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.

Characteristics, treatment trends, and long-term outcomes of Japanese patients with pregnancy-associated breast cancer (PABC).

PURPOSE: To clarify the characteristics, treatment trends, and long-term outcomes of patients with pregnancy-associated breast cancer (PABC). METHODS: PABC includes breast cancer diagnosed during pregnancy (PBC) and breast cancer diagnosed within 1 year after childbirth or during lactation (LBC). We compared clinical characteristics of 126 patients with LBC and 49 patients with PBC who underwent surgery at our hospital from 1946 to 2018. Survival was compared between patients with LBC and those with PBC in terms of breast cancer-specific disease-free survival (BC-DFS) and overall survival (OS). RESULTS: Patients with LBC were more likely to have family history, lymph node metastasis, lymphatic invasion, and to receive chemotherapy than patients with PBC. Patients with LBC showed poorer BS-DFS and OS than patients with PBC. Among patients with LBC, those treated after 2005 were older at surgery, had a smaller tumor size, received more systemic therapy, and had a more favorable prognosis than patients treated before 2004. Family history, breast cancer within 1 year after childbirth, and surgery before 2004 as well as cStage, lymph node metastasis, and lymphatic invasion were significantly associated with poor prognosis in patients with LBC. In the multivariate analysis for BC-DFS and OS among patients with PABC, LBC vs PBC did not remain as an independent prognostic factor while cStage remained. CONCLUSION: Patients with LBC had a poorer prognosis than those with PBC, most likely due to disease progression rather than biological characteristics. Early detection and optimization of systemic treatments are critical for improving the outcomes of patients with LBC.

Infection control of COVID-19 in operating theaters in a designated hospital for specified infectious diseases in Japan.

At the beginning of the COVID-19 pandemic in 2020, many hospitals around the world recommended stopping elective surgery as a precaution to stop the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The number of elective surgeries was reduced in Japan due to several waves of the pandemic. This work describes the management of COVID-19 and actual polymerase chain reaction (PCR) screening in operating theaters at the National Center for Global Health and Medicine (NCGM), a designated hospital for specified infectious diseases in Japan. The following three steps for COVID-19 infection control were taken to maintain the operating theater: i) Do not bring COVID-19 into the operating theater, ii) Infection control for all medical staff, and iii) Surgical management of surgical patients with COVID-19. We introduced checklists for surgical patients, simulations of surgery on infected patients, screening PCR tests for all surgical patients, and use of a negative pressure room for infective or suspected cases. We determined the flow and timing of surgery for patients with COVID-19. However, many aspects of COVID-19 infection control measures in the operating theater are still unclear. Therefore, infection control measures require further advances in the future to manage new infections.

Breast Cancer Treatment in a Patient with Decubitus Ulcer Infection Secondary to Spina Bifida: Surgical Resection versus Neoadjuvant Chemotherapy.

Spina bifida (SB) is a congenital neural tube defect that often presents with neurological disability and decubitus ulcers. A 66-year-old woman with SB presented to our hospital with decubitus ulcers and was treated by a plastic surgeon. She was referred to our department because of a mass measuring 5 × 4 cm in the superolateral quadrant of the right breast. The size of the right axillary lymph node (LN) was 2 × 1 cm. A core-needle biopsy revealed an invasive ductal carcinoma. Total mastectomy and axillary LN dissection were planned. However, 2 days prior to surgery, the size of the mass and the LN rapidly increased to 7 × 4 cm and 3 × 2 cm, respectively. Furthermore, the enlarged LN was close to the thoracodorsal artery. Since complete resection was difficult, neoadjuvant chemotherapy was also administered. On day 11 of neoadjuvant chemotherapy, the patient was febrile and developed a decubitus ulcer infection at the buttock. The neutrophil count was within normal limits; thus, she was not diagnosed with febrile neutropenia. Follow-up computed tomography revealed a shrinking of the mass to 5 × 4 cm after the first cycle of neoadjuvant chemotherapy. After 17 days of antibiotic therapy and drainage, total mastectomy and axillary LN dissection were performed. Due to the risk of recurrence of infection, adjuvant chemotherapy was discontinued and hormone therapy was initiated. In conclusion, indications for chemotherapy should be carefully evaluated in SB patients with lower limb paralysis and decubitus ulcers.

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.

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome.

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

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.

Five screening-detected breast cancer cases in initially disease-free BRCA1 or BRCA2 mutation carriers.

Individuals carrying pathogenic BRCA1 or BRCA2 mutations have an increased lifetime risk of breast and/or ovarian cancer. The incidence of breast cancer amongst disease-free BRCA mutation carriers under surveillance and the clinical and pathological characteristics of those who subsequently develop the disease remain unclear in Japan. We reviewed the records of 155 individuals with BRCA1 or BRCA2 mutations identified by genetic testing between January 2000 and December 2016. At the time of genetic testing, 26 individuals with one of these mutations had no history of breast cancer and were therefore enrolled in a surveillance program that included biannual ultrasonography, clinical breast examination, annual mammography, and conditional magnetic resonance imaging for the early detection of primary breast cancer. During the surveillance period, 5 individuals with BRCA1 or BRCA2 mutations were diagnosed with primary breast cancer. The mean surveillance duration until breast cancer diagnosis was 48 months. The incidence of primary breast cancer during surveillance in initially disease-free BRCA mutation carriers was 4.23%/year. In two cases, the tumors were only detectable on MRI. The case 5 patient who presented with a tumor that was detected by self-examination, which then grew rapidly, had stage IIB triple-negative breast cancer. In conclusion, our results show that some challenges exist in the early detection of breast cancers in BRCA1 or BRCA2 mutation carriers. There are also some difficulties in approaching those individuals in Japanese society.

[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.

Ductal Carcinoma in situ Detected during Prospective MR Imaging Screening of a Woman with a BRCA2 Mutation: The First Case Report in Japan.

The present case is the first report in Japan in which a breast cancer was discovered as a result of prospective magnetic resonance imaging (MRI) screening study for BRCA1/2 mutation carriers who were free of breast or ovarian cancer. This case is significant and it verifies the importance of MRI screening in breast or ovarian cancer-free BRCA1/2 mutation carriers who do not exhibit positive mammographic or ultrasonographic findings.

[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.