Pathogenicity assessment of variants for breast cancer susceptibility genes based on BRCAness of tumor sample.

Genes involved in the homologous recombination repair pathway-as exemplified by BRCA1, BRCA2, PALB2, ATM, and CHEK2-are frequently associated with hereditary breast and ovarian cancer syndrome. Germline mutations in the loci of these genes with loss of heterozygosity or additional somatic truncation at the WT allele lead to the development of breast cancers with characteristic clinicopathological features and prominent genomic features of homologous recombination deficiency, otherwise referred to as "BRCAness." Although clinical genetic testing for these and other genes has increased the chances of identifying pathogenic variants, there has also been an increase in the prevalence of variants of uncertain significance, which poses a challenge to patient care because of the difficulties associated with making further clinical decisions. To overcome this challenge, we sought to develop a methodology to reclassify the pathogenicity of these unknown variants using statistical modeling of BRCAness. The model was developed with Lasso logistic regression by comparing 116 genomic attributes derived from 37 BRCA1/2 biallelic mutant and 32 homologous recombination-quiescent breast cancer exomes. The model showed 95.8% and 86.7% accuracies in the training cohort and The Cancer Genome Atlas validation cohort, respectively. Through application of the model for variant reclassification of homologous recombination-associated hereditary breast and ovarian cancer causal genes and further assessment with clinicopathological features, we finally identified one likely pathogenic and five likely benign variants. As such, the BRCAness model developed from the tumor exome was robust and provided a reasonable basis for variant reclassification.

Phase I dose-escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer.

The formation of premetastatic niches creates a fertile environment for the seeding of disseminated cancer cells in selected secondary organs. This is crucial for the development of metastasis in various malignancies, including breast cancer (BC). We previously reported that the loss of FBXW7 in bone marrow-derived stromal cells promoted cancer metastasis by increasing the production of the chemokine CCL2, which attracts myeloid-derived suppressor cells and macrophages to the premetastatic niche. Furthermore, treatment with the CCL2 inhibitor propagermanium (PG), which has been used in Japan as a therapeutic agent against chronic hepatitis B, was shown to block the enhancement of metastasis in FBXW7-deficient mice through inhibiting the formation of premetastatic niches. Here, we describe a phase I dose-escalation study of PG used as an antimetastatic drug for perioperative patients with primary BC. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Twelve patients were enrolled in the study. Dose-limiting toxicity was not observed, and the maximum dose was determined to be 90 mg/body/day. The serum concentrations of PG were nearly within the normal range in all observation days. We observed an inverse correlation between FBXW7 mRNA levels in blood and the serum concentrations of CCL2 and interleukin (IL)-6, in agreement with our previous mouse model. Also, IL-6 was downregulated in a PG dose-dependent manner, as observed in mice. Thus, PG was given safely and it is expected to have antimetastatic potential in BC. This trial is registered in the UMIN Clinical Trials Registry as UMIN000022494.

[Combined Modality Therapy for Giant Hepatocellular Carcinoma and Multiple Lung Metastases-A Case Study].

Here, we present the case of a 47-year-old woman with liver masses having distinct borders, which were located approximately 13 cm from the left hepatic lobe S4, as visualized on a CT scan. Hepatocellular carcinoma(HCC)was suspected from these contrast findings. Additionally, we found nodules in the right upper lobe of the lung and in the left apex. Although test results for hepatitis B and C viruses were negative, the α-fetoprotein(AFP)level was elevated. The tumor was diagnosed as a HCC with suspected multiple lung metastases. Thereafter, a resection was performed for the HCC. However, multiple recurrences were observed. Arterial embolization using transcatheterization was performed thrice 5 months after resection. Further, 6 months after resection, lenvatinib therapy was initiated as the pulmonary nodule increased in size. One year after the operation, a recurrent neoplastic lesion in the liver was detected on the contrast-enhanced MRI. Since the earlier treatment with transcatheter arterial embolization proved to be minimally effective, we opted for arterial injection chemotherapy with cisplatin plus 5-FU for approximately 3 months. The contrast-enhanced CT revealed that the lesion became a low absorption lesion in the liver outside the central area, and the AFP also decreased rapidly. Therefore, the therapy was considered effective. As a side effect of arterial injection chemotherapy, the patient developed a duodenal ulcer. However, after treating the ulcer, a pulmonary metastasectomy was performed and no obvious recurrence was noted. Typically, for treatment of extrahepatic metastases of HCC, drugs such as sorafenib or lenvatinib that have molecular targets are selected according to a treatment algorithm based on liver cancer practice guidelines. However, these drugs were not effective in this case, whereas arterial injection chemotherapy showed satisfactory therapeutic effect on the recurrences in the liver. Although there was a complication of duodenal ulcer, this case report highlights that combined modality therapy including arterial injection chemotherapy is successful in treating HCC.

[Study of the Treatment for Colorectal Cancer(CRC)in Elderly People Aged 80 Years or Older].

Aging in local cities is increasing in Japan, and Kitakyushu city is one of them. In particular, in the area in which our hospital is located, the old-age dependency ratio(ie, individuals who are 65 years old or older per hundred individuals who are 15-64 years old)is 35.2%, which is much higher than the old-age ratio of 26% in Japan, and the average age is 50.6 years. In Yahatahigashi-ku, elderly people who are older than 80 years of age account for 35.4%of the population. In consideration of this, we examined how far to do the treatment administered for CRC in elderly patients. We studied 17 patients who were older than 80 years of age and diagnosed with CRC in 2017. The performance status(PS)scores were PS 0, 1, 2, 3, and 4 in 4, 5, 1, 6, and 1 cases(s), respectively. The patients who were immobile, but still able to retain regular dietary intake, also underwent surgery. The degree of progression of the cancer was Stage Ⅰ, Ⅱ, ⅢA, ⅢB, and Ⅳ in 1, 11, 3, 0, and 2 cases, respectively, and chemotherapy was administered for the 2 patients with Stage Ⅳcancer. One patient died unexpectedly due to thoracic aortic rupture after the surgery. In our hospital, we positively perform surgeries for CRC to avoid decreases in ADL. On the other hand, we often encounter unexpected complications due to many comorbidities. We report the CRC treatment strategy for elderly people in our hospital with specific examples.

[A Case Report of Gastrointestinal Bleeding with Difficulty in Diagnosis].

The authors report a case involving a 55-year-old female patient who presented with melena and anemia 8 years ago. Esophagogastroduodenoscopy, colonoscopy, and CT did not reveal any sign of lesions except multiple uterine myoma. On reevaluation after the onset of melena, we did not find any lesions. However, the patient had a recurrent episode of melena with progressive anemia(Hb level 12.8 g/dL→9.8 g/dL). CT revealed a 29mm mass in the right side of the pelvis, which was retrospectively observed in the past CT scan, although its position had changed. We suspected gastrointestinal stromal tumor (GIST). Small intestine fluoroscopy revealed the tumor with effusion of barium inside the translucent areas of the ileum. For diagnostic treatment, laparoscopic partial jejunum resection was performed. Pathological diagnostic examination revealed that the tumor consisted of spindle cell disarray with moderate density, fewer heterocysts, and rare mitosis. The tumor cells were c-kit positive and CD34 negative in immunohistochemistry. All the results were consistent with GIST. Eight years had passed before diagnosis and surgical treatment were performed. This case report emphasizes the difficulty of diagnose of GIST because of its low malignancy and slow progression.

[Appendix Cancer with Long-Term Survival after Multimodality Therapy-A Case Report].

We report a case of long-term survival in a 65-year-old woman with recurrent appendix cancer. In March 2002, she was diagnosed with appendix cancer and underwent ileocecal resection. The pathological diagnosis was mucinous cystadenocarcinoma, pT2N0M0, Stage Ⅰ. In April 2006, ovariohysterectomy was performed for right ovarian metastases. In February 2011, tumor resection was performed for disseminated recurrence after 4 courses of systemic chemotherapy(bevacizumab plus mFOLFOX6). Although no recurrent lesions had been detected on imaging, stepwise elevation of serum CEA level was observed from June 2016. In November 2017, computed tomography scan revealed a slow-growing tumor on the liver. We performed partial resection of the right hemidiaphragm for the disseminated tumor, and the pathological diagnosis was mucinous adenocarcinoma. The patient has been on continuous postoperative follow-up without recurrence until June 2019. Appendix cancer is relatively rare and has a worse prognosis compared to colorectal cancer because of higher frequency of disseminated metastases. With the multimodality therapy, our patient showed long-term survival over 17 years despite a disseminated recurrence. In cases of mucinous cystadenocarcinoma of the appendix, persistent follow-up and aggressive treatment are recommended.

[Giant Retroperitoneal Liposarcoma Treated by Surgical Resection and Chemotherapy - A Case Report].

As the treatment for the liposarcoma, there is no effective chemotherapy and a surgical remedy is required. We present the case of a 64-year-old man who complained about difficulty in swallowing and discomfort of throat. Computed tomography revealed a large enhancing left sided retroperitoneal mass invading the retroperitoneal space and it was displaced to the right. Preoperative diagnosis was retroperitonealmal ignant tumor. Tumor excision were performed and around 4.0 kg tumor was removed though its size was too big and resected it separately. Tumors increased 5 months later and became the second enucleation. After the second operation, we used eribulin as postoperative adjuvant chemotherapy. However, we needed extraction 3 times by the surgery because it recurred as peritonealdissemination. We continue surgicaltreatment and chemotherapy together as there are a part increasing relatively slowly and a high grade part increasing rapidly.

Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.

In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

[A Case Involving the Re-Application of TAE for the Rupture of Recurrent Dissemination Lesion after Initial TAE and Hepatectomy Was Performed for A Previous Rupture of HCC].

The patient was a 65-year-old man who had been previously diagnosed with chronic hepatitis B, but the patient had discontinued treatment while in his thirties. The patient was admitted to the emergency department after losing consciousness due to abdominal pain. Emergency contrast CT was performed in the shock state, and the diagnosis was hemorrhagic shock due to rupture of hepatocellular carcinoma(HCC). Emergency TAE was performed, and hemostasis was successful due to left hepatic arterial embolism. The tumor was confined to the liver lateral area and it was judged to be resectable curatively, upon state restoration. Ten days after TAE, lateral segmentectomy of the liver was performed. Pathological findings indicated moderately differentiated HCC, mostly necrotic and partially viable. He was discharged on 11POD. On 69POD, the patient reexperienced sudden abdominal pain after lunch. The abdominal pain continued while emergency contrast CT was performed at the time of visit in the shock state. Recurrence of multiple dissemination via high-absorption ascites was found around the largest tumor nest with lower left diaphragm diameter of 15cm, and it was judged that the HCC disseminated recurrence had ruptured. Emergency TAE was performed again, and hemostasis was successful by embolization of the left gastric artery and lower left diaphragm artery. Subsequently, tumor growth slowed after initiating oral administration of sorafenib, and the patient is alive 8 months after re-TAE.

[Dedifferentiated Chondrosarcoma of the Chest Wall].

A 79-year-old man complaining of an anterior chest mass with pain had an abnormal shadow on chest X-ray. A mass, 7 cm in size, with destruction of the right 4th rib was found on chest computed tomography. A F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) corresponding to the lesion showed an abnormal accumulation of FDG with the standardized uptake value(SUV) max=16.19. A malignant tumor of the chest wall origin was suspected and the tumor was resected with the 3th, 4th, and 5th ribs. Histologically, the tumor was diagnosed as dedifferentiated chondrosarcoma. He died of local recurrence about 5 months after the operation.

Prolonged survival after diagnosis of brain metastasis from breast cancer: contributing factors and treatment implications.

OBJECTIVE: The prognosis of breast cancer-derived brain metastasis is poor, but new drugs and recent therapeutic strategies have helped extend survival in patients. Prediction of therapeutic responses and outcomes is not yet possible, however. In a retrospective study, we examined prognostic factors in patients with breast cancer-derived brain metastasis, and we tested the prognostic utility of a breast cancer-specific Graded Prognostic Assessment in these patients. METHODS: Sixty-three patients diagnosed with brain metastasis from breast cancer treated surgically and adjuvantly were included. We examined clinical variables per primary tumor subtype: ER+/HER2- (luminal), HER2+ (human epidermal growth factor receptor type 2-enriched) or ER-/PR-/HER2- (triple negative). We also categorized patients' breast cancer-specific Graded Prognostic Assessment scores and analyzed post-brain metastasis survival time in relation to these categories. RESULTS: The breast cancers comprised the following subtypes: luminal, n = 18; human epidermal growth factor receptor type 2-enriched, n = 27 and triple-negative, n = 18; median survival per subtype was 11, 37 and 3 months, respectively. Survival of human epidermal growth factor receptor type 2-enriched patients was longer, though not significantly (P = 0.188), than that of luminal patients. Survival of triple-negative patients was significantly short (vs. human epidermal growth factor receptor type 2-enriched patients, P < 0.001). Karnofsky performance status, HER2 status and the disease-free interval (from initial treatment to first recurrence) were shown to be significant prognostic factors (Karnofsky performance status < 70: relative risk 2.08, P = 0.028; HER2+: relative risk 2.911, P = 0.004; disease-free interval < 24 months: relative risk 1.933, P = 0.011). Breast cancer-specific Graded Prognostic Assessment scores reflected disease-free intervals and survival times. CONCLUSIONS: Our data indicate that breast cancer-specific Graded Prognostic Assessment-based prediction will be helpful in determining appropriate therapeutic strategies for patients with brain metastasis from breast cancer.

[Resected Pulmonary Cryptococcosis Suspected as Lung Cancer;Report of a Case].

We report a case of pulmonary cryptococcosis suspected of lung cancer. A 65-year-old woman had an abnormal shadow on chest X-ray. A solitary nodule, 12 mm in size, with pleural indentation and spicula in S3 of the left lung was found on chest computed tomography. A serum cryptococcal antigen was negative. An abnormal accumulation of fluoro-2-deoxy-D-glucose(FDG)in the nodule was found with the standardized uptake value (SUV) max 5.04, suggesting lung cancer. The nodule was diagnosed as pulmonary cryptococcosis by surgical resection.

[Complete response in a case of anastomotic recurrence of rectal cancer treated with S-1 monotherapy].

A 63-year-old woman underwent a low anterior resection for rectal cancer in 2002.A n anastomotic recurrence was diagnosed in July 2011.S he rejected the possibility of colostomy as radical surgery.Chemotherapy consisting of capecitabine+ oxaliplatin (XELOX) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX6) + bevacizumab were not possible because of high costs. In view of the lower costs and the potential for ambulation, S-1 monotherapy was started. After 3 months, a reduction in the recurrent lesion was observed.After 19 months, the recurrent lesion revealed a scar, which was judged by biopsy to be Group 1.We had achieved a pathological complete response (CR).The standard treatment for recurrent colon cancer is surgical resection or multidrug chemotherapy. However, in view of a patient's quality of life (QOL), S-1 monotherapy may be considered as a potential therapy.

[No recurrent case of the combination of surgical management with chemotherapy].

A 61-year-old man consulted a nearby doctor with the chief complaint of lassitude in June 2010. Blood tests revealed a hemoglobin level of 3.7 g/dL. The observation of significant anemia resulted in a full medical workup. On computed tomography (CT) findings, a large mass (17 × 10 cm in diameter) was found in the abdominal region. The lumen was distended with accumulation of air and fluid. In addition, I continued with a bladder wall, but did not recognize the abnormality that was apparent to a bladder lumen. There was no evidence of ileus. A diagnosis of appendix cancer or sarcoma was made preoperatively. During surgery, the bladder was observed to have some permeation, but the bladder wall contained a lesion of small intestinal origin with only slight permeation. The neighboring small intestine was surrounded by the tumor, with 3 sites of penetration. Histopathologic diagnosis indicated a high-risk gastrointestinal stromal tumor (GIST) with mitotic figures (44/50 high power fields). In accordance with the recommended guidelines, imatinib was administered for 1 year. Two sites of recurrences were observed by CT after discontinuing imatinib. A second operation was performed without increase because of the absence other lesions. Separate lesions in the sigmoid colon and jejunum were removed surgically. The tumor in the sigmoid colon was a lesion with high denaturation for mesenchymal system tumor such as GISTs by pathologic diagnosis. The lesion in the small mesentery was a suture granuloma. In this case, the combination of surgical management with chemotherapy resulted in good quality of life with no recurrence despite the presence of a high-risk GIST.

[Multi-modarity treatment for colon liver metastases using biliary stent-report of a case].

We report the case of a 69-year-old male patient with diagnoses of sigmoid colon cancer, ascending colon cancer, and metastatic liver cancer. We performed sigmoidectomy, right hemicolectomy, and central venous port placement. Because the liver metastasis was multifocal, chemotherapy was first initiated and then hepatic resection was performed. However, during chemotherapy, ileus, with a peritoneal dissemination to the small intestine, developed. Small intestine resection and radiation therapy to the pelvic region of the transition were further performed. Thereafter, obstructive jaundice due to obstruction of the bile duct in the hilar area developed, and therefore, we inserted a biliary stent. However, 2 years 9 months after the first medical examination, this patient died of colon cancer. The guidelines above, still chemotherapy developed, treatment policy of recurrent colorectal cancer, have recommended surgical resection with respect to what resectable as local therapy. This case shows that combination therapy with chemotherapy, surgical therapy, radiation therapy, and local therapy such as biliary stenting, is useful.

[Case of early antral gastric cancer diagnosed during follow up of pyloric stenosis by the gastro-duodenal ulcer].

A 65-year-old man was admitted to our hospital with nausea, vomiting and appetite loss. First upper endoscopic examination and X-ray examination showed a peptic ulcer and a pyloric stenosis. Fiberscope could not go through the pyloric ring. Computed tomography examination and biopsy showed no evidence of malignancy. Though we considered surgical resection of the stenosis at first, he could eat a staple food with therapy of proton pump inhibitor. So we followed up with upper endoscopic examinations. Second, third and forth upper endoscopic examinations showed no evidence of malignancy. Fifth upper endoscopic examination showed an ulcer scar on the pyloric ring and a 0-IIc carcinoma in the antral greater curvature. Distal gastrectomy with D2 lymph node dissection and B-II reconstruction. Pathologically, a mucosal carcinoma with no lymph node metastasis and U1-III peptic ulcer were diagnosed.

Severe cytopenia during adjuvant chemotherapy for early breast cancer in a patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disorder characterized by decreased CD4+ T-cell counts in the absence of human immunodeficiency virus (HIV) infection. Similar to HIV infection, ICL is commonly associated with acquired immunodeficiency syndrome-defining cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer; however, the presentation of breast cancer in a patient with ICL is rare. The current study presented the clinical course of a patient with early breast cancer and ICL. Following surgery, the patient underwent adjuvant chemotherapy comprising doxorubicin plus cyclophosphamide, followed by paclitaxel. The patient's immunodeficiency status required the prophylactic administration of clarithromycin, trimethoprim-sulfamethoxazole and valganciclovir. Throughout the course of chemotherapy, the patient experienced severe complications of febrile neutropenia, anemia, neutropenia and thrombocytopenia, and was eventually forced to discontinue anticancer chemotherapy, as the relative dose intensity (RDI) could not be maintained. Similar hematological complications and reduced RDI, leading to worse outcomes, are also common in patients with HIV infection receiving chemotherapy, suggesting that CD4+ T cell-deficient patients are prone to developing cytopenia during chemotherapy. The present study demonstrates the importance of further data accumulation in patients with ICL with cancer and the development of a methodology for maintaining the RDI.

Usefulness of indocyanine green fluorescence-guided small intestinal bleeding site identification in small bowel resection: a report of two cases and literature review.

Small bowel bleeding that does not respond to conservative therapy requires surgical resection. However, identifying the bleeding sites intraoperatively is challenging. Indocyanine green (ICG) fluorescence imaging improves diagnosis of small bowel bleeding and surgical decision-making by visualizing blood flow. Herein, we reported two cases of small bowel bleeding that were successfully treated by using ICG to identify the bleeding sites and determine the extent of small bowel resection. The patients were a 46-year-old and a 75-year-old woman, both of whom presented with melena. Contrast-enhanced computed tomography and arteriography confirmed small bowel bleeding, and rebleeding occurred in both patients after transcatheter arterial embolization. Emergent surgeries were performed, and intraoperative selective angiography with ICG injections was conducted to identify obscure bleeding sites. ICG fluorescence identified all bleeding sites in both cases, and small bowel resections were successfully performed. The postoperative courses were uneventful, and both patients had a favorable postoperative course without recurrence of bleeding. ICG fluorescence imaging can safely identify the sites of intestinal bleeding and determine the appropriate extent of bowel resection.

[A case of primary breast cancer responding to pre-operative chemotherapy with the combination of paclitaxel and carboplatin for ovarian cancer].

A 62-year-old woman was diagnosed with primary left breast cancer during a follow-up for an ovarian tumor. She had at first undergone surgical resection of an ovarian tumor, and a pathological examination had revealed ovarian cancer. Gynecologists decided to treat her ovarian cancer with chemotherapy, and we were initially planning to provide treatment for breast cancer after that was completed. Sentinel lymph node biopsy performed before chemotherapy revealed no axillary metastases. The patient received six courses of intravenous PTX (175 mg/m2 on day 1, every 3 weeks) and intravenous CBDCA (AUC6 on day 1, every 3 weeks) as combination therapy. Abdominal lymph node dissection was performed between chemotherapy courses 3 and 4. The lump in the left breast showed partial clinical response, and partial resection of the left breast was performed after completion of chemotherapy. In Japan, few cases of primary breast cancer treated preoperatively using carboplatin-containing regimens have been described.