has survived for more than 13 years after the primary extended radical operation.

Gallbladder cancer is a disease with poor prognosis, especially when it is associated with distant metastasis. Here we report a rare case of a patient with gallbladder cancer with extensive local and distant lymph node metastases and multiple liver metastases who has survived for more than 13 years through aggressive treatments. A 54-year-old woman developed right upper quadrant pain. Computed tomography (CT) revealed a papillary tumor in the gallbladder. Low-density tumors in segments 4, 5, and 8 of the liver and extensive paraaortic lymph node swelling were observed. She underwent central hepatic bisectionectomy and paraaortic lymphadenectomy. Two months later, hepatic metastases were found in segments 2, 3, 6, and 7, and percutaneous ethanol injection and transcatheter arterial chemoembolization were performed. Twelve months after the first surgery, CT revealed lymph node swelling around the right external iliac artery and behind the left renal vein. Metastatic lymph node dissection and resection and reconstruction of the right external iliac artery and vein with artificial graft replacements were performed. Two months later, CT revealed a paraesophageal lymph node swelling, which was treated by radiotherapy. At present, 13 years after the first surgery, and 11 years after the last radiotherapy, she is alive without any sign of recurrence.

Activities of daily living and quality of life of elderly patients after elective surgery for gastric and colorectal cancers.

OBJECTIVE: To establish reliable standards for surgical application to elderly patients 75 years old or older with gastric or colorectal cancer with special reference to the postoperative recovery of activities of daily living (ADL) and quality of life (QOL). SUMMARY BACKGROUND DATA: ADL and QOL are important outcomes of surgery for the elderly. However, there has been only limited evidence on the natural course of recovery of functional independence. METHODS: Two hundred twenty-three patients 75 years old or older with gastric or colorectal cancer were prospectively examined. Physical conditions, ADL, and QOL were evaluated preoperatively and at the first, third, and sixth postoperative month. RESULTS: The mortality and morbidity rates were 0.4% and 28%, respectively. Twenty-four percent of patients showed a decrease in ADL at 1 month postoperatively, but most patients recovered from this transient reduction, with only 3% showing a decline at the sixth postoperative month (6POM). ADL of these patients was likely to decrease after discharge from the hospital. QOL of the patients showed a recovery to an extent equal to or better than their average preoperative scores. CONCLUSIONS: Of the patients 75 years old or older who underwent elective surgery for gastric or colorectal cancer, only a few showed a protracted decline in ADL and most exhibited better QOL after surgery. This indicates that surgical treatment should be considered, whenever needed, for elderly patients 75 years old or older with gastric or colorectal cancer. Estimation of Physical Ability and Surgical Stress is useful for predicting postoperative declines in ADL and protracted disability; this could aid in establishing a directed rehabilitation program for preventing protracted disability in elderly patients.

Primary choriocarcinoma of the jejunum: report of a case.

We report a case of primary choriocarcinoma of the jejunum in a 45-year-old man, which was finally diagnosed by immunohistochemical analysis of a surgically resected specimen. Despite combined systemic chemotherapy, the patient died of progressive liver metastases 5 months after surgery. The serum human chorionic gonadotropin (HCG) level increased dramatically as the liver tumor progressed. According to our review of the 13 cases of primary or secondary choriocarcinoma of the small intestine reported in the English-language literature up until 2001, the characteristic symptoms are massive gastrointestinal bleeding and elevation of the serum HCG. Early diagnosis and prompt initiation of chemotherapy provide the only chance of improving the extremely poor prognosis associated with this rare neoplasm.