[A Case of Recurrent Breast Cancer with Delayed Wound Healing Induced by Bevacizumab].

Bevacizumab plus paclitaxel therapy for recurrent breast cancer did not prolong overall survival(OS)in clinical trials, but it was efficacious for treating life-threatening HER2-negative recurrent breast cancer. This regimen is often used in daily clinical practice by breast surgeons. However, bevacizumab therapy results in unique adverse events, of which proteinuria and hypertension are relatively frequent. Moreover, the symptoms often improve on reducing the dose or discontinuing the drug. In this case, bevacizumab administration caused delayed wound healing, making subsequent anticancer treatment difficult, and consequently we could not prolong the patient's life.

[A Case of COVID-19 Infection during Postoperative Chemotherapy for Breast Cancer Treated with Antibody Cocktail Therapy to Prevent Disease Aggravation].

The outbreak of COVID-19 has caused a global pandemic, and it has been reported that patients with cancer are at high risk of developing complications from the disease. However, we believe that prolonged interruption of chemotherapy due to extended COVID-19 treatment is not desirable, given the intensity of cancer treatment. We report a case of COVID-19 infection during postoperative chemotherapy for breast cancer, in which antibody cocktail therapy prevented disease aggravation and delayed breast cancer treatment. The patient is a 45-year-old woman who came to our hospital with a complaint of a right mammary mass. The mass was diagnosed as invasive ductal carcinoma with an ER and PR of 0%, a HER2 score of 1+, and a Ki-67 of 90%. After preoperative chemotherapy, she underwent a right mastectomy and axillary dissection. The pathology result showed non-pCR. The administration of capecitabine was started as adjuvant therapy. On day 8 of cycle 3, she developed a fever in the 39℃ range, and on the next day, a COVID-19 POC gene test confirmed that the patient was positive for infection. On the same day, neutralizing antibody drugs(casirivimab and imdevimab)were administered as antibody cocktail therapy. Two days after treatment(day 11), a blood test showed Grade 3 neutropenia, but there was no recurrence of fever or evidence of pneumonia. After 2 weeks, capecitabine was resumed, and the patient was able to complete 8 cycles of capecitabine therapy without any major complications.

[ESR1 Mutation-Positive Recurrent Breast Cancer Successfully Treated with Letrozole plus Abemaciclib].

Approximately 70% of breast cancers are estrogen receptor(ER)positive, an indication for endocrine therapy. The first choice of treatment for ER-positive metastatic recurrent breast cancer is endocrine therapy, which has relatively few side effects; however, many of these side effects become resistant during treatment. One of the resistance mechanisms is mutations in the ESR1 gene, which have also been found to occur after long-term aromatase inhibitor(AI)treatment. Here, we describe our experience of a case in which long-term PR was achieved with AI(letrozole)plus abemaciclib despite ESR1 mutation positivity in cancer genetic screening and review the literature.

[Olaparib Could Be Re-Administered after Chemotherapy].

Olaparib, a PARP inhibitor, was approved in 2018 for BRCA1/2 gene mutation and HER2-negative inoperable or recurrent breast cancer with previous chemotherapy. Olaparib is an important drug with minor adverse events compared to chemotherapeutic drugs. In addition, it is expected to exert a high therapeutic effect on breast cancer with BRCA mutations due to its characteristics. We report a case of BRCA2-mutated breast cancer in a patient in whom olaparib was initiated. The patient complained of strong nausea; however, the treatment could be continued by reducing the dose of olaparib to 400 mg and using multiple drugs such as antiemetics and anxiolytics in advance.

[A Case of Severe Drug-Induced Lung Injury during Preoperative Chemotherapy for Breast Cancer in the Early Stages of the COVID-19 Epidemic].

Drug-induced interstitial lung disease(DILD)is defined as a drug-related respiratory disorder that occurs during drug administration. For diagnosis, it is important to differentiate similar diseases. We report a case of severe drug-induced lung injury during preoperative chemotherapy for breast cancer in the early stages of the COVID-19 epidemic, which was difficult to diagnose. The patient was a 48-year-old woman. The chief complaint was fever and dyspnea. She was diagnosed with left breast cancer(ER 30-40%, PR 0%, HER2 1+, Ki-67 84%), cT4bN1M0, cStage ⅢB and was treated with dose-dense AC therapy and docetaxel sequentially as preoperative chemotherapy. On the 21st day of the first course of docetaxel, the patient developed respiratory failure. A CT scan of the chest showed diffuse ground-glass shadows in the bilateral lung fields, suggesting severe viral pneumonia caused by COVID-19, and the patient was admitted to the isolation ward and managed with an intubated ventilator. PCR and LAMP were negative, and COVID-19 was ruled out. Based on the clinical course and CT findings, we started steroid pulse therapy with DILD in mind. The patient was extubated on the 5th day after the onset of the disease because the steroid pulse therapy was successful and her respiratory condition was stable. Preoperative chemotherapy was stopped, and a left mastectomy and axillary dissection were performed. In this case, COVID-19 should have been suspected first, but we were able to minimize the interruption of treatment by taking early action and keeping DILD in mind.

Transplantation of Graft Anti-Host Cytotoxic T Lymphocytes Along with Allogeneic Bone Marrow Skips Macrophage-Induced Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) is a physiological response of the graft to allogeneic hosts. However, the effector cells, affected organ(s), and cytokines in the GVHD remain controversially discussed, without having determined a particular cytotoxic activity of the graft against the host. After i.v. injection of C57BL/6 (H-2b) spleen cells into irradiated BDF1 (H-2b/d) mice, the hosts developed interferon-gamma (IFN-γ)-dependent bone marrow (BM) GVHD on days 5-17. When H-2DdKd transgenic H-2b lymphoma cells were i.p. inoculated into irradiated, H-2b splenocyte-transplanted H-2b/d mice, the infiltration of macrophages cytotoxic against H-2DdKd transgenic H-2b mouse skin epithelia (a GVHD activity) into the peritoneal cavity preceded several days the infiltration of interleukin (IL)-2-dependent cytotoxic T lymphocytes (CTLs) to achieve a graft-versus-leukemia (GVL) effect. In contrast, allogeneic BM transplanted alone into the irradiated mice did not induce GVHD for 44 days, whereas i.v. injection of graft anti-host macrophages or graft anti-host CTLs along with allogeneic BM, respectively, induced GVHD or promoted the GVL effect in the absence of GVHD. These results revealed that macrophage-induced GVHD and the CTL-mediated GVL effect were a set (Th1: IFN-γ/IL-2) response of the graft to allogeneic hosts and leukemia cells, respectively, and that graft T cell activation rather than inhibition skipped GVHD after BM transplantation.

Duodenal obstruction due to chronic pancreatitis of the pancreas tail treated by surgical intervention: A case report.

RATIONALE: Duodenal obstruction (DO) sometimes induces the groove pancreatitis. However, the case of DO due to chronic pancreatitis in pancreas tail (CPPT) is extremely rare. Therefore, the managements of DO caused by CPPT have not been established yet. PATIENT CONCERNS: A 68-year-old man, who was under the treatment of chronic pancreatitis, presented to our hospital with nausea and abdominal pain. He was diagnosed as DO caused by CPPT. The Conservative treatment, including the nasogastric aspiration and intravenous infusion under the absence of food, was performed. The drainage fluid from naso-gastric tube had been more than 2000 ml per a day although continuing treatment for 14 days. Hence, we decided that the conservative therapy was failed and the surgical intervention was required. DIAGNOSIS: Computed tomography showed gastroduodenal expansion due to stenosis at the horizontal portion of the duodenum with increasing pancreatic pseudocyst. The contrast radiography of the duodenum showed severe stenosis around Treitz ligament. His pre-surgical diagnosis was DO due to CPPT through exclusion of other etiologies for DO such as annular pancreas, SMA syndrome, duodenal diaphragm and Crohn disease. INTERVENTION: Spleen preserving distal pancreatectomy (Warshaw operation) was performed with gastrojejunostomy. During surgery, marked redness and thickness of the mesenteric serosa around Treiz ligament were observed. His surgical findings were supported our preoperative prediction. OUTCOMES: The patient was successfully treated and discharged uneventfully after postoperative day 14. At the 9 months follow-up visit, the patient is still doing well without any symptoms. CONCLUSION: Combination of gastrojejunostomy and Warshaw operation is one of the ideal surgical procedures for patients of DO due to CPPT.

Comparison of a chymase inhibitor and hyaluronic acid/carboxymethylcellulose (Seprafilm) in a novel peritoneal adhesion model in rats.

Adhesion formation that occurred after alkali-induced injury of the cecum was used as a novel adhesion model in rats, and it was compared with that of a common adhesion model after abrading the cecum. Using the novel adhesion model, inhibition of adhesion formation by a chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, and by sodium hyaluronate/carboxymethylcellulose (Seprafilm) was evaluated, and their mechanisms were assessed. The degree of adhesion formation was more severe and more stable in the alkali-induced injury model than in the abrasion-induced injury model. Both the chymase inhibitor and Seprafilm showed significant attenuation of the degree of adhesion 14 days after alkali-induced injury. Chymase activity in the cecum was significantly increased after alkali-induced injury, but it was significantly attenuated by the chymase inhibitor and Seprafilm. Myeloperoxidase and transforming-growth factor (TGF)-ß levels were significantly increased after alkali-induced injury, but they were attenuated by both the chymase inhibitor and Seprafilm. At the level of the adhesions, the numbers of both chymase-positive cells and TGF-ß-positive cells were significantly increased, but their numbers were reduced by the chymase inhibitor and Seprafilm. In conclusion, a chymase inhibitor attenuated the degree of adhesions to the same degree as Seprafilm in a novel peritoneal adhesion model that was more severe and more stable than the common adhesion model, and not only the chymase inhibitor, but also Seprafilm reduced the chymase increase at the adhesions.

Surgical Outcome and Hepatic Regeneration after Hepatic Resection for Hepatocellular Carcinoma in Elderly Patients.

INTRODUCTION: The rising proportion of elderly patients (aged 80 yearsor above) in our population means that more elderly patients are undergoing hepatectomy. METHODS: Five-hundred and thirty patients who underwent hepatectomy for hepatocellular carcinoma (HCC) were retrospectively analyzed with respect to their preoperative status and perioperative results, including remnant liver regeneration. The remnant liver volume was postoperatively measured with multidetector CT on postoperative day 7 and 1, 2, 5, and 12 months after surgery. An elderly group (aged 80 or older) was compared with a non-elderly group (aged less than 80 years). RESULTS: Underlying diseases of the cardiovascular system were significantly more common in the elderly group (57.8%, p = 0.0008). The postoperative incidence of Clavien-Dindo Grade IIIa or higher complications was 20.0% in the elderly group and 24.3% in the non-elderly group, and this difference was not significant. As for regeneration of the remnant liver after resection, this was not morphologically delayed compared to the non-elderly group. CONCLUSIONS: In this study, we have demonstrated that safe, radical hepatectomy, similar to procedures performed on non-elderly patients, can be performed on patients with HCC aged 80 and older with sufficient perioperative care.

A Concealed "Natural Orifice": Umbilicus Anatomy for Minimally Invasive Surgery.

INTRODUCTION: A recent development in minimally invasive surgery (MIS) is single-port surgery, where a single large multiport trocar is placed in the umbilicus. All medical schools require that students complete an anatomy course as part of the medical curriculum. However, there is limited instruction regarding the detailed parts of the "umbilicus." In several famous anatomy atlases, the umbilicus is not dissected at all and is merely represented as a button. Until now, the true nature of the umbilicus has not been anatomically demonstrated. METHODS: Five cadavers were obtained from the Osaka Medical College medical student anatomy class. The umbilicus was dissected in the anatomy laboratory, to demonstrate all the layers. A detailed dissection was performed, focusing on the exact center of the umbilicus, in order to ascertain whether there exists a "natural orifice" or a fascial defect. RESULTS: In all cadavers, a small defect of fascia was identified just below the center of the umbilicus. Yellow fatty tissue was present just below the skin in the exact center of the umbilicus. A probe placed exactly in the middle of this defect passes easily through into the abdominal cavity. CONCLUSIONS: With the widespread use of MIS, umbilical incision is commonly used to reduce pain and improve cosmetic results. This study consistently revealed a natural defect of fascia in the center of the umbilicus. Therefore, the umbilicus can be called a concealed "natural orifice." It is important to recognize and utilize this defect effectively to minimize unnecessary tissue trauma during MIS.

Prognostic factors of hepatectomy in initially unresectable colorectal liver metastasis: Indication for conversion therapy.

The aim of the present study was to retrospectively identify prognostic factors for long-term cumulative survival following liver resection in patients with primarily unresectable colorectal cancer who had previously received conversion therapy. A multicentre study was designed to ascertain the appropriate indication for conversion therapy. The study included 34 patients who underwent conversion therapy at 5 university hospitals. Patients' background, operative factors, recurrence rate and survival rate were evaluated, and factors influencing therapy outcomes were identified. The median duration of preoperative chemotherapy was 3 months and the response rate was 39.8%. Upon resection, the median tumour size was 47 mm and the median number of tumours was 4. The recurrence-free and cumulative survival rates 5 years after liver resection were 13.7 and 39.3%, respectively. Postoperative complications developed in 12 patients. A response rate >40% was indicated with regards to the assessed prognostic factors for long-term cumulative survival following liver resection and an absence of postoperative complications was noted. It was revealed that conversion therapy should be considered prior to liver resection, particularly for patients with response rates exceeding 40%. Absence of postoperative complications is also an independent predictor of long-term cumulative survival after liver resection. In light of these findings, it was consisted that an optimal response rate >40% could be used as an indicator for surgical resection in conversion therapy. In addition, meticulous intra- and postoperative managements are important for decreasing postoperative complications and improving long-term cumulative survival.

A complete response to capecitabine and oxaliplatin chemotherapy in primary duodenal carcinoma with liver and nodal metastases: a case report.

BACKGROUND: Primary duodenal adenocarcinoma (PDC) is a rare and lethal disease, and cases with nodal or distant metastasis have a poor prognosis. There are several reports of unresectable duodenal adenocarcinoma responding to systemic chemotherapy. However, there is little data on conversion surgery for PDC with distant metastasis. CASE PRESENTATION: We report a 55-year-old man with unresectable PDC with liver and nodal metastases responding to systemic chemotherapy with capecitabine and oxaliplatin (XELOX). His metastatic lesions completely disappeared by 18-fluorodeoxyglucose positron emission tomography/computed tomography after six courses of XELOX. Then, he underwent pancreaticoduodenectomy with lymph node dissection and partial resection of the liver. Postoperatively, the histological effect was determined to be grade 3, and the patient was diagnosed as having achieved pathological complete response (pCR). He is disease-free with no evidence of metastatic lesion for 14 months after surgery. Conversion surgery allowed R0 resection for unresectable PDC, and pCR can be achieved with XELOX treatment. CONCLUSION: To the best of our knowledge, this case is the first report of conversion surgery for unresectable PDC with liver and para-aortic lymph node metastases.

Nogo-B (Reticulon-4B) functions as a negative regulator of the apoptotic pathway through the interaction with c-FLIP in colorectal cancer cells.

Nogo-B is a member of the Nogo/Reticulon-4 family and has been reported to be an inducer of apoptosis in certain types of cancer cells. However, the role of Nogo-B in human cancer remains less understood. Here, we demonstrated the functions of Nogo-B in colorectal cancer cells. In clinical colorectal cancer specimens, Nogo-B was obviously overexpressed, as determined by immunohistochemistry; and Western blot analysis showed its expression level to be significantly up-regulated. Furthermore, knockdown of Nogo-B in two colorectal cancer cell lines, SW480 and DLD-1, by transfection with si-RNA (siR) resulted in significantly reduced cell viability and a dramatic increase in apoptosis with insistent overexpression of cleaved caspase-8 and cleaved PARP. The transfection with Nogo-B plasmid cancelled that apoptosis induced by siRNogoB in SW480 cells. Besides, combinatory treatment with siR-Nogo-B/staurosporine (STS) or siR-Nogo-B/Fas ligand (FasL) synergistically reduced cell viability and increased the expression of apoptotic signaling proteins in colorectal cancer cells. These results strongly support our contention that Nogo-B most likely played an oncogenic role in colorectal cancer cells, mainly by negatively regulating the extrinsic apoptotic pathway in them. Finally, we revealed that suppression of Nogo-B caused down-regulation of c-FLIP, known as a major anti-apoptotic protein, and activation of caspase-8 in the death receptor pathway. Interaction between Nogo-B and c-FLIP was shown by immunoprecipitation and immunofluorescence studies. In conclusion, Nogo-B was shown to play an important negative role in apoptotic signaling through its interaction with c-FLIP in colorectal cancer cells, and may thus become a novel therapeutic target for colorectal cancer.

Therapeutic experience with hepatoblastoma associated with trisomy 18.

Trisomy 18 is often fatal, but patients with this disease can now have longer survival due to proactive treatment intervention. However, hepatoblastomas may develop in these patients. In this study, we report four cases of hepatoblastoma associated with trisomy 18. All of the patients had congenital heart disease and three had undergone intracardiac surgical repair. Tumor growth was relatively slow in all cases, and there were no problems with chemotherapy tolerability and surgical resection. Three of the patients are currently disease-free and the fourth is alive with remaining of the tumor. These cases suggest that combined chemotherapy and surgical resection may be an option to treat hepatoblastoma associated with trisomy 18 when cardiac pulmonary function is relatively stable.

Preoperative Chemotherapy May Not Influence the Remnant Liver Regenerations and Outcomes After Hepatectomy for Colorectal Liver Metastasis.

BACKGROUND: Various chemotherapy regimens have been shown to improve outcomes when administered before tumor excision surgery. However, there is no consensus on the utility of multidisciplinary treatment with preoperative chemotherapy for treating colorectal liver metastasis (CLM). MATERIALS AND METHODS: Two hundred-fifty patients who underwent hepatectomy were retrospectively analyzed using propensity score matching. Postoperative outcomes were evaluated with a focus on the effect of pre-hepatectomy chemotherapy on regeneration of the remnant liver in patients with CLM. The remnant liver volumes (RLVs) were postoperatively measured with multidetector computed tomography on days 7 and months 1, 2, 5, and 12 after the operation. RESULTS: RLV regeneration and blood test results did not significantly differ between patients who underwent preoperative chemotherapy versus those who did not immediately after surgery or at any time point from postoperative day 7 to postoperative month 12. The 1-, 2-, and 3-year overall survival (OS) rates for all patients were 94.6, 86.2, and 79.9%, respectively; the corresponding disease-free survival (RFS) rates were 49.3, 38.6, and 33.7%, respectively. There were no significant differences in OS and RFS between the two groups after hepatic resection. The recurrence rates, including marginal and intrahepatic recurrences, as well as resection frequency of the remnant liver were not significantly different between the two groups. CONCLUSION: Preoperative chemotherapy may have no appreciable benefit for patients with CLM in terms of perioperative and long-term outcomes.

Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma.

Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag-2 family of ligands for the Notch receptor and plays a role in Notch signaling. We have previously revealed that the expression of DLL3 is silenced by aberrant DNA methylation and that overexpression of DLL3 in the HuH2 hepatocellular carcinoma (HCC) cell line induced apoptosis. In the present study, we first confirmed the methylation of DLL3 in HuH2 cells and analyzed the methylation status of the DLL3 promoter region by bisulfite sequencing. Furthermore, we investigated whether other epigenetic modifications, such as histone acetylation and histone methylation, affected the expression of DLL3. Treatment with the DNA methylation inhibitor, 5-azadeoxycytidine (5-Aza-dC) slightly reactivated DLL3 mRNA expression and bisulfite sequencing revealed that CpG sites in the DLL3 promoter region of the HuH2 cells were densely-methylated. In addition, a significant increase in the expression of DLL3 was observed when the cells were treated with 5-Aza-dC in combination with the histone deacetylase inhibitor trichostatin A. However, an inhibitor of the dimethylation of histone H3 lysine 9 (H3K9me2) or the trimethylation of histone H3 lysine 27 (H3K27me3), modifications that are associated with gene silencing, had no effect on DLL3 reactivation. In combination with the findings from our previous study, these results indicated that DLL3 expression was silenced in HCC cells by DNA methylation and was more readily affected by histone acetylation than histone methylation (H3K9me2 or H3K27me3).

Short- and Long-Term Results of Laparoscopic Parenchyma-Sparing Hepatectomy for Small-Sized Hepatocellular Carcinoma: A Comparative Study Using Propensity Score Matching Analysis.

The aim of this study was to evaluate the degree of invasiveness and the clinical outcomes of laparoscopic parenchyma-sparing hepatectomy (LPSH) for a maximum hepatocellular carcinoma (HCC) size ≤5 cm. Sixty-one LPSHs and 175 open parenchyma-sparing hepatectomies (OPSHs) for small-sized HCC were analyzed using a propensity score matching analysis. The median operative time was significantly shorter in the LPSH group (194 min) than in the OPSH group (275 minutes) (P < 0.0001). The estimated blood loss was significantly lower in the LPSH group (100 mL) than in the OPSH group (380 mL) (P < 0.0001). The incidences of superficial incisional surgical site infections and respiratory complications were significantly lower in the LPSH group than in the OPSH group (P = 0.0161 and 0.0285, respectively). During the postoperative course, the white blood cell counts and C-reactive protein levels were significantly lower in the LPSH group. There were no differences in overall survival and disease-free survival (P = 0.1293 and 0.4039, respectively), and no significant differences in terms of type of recurrence and site of intrahepatic recurrence (P = 0.1410). The data from the present series suggest the lesser invasiveness and safety of LPSH even for small-sized HCC patients.

Delta-like 3 is silenced by HBx via histone acetylation in HBV-associated HCCs.

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. We previously showed that expression of Delta-like 3 (DLL3), a member of the family of Delta/Serrate/Lag2 ligands for the Notch receptor, is silenced by aberrant DNA methylation and that overexpression of DLL3 in an HCC cell line induces cellular apoptosis. However, how DLL3 expression is regulated during hepatocarcinogenesis is still unclear. Here, we show that silencing of DLL3 during hepatocarcinogenesis is closely related to viral infection, especially hepatitis B virus (HBV) infection (p = 0.005). HepG2.2.15 cells, which are stably transformed with the HBV genome, showed lower DLL3 expression than the parent cell line, HepG2 cells. Treatment with Hepatitis B virus X protein (HBx) small interfering RNA upregulated DLL3 expression in HepG2.2.15 cells, and overexpression of HBx in HepG2 cells downregulated DLL3 expression. Treatment of cells with a histone deacetylase inhibitor induced DLL3 expression in HepG2.2.15 cells. These data suggest that DLL3 expression is silenced during hepatocarcinogenesis in association with HBV infection via an epigenetic mechanism.

Span-1 and CA19-9 as Predictors of Early Recurrence and Lymph Node Metastasis for Patients with Invasive Pancreatic Cancer after Pancreatectomy.

Because pancreatic cancer is a disease with a dismal prognosis due to the high rate of early recurrence even after curative surgery, selecting the most effective treatment in an individual requires preoperative assessment of the tumor characteristics, including the potential for early recurrence. The study cohort included 84 patients undergoing surgical resection of pancreatic cancer. Univariate and multivariate analyses were conducted to identify the risk factors for early recurrence within six months after curative resection. Early recurrence was associated with a platelet-lymphocyte ratio ≥0.23 (P = 0.04), carbohydrate antigen 19-9 (CA19-9) ≥200 (P = 0.01), and S-pancreas-1 antigen (Span-1) ≥37 (P = 0.0004) by univariate analysis. Multivariate analysis identified CA19-9 ≥200 and Span-1 ≥37 as independent risk factors for early recurrence. Patients with both risk factors had a significantly higher rate of lymph node metastasis than those with no or one risk factor. Span-1 ≥ 37 and CA19-9 ≥ 200 are independent risk factors for early recurrence in patients who underwent surgical resection, and the combination of Span-1 ≥37 and CA19-9 ≥200 is a useful indicator of lymph node metastasis.