[Patient and Public Involvement in Cancer Clinical Research].

The involvement of patients and the public with researchers is essential in clinical research on cancer treatment. In recent years, patient and public involvement(PPI)has been required in all medical research processes. This paper summarizes practical considerations and examples of the PPI process referred to in the"Patient and Public Involvement(PPI)Guidebook"of the Japan Agency for Medical Research and Development(AMED). The process consists of the introduction of PPI, recruitment of PPI participants, conflict of interest management and rewards for PPI participants, the confidentiality of PPI participants, and reporting results and feedback. It is difficult to provide a standardized procedure because PPI activities vary among the research projects. It is recommended to implement PPI activities into your research project by utilizing the actual cases or existing information sources.

[Two Cases of Carcinoma en Cuirasse, as Cutaneous Metastasis of Breast Cancer].

We present 2 cases of carcinoma en cuirasse, an uncommon clinical manifestation of metastatic cutaneous breast cancer. Case 1, a 70-year-old woman, presented with diffuse erythematous, indurated skin lesions that covered her entire anterior chest wall. Skin biopsy revealed tumor cells in the dermis which were ER and PgR positive and HER2 negative. CT showed pleural and pericardial effusion which led to a final diagnosis of cutaneous metastasis from breast cancer. Fulvestrant monotherapy was initiated and maintained a good clinical effect for 40 months. She died of multiple liver metastasis after 53 months from her first visit. Case 2 was a 71-year-old woman, with a 24 month history of a left breast tumor that gradually accompanied erythematous skin indurations and erosion, which spread to her entire left chest wall and contralateral breast. Following skin biopsy and CT, she was diagnosed to have triple negative breast cancer with multiple lymph node and cutaneous metastasis. After 4 cycles of EC, capecitabine was administrated and her skin lesions improved rapidly, including the lymph nodes. She is currently alive after 12 months since her first visit and under chemotherapy against new cutaneous metastasis.

Where Can Patients Obtain Information on the Preapproval Access Pathway to Investigational Treatment in Japan? A Survey of Patient Advocacy Organizations' Websites.

Investigational treatments are those that have been approved for testing in humans but are not yet available as an approved treatment option. For many patients with a terminal illness who have no approved treatment option and are not eligible for a clinical trial, investigational treatments are the last resort. However, not much is known about the dissemination of information by patient advocacy organizations (PAOs). We evaluated the quantity and quality of information on preapproval access to investigational therapies provided by Japanese PAO websites between January 24 and March 29, 2019. A total of 49 PAOs were identified. Of these, 16 (33%) provided no relevant information. The most frequent information provided was the PAO's own clinical trial finder or list of clinical trials (n = 15, 31%); of the 10 cancer-related PAOs, 5 (50%) provided this information. Nine (18%) PAOs had developed patient registries or provided a link to relevant registries. Only 1 PAO (2%) provided a link about the Ministry of Health, Labour, and Welfare trials that described the process and regulations of clinical trials. Our results indicate that PAOs do not disseminate adequate information on preapproval pathways. We suggest that the government involve PAOs in disseminating this information to both patients and physicians.

Lateral thoracoaxillar dermal-fat flap for breast conserving surgery: the changes of the indication and long-term results.

BACKGROUND: Oncoplastic breast conserving surgery had been challenged to achieve both of local control and the cosmetic appearance of preserved breast. We developed the lateral thoracoaxillar dermal-fat flap (LTDF) as an oncoplastic procedure to fill the defect of breast-conserving surgery in 1999. METHODS: A total of 2338 breast cancer patients underwent surgery from January, 2000 to December, 2017. Mastectomy was performed in 706 patients (30%), and breast conservative surgery (BCS) was performed in 1634 patients (70%). The LTDF was adopted in 487/1634 (30%) of BCS cases to fill the large defect left by partial resection. we divided all patients into 3 groups: breast total mastectomy (BT group), the breast partial resection (BP) with LTDF (LTDF group), and Bp without LTDF (BP group) and compared the clinical characteristics, and recurrence rate. RESULTS: The Indications for LTDF increased up to 40% in 2010, while they decreased to 20%-30% in the most recent period, in accordance with the frequency of breast reconstruction increased. Patients who underwent BP + LTDF (LTDF group) included significantly higher proportions of stage II diseases and cases treated by neoadjuvant chemotherapy than those in BP or BT groups.. We found no marked difference of local recurrence and distant metastases between the LTDF and Bp groups. However, the rate of distant metastasis was significantly higher in BT group than in the Bp or LTDF group. Concerning the complications of LTDF, we experienced a few complications of Grade 3-4 requiring surgical management, namely one case of dislocation of the LTDF, three cases of bleeding, and five cases each of skin necrosis and fat necrosis. CONCLUSIONS: We reported satisfying long-term outcomes of 487 cases treated by LTDF. LTDF is a suitable oncoplastic technique for BCS.

Fat necrosis after breast-conserving oncoplastic surgery.

BACKGROUND: Fat necrosis is a subjective early as well as delayed complication, which sometimes mimics local recurrence and ruins the quality of life by pain and poor cosmetic result. While, the frequency and severity of fat necrosis are important issues that breast surgeons should explain to the patient, these data are not revealed well. METHODS: A total of 1476 patients who underwent breast surgery from January 2000 to December 2012 were enrolled in the present study. We assessed fat necrosis by mammographic and physical findings and created grading criteria: Grade (G) 0, no fat necrosis; G1, no symptomatic fat necrosis (mammographic dystrophic calcification); G2, mild symptomatic necrosis (mammographic dystrophic necrosis with tumor); G3, severe symptomatic necrosis (mammographic dystrophic necrosis with pain or skin change); and G4, symptomatic necrosis requiring surgical intervention. RESULTS: Of the 1476 patients enrolled, 393 (27%) underwent mastectomy, and 1083 (73%) underwent breast-conserving surgery. We achieved a high rate of breast-conserving surgery at a total rate of 73% over the study period and maximum rate of 88% in 2010, using oncoplastic procedures. We mainly adopted a pedicled fat flap (417/1083; 39%) and a free dermal fat flap (40/1083; 3.7%). Among the 626 patients who underwent partial resection with no replacement for the defect, G1-G2 fat necrosis was seen in 29/626 (4.6%). While, the incidence of fat necrosis with pedicled fat flap and free dermal fat graft was 68/417 (16%) and 40/40 (100%), respectively, showing a significant difference (p < 0.01). Furthermore, the incidence of G3-G4 fat necrosis was significantly higher with free dermal fat grafts (25%; 10/40) than with pedicled flap (2.9%; 12/417) (p < 0.01). Among pedicled flaps, the incidence of fat necrosis with inframammary adipofascial flaps was 56% (14/25) which was higher than that with lateral epidermal fat flaps (12%; 33/276) (p < 0.01), and rotation of surrounding breast tissues (8%; 21/116) (p < 0.01). The incidence of G3 fat necrosis was also high at 20% (5/25) in inframammary adipofascial flaps. CONCLUSIONS: Breast-conserving oncoplastic surgery carries a risk of fat necrosis as a delayed complication. The incidence rate and severity of fat necrosis with each procedure should be assessed. We should select fat grafts with a good blood supply to replace defects of breast-conserving therapy.

Rapid Changes in Circulating Tumor DNA in Serially Sampled Plasma During Treatment of Breast Cancer: A Case Report.

BACKGROUND The analysis of circulating tumor DNA (ctDNA) is expected to be a modality to determine the status of cancer in real time. This case indicated utilities and issues in measuring the ctDNA in cancer patients. CASE REPORT A 45-year-old woman with metastatic breast cancer was treated with bevacizumab and paclitaxel. The lung metastases were decreased but the meningitis carcinoma developed rapidly and she died. During the treatment with bevacizumab and paclitaxel, blood samples were taken serially and ctDNA was analyzed using a next-generation sequencer. TP53 frameshift mutation (TP53; p.Arg158fs with 7 nucleotides deletion) was identified in the tumor, and dynamic change in this mutation in ctDNA was observed in serially sampled plasma in this patient. We observed a rapid decrease of TP53 mutation at the beginning of treatment, then it increased as a sign of relapse. However, the high allelic fraction value of TP53 mutation was not consistent during the progression of cancer, suggesting that several factors affected the value of ctDNA. CONCLUSIONS Although this is a single-case experience, it strongly suggests ctDNA could be a modality to determine the cancer status in real time. However, we found that several factors affected the value of ctDNA. Further investigations are needed to reveal the significance of these very high-sensitivity changes.

Specific sites of metastases in invasive lobular carcinoma: a retrospective cohort study of metastatic breast cancer.

BACKGROUND: Invasive lobular carcinoma (ILC) is known to be the second most common histological type following invasive ductal carcinoma (IDC). Definitive clinical features of ILC are controversial. METHODS: We retrospectively analyzed a cohort of 330 patients with metastatic breast cancer, 303 of IDC, 19 of ILC, and 8 of others. We compared the patient age and tumor-node-metastasis factors, disease-free survival (DFS), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression at the primary site between ILC and IDC. We then selected the patients in the ER+ or PR+/HER2- subtype specifically and compared sites of recurrence, and the survival curve starting from the point of development of metastatic disease. RESULTS: The clinical stage was significantly higher in the ILC patients than in the IDC (p = 0.001). The mean (±SD) of DFS for the ILC and IDC patients was 2.6 ± 0.6 and 2.4 ± 0.3 years, respectively, with no significant difference (p = 0.18). However, the hormone receptor status was same between both groups; the rate of HER2 positivity was significantly lower in the ILC group (0%) than in the IDC group (16.2%) (p = 0.05). In ER+ or PR+/HER2- subtype, the mean DFS for the ILC and IDC was 2.9 ± 0.6 and 3.1 ± 0.3 years, and the median survival time after the recurrence for ILC and IDC patients was 4.2 ± 0.7 and 5.6 ± 0.7 years, respectively, with no significant difference (p = 0.77). The frequency of lung metastases was significantly lower in the ILC group (6.3%) than in the IDC group (53.7%) (p < 0.01), while the frequency of peritoneal metastases was significantly higher in the ILC group (68.8%) than in the IDC group (1%) (p = 0.00). Of note, the prognosis after the diagnosis of peritoneal metastases was poor, with a median survival time of 19 ± 9 months and resistance to hormone therapy. CONCLUSIONS: The extremely high rate (68.8%) of peritoneal metastases was observed in long-term follow-up for the metastatic breast cancer patients with ILC. We need to reveal the definitive feature of ILC and develop new therapeutic strategies to prevent the dissemination of ILCs.

Biliary cancer developed after the reparative surgery for congenital choledochal cyst: a case report and review of the literature.

The incidence of bile duct cancer developed in the patients with congenital choledochal cysts (CC) with a history of reparative surgery is not well known. We experienced a case developed choleductal cancer 45 years after reparative surgery. She underwent reparative surgery with cyst excision and hepatic bile duct duodenal anastomosis at 1 year of age. She developed the symptoms of jaundice, anorexia, and dull pain in the right upper part of the abdomen at 47 years of age. The carcinoma arose from the dilated proximal bile duct anastomosed with the duodenum. Cholestasis and regurgitation of duodenal fluids seemed to have influenced the development of cancer in this patient. We additionally reviewed seven cohort studies concerning the incidence of biliary carcinoma after surgery for congenital choledocal cysts. The incidence of biliary cancer developed after surgery was 2.2 ± 2.5 (ranged 0-6.5)%. We also reviewed 33 Japanese case reports cited in Japan MEDLINE from 1986 to 2015. Regarding the CC types according to the Totani's classification, 12 were type I and 14 type IVa, 1 was type II and 6 were unknown type. The rate of coexistence of pancreaticobiliary maljunction (PBM) was 92%, (22/24; other 9 cases were not documented), and biliary cancer arose from the proximal stump of the reparative surgery in 68% (17/25) and from the distal stump in 32% (8/25) of cases. These findings suggested that the reflux of pancreatic juice due to PBM only partially explained the carcinogenesis of CCs. Intensive follow-up of such patients throughout their lives is necessary to avoid cancer death even after standard reparative surgery.

Pseudomyxoma peritonei due to low-grade appendiceal mucinous neoplasm with symptoms of inguinal hernia and uterine prolapse: a case report and review of the literature.

Pseudomyxoma peritonei (PMP) is an unusual condition in which massive amounts of mucinous ascites in conjunction with mucinous peritoneal and omental implants occur. We herein report a case of PMP due to low-grade appendiceal neoplasm (LAMN) and a literature review to clarify the clinical features of PMP. A 68-year-old female suffered from anorexia and abdominal distension and was referred to the emergency department of our hospital. Right-side inguinal hernia and uterine prolapse were revealed by a physical examination. Abdominal computed tomography at admission indicated massive ascites and a ruptured cystic mass in the lower-right abdomen. We diagnosed the patient with a ruptured appendiceal mucinous adenoma and PMP and scheduled a laparotomy. We performed an appendectomy containing the cystic mass, bilateral oophorectomy, and a biopsy for the peritoneum. We irrigated the abdominal cavity using 3000 ml of dextran solution. The macroscopic findings showed a ruptured cystic mass measuring 5 × 4 cm arising from the middle of the appendix. The bilateral ovaries and peritoneum were also covered with yellow mucin. The pathologic findings revealed the presence of low-grade atypical cells inside the capsule. However, no tumor cells were found on the surface of the ovary or peritoneum. A literature review revealed that the prognosis of PMP due to LAMN is relatively good, with a 5-year survival rate of 80%, and hernia is occasionally caused by PMP. According to this literature review, we knew this case might be a typical case. However, PMP is very rare; we need further follow-up data to select an optimal treatment for preventing the relapse of PMP.

Periaortitis induced by epirubicin and cyclophosphamide for a patient with advanced breast cancer.

Aortitis is an extremely rare condition, and it may mimic febrile neutropenia during cancer chemotherapy. A 55-year-old female diagnosed with T2N1M1 stage IV breast carcinoma received chemotherapy with EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks). At the eleventh day after the first administration of EC, she developed a high-grade fever of 38 °C and stomatitis. We started the intravenous administration of antibiotics at hospitalization, because the laboratory data showed normal white blood cell values 3800/µl but a severe inflammatory reaction (CRP 25.13 mg/dl). The fever and high CRP value continued, and the WBC rose to 14,500/µl at 20th day. However, her condition was stable. On the 25th day after the administration of EC, she complained of back pain, so we performed computed tomography (CT) again and observed thickening of the rind surrounding the descending aorta and bilateral pleural effusion, indicating acute periaortitis. We performed examinations concerning vasculitis and connective tissue disease, but the values were all within normal ranges showing no relationship with other diseases. We stopped the administration of antibiotics on the 20th day, and while we did not administer corticosteroids, however, the fever was resolved and her WBC decreased. She was discharged on day 33, and the other chemotherapy was restarted with pertuzumab, trastuzumab and docetaxel. The patient has remained well without inflammatory reactions. CT at 90 days after EC therapy showed the resolution of the thickened rind of the descending aorta and no aneurysmic changes.

A study of tumor heterogeneity in a case with breast cancer.

Tumor heterogeneity has been suggested based on clinical and pathological findings. Several clinical findings can be explained by tumor evolution during progression and metastasis. We herein report a case of metastatic breast cancer indicated tumor heterogeneity by clinical findings and a genomic analysis. A 64-year-old woman with advanced breast cancer was treated with primary chemotherapy, to which primary tumor responded. After a 6 month treatment pause, lung, liver, and skin metastases developed and her serum tumor markers were elevated. None of those serum markers had been elevated before the treatment, despite the large tumor burden. Notably, there was discordance in the expression of human epidermal growth factor receptor 2 (HER2) between the primary tumor and metastatic skin lesions, with the former being negative and the latter positive. A genomic analysis was performed by in-house Breast Cancer Panel, which consisted of 53 pre-selected genes. Twenty-three somatic mutations were found in primary breast tumor and 7 in the skin metastasis. None of these 30 genes matched. However, the cell-free (cf) DNA in the plasma taken at the time of skin metastasis contained 10 mutations, 7 from the primary lesion and 3 from the metastasis. These data indicate that the clonal changes or tumor heterogeneity was shown in two solid tumors by clinical and the result of a genomic analysis. Of particular interest was that cell-free DNA could be a powerful tool to look into these dynamic changes.

Report of a case with gallbladder carcinoma: P53 expression of the peritumor epithelium might predict biliary tract recurrence.

INTRODUCTION: The over-expression of P53 protein in gallbladder carcinoma is a biomarker correlating with a poor survival. However, the significance of P53 expression in peritumor tissues is unknown. We experienced a case of gallbladder carcinoma where the operative specimen showed over-expression of P53 on the peritumor epithelium, and early recurrence developed at the biliary tract. PRESENTATION OF CASE: A 74-year-old female patient was referred to our hospital due to wall thickening of the gallbladder on ultrasonography. Radiographic examinations revealed wall thickening at the fundus of gallbladder and no abnormalities of the biliary tract or surrounding lymph nodes. We performed open cholecystectomy and lymph node dissection without extrahepatic bile duct resection, as a frozen section of the surgical stump of the cystic duct was cancer-free. However, a pathological examination revealed over-expression of P53 protein in the epithelium of the peritumor to the cystic duct, which were diagnosed as normal on hematoxylin eosin staining. The patient developed bile duct metastases, two and half years after the operation. She underwent endoscopic stenting for the obstruction of bile duct with no additional therapy, and died 6 months later. DISCUSSION AND CONCLUSION: The immunohistochemical staining of the GB wall or surgical stump for a surgical specimen of GBC may be crucial to predict the bile duct recurrence.

Pseudo-Meigs' syndrome due to ovarian metastases from colon cancer: a case report and review of the literature.

We herein experienced a case with pseudo-Meigs' syndrome that developed both synchronous and metachronous metastases to the ovary from ascending colon cancer. A 57-year-old female visited a hospital for a 2-month history of abdominal distension and voiding difficulty. Massive pleural effusion on the right side and a small amount of left-sided pleural effusion were detected on CT. She underwent emergent laparotomy due to the severe symptom of abdominal distention. The tumor originated from the left ovary, and left-sided oophorectomy was performed.The histologic finding was moderately differentiated adenocarcinoma suggesting metastatic carcinoma from the colon. Left thoracic effusion disappeared at 3 days after the removal of the ovarian tumor. Subsequently, colon carcinoma of the cecum was detected by colonoscopy. The patient underwent second laparotomy of right colectomy and lymph node dissection. However, 6 months after the operation, pleural effusion on the right side re-developed again, and the serum levels of CEA and CA125 were elevated at 105 ng/ml and 125 U/ml, respectively. CT again revealed a large ovarian tumor. She subsequently underwent third laparotomy of right-sided oophorectomy and hysterectomy. Pleural effusion and ascites disappeared in a few days after the operation.The patient developed both synchronous and metachronous ovarian metastases and achieved a 7-year disease-free survival after the operation. The pathogenesis of pseudo-Meigs' syndrome should be distinguished from carcinomatous peritonitis and/or pleuritis of malignant disease.

Report of a case with a spontaneous mesenteric hematoma that ruptured into the small intestine.

INTRODUCTION: A spontaneous mesenteric hematoma is a rare condition. Furthermore, it is extremely rare that the mesenteric hematoma caused gastrointestinal bleeding with an unknown etiology. We experienced a case with a spontaneous mesenteric hematoma that ruptured into the jejunum. PRESENTATION OF CASE: A 75-year-old man was referred to our hospital because of anal bleeding and anemia. Abdominal computed tomography (CT) showed a low density mass measuring 3.0cm in diameter, including an enhanced spot. This finding suggested that a pseudo-aneurysm or mesenteric hematoma caused active bleeding into the jejunum. He underwent emergent laparotomy and partial resection of the jejunum and the mesentery including the tumor. A histological examination of the jejunum indicated no pathogenic findings causing active bleeding. And there were no findings suggesting the mesenteric aneurysm had developed. The patient had no history related to the development of a mesenteric hematoma, such as trauma, labor, surgery, or anticoagulant treatment. Therefore, we finally diagnosed that a spontaneous mesenteric hematoma had ruptured into the jejunum. DISCUSSION AND CONCLUSION: We reported extremely rare condition that the mesenteric hematoma was developed and ruptured into the jejunum without definitive etiology.

Compensation programs after withdrawal of the recommendation for HPV vaccine in Japan.

HPV vaccinations were recommended with the backing of a Japanese government subsidy program in 2010, and were included in the National Immunization Program in April 2013. However, the Ministry of Health, Labour, and Welfare withdrew the recommendation for the HPV vaccination in June 2013. We investigated HPV vaccine injury compensation programs for both the national and local governments. Approximately 3.38 million girls were vaccinated, and 2,584 complained of health problems. The majority of these received the vaccine shot as a non-routine vaccination. In total, 98 people developed health problems and applied for assistance from 2011 to 2014, but no cases have been processed since October 2014. Several local governments are providing their own compensation program for cases of vaccine adverse reactions, but the number is extremely low (16 of 1,741 municipalities and 1 of 47 prefectures). The local governments that are providing compensation are largely those where HPV vaccine victim support groups are prominent. The confusion regarding the national program for HPV vaccine injury was caused by the discrepancy between the compensation programs for those vaccinated under the immunization law and for those who received voluntary vaccinations. The establishment of a new compensation program might be key to finding a lasting resolution.

How do medical journalists treat cancer-related issues?

Cancer patients can obtain information about their illness through a variety of media sources. Therefore, it is important to know how medical journalists treat cancer-related issues; to that end, we sent self-administered questionnaires to 364 journalists in 82 organisations who had reported on medical issues for the Japanese media, asking for their reasons for reporting on cancer-related issues and the difficulties they had faced. The most common reason for reporting on health-related issues was their personal interest in a particular issue (n = 36). They mainly covered conventional therapies (n = 33), healthcare policy (n = 30), new therapies (n = 25), and diagnosis (n = 25). All of the journalists that were surveyed experienced some difficulties in reporting health issues. Significant concerns included the quality of information (n = 36), social impact (n = 35), lack of technical knowledge (n = 35), and difficulty in understanding technical terms (n = 35). Journalists commonly used personal networks, including physicians, as information sources (n = 42), as well as social media (e.g., e-mail, Twitter and Facebook) (n = 32). Topic selection was biased, with 35 of 48 journalists having never reported on topics concerning hospices. Physicians were the most trusted source of information about cancer, and journalists attached high importance to interviewing them. As medical knowledge is advancing rapidly, journalists may have increasing difficulty covering cancer-related issues.

Report of a case with T1a gallbladder poorly differentiated adenocarcinoma, solid type, which developed into lymph node metastases.

We experienced a case with gallbladder carcinoma growing limited to the mucosa (T1a), which developed massive lymphatic vessel spread and lymph node metastases.A 72-year-old man was referred to our hospital for the swelling of his gallbladder during a routine ultrasound sonography checkup. We diagnosed the patient with gallbladder carcinoma with lymph node metastasis according to the radiographic findings and performed the open cholecystectomy and lymph node dissection. A histological examination showed poorly differentiated adenocarcinoma, solid type, and the tumor was limited to the mucosa. The number of lymphatic vessels was increased in the tumor and peritumor areas, and cancer cells were observed in the lymphatic vessels, which were detected via D2-40 immunohistochemistry. A careful histological examination and follow-up is required for T1a gallbladder carcinoma.

Development of a national agreement on human papillomavirus vaccination in Japan: an infodemiology study.

BACKGROUND: A national agreement on human papillomavirus (HPV) vaccination was achieved relatively quickly in Japan as compared to the United States and India. OBJECTIVE: The objective was to identify the role of print and online media references, including references to celebrities or other informants, as factors potentially responsible for the relatively rapid national acceptance of HPV vaccination in Japan. METHODS: A method of text mining was performed to select keywords, representing the context of the target documents, from articles relevant to the promotion of HPV vaccination appearing in major Japanese newspapers and Web pages between January 2009 and July 2010. The selected keywords were classified as positive, negative, or neutral, and the transition of the frequency of their appearance was analyzed. RESULTS: The number of positive and neutral keywords appearing in newspaper articles increased sharply in early 2010 while the number of negative keywords remained low. The numbers of positive, neutral, and negative keywords appearing in Web pages increased gradually and did not significantly differ by category. Neutral keywords, such as "vaccine" and "prevention," appeared more frequently in newspaper articles, whereas negative keywords, such as "infertility" and "side effect," appeared more frequently in Web pages. The extraction of the positive keyword "signature campaign" suggests that vaccine beneficiaries cooperated with providers in promoting HPV vaccination. CONCLUSIONS: The rapid development of a national agreement regarding HPV vaccination in Japan may be primarily attributed to the advocacy of vaccine beneficiaries, supported by advocacy by celebrities and positive reporting by print and online media.