[A Case of Pancreatic Cancer That Developed Peritoneal Recurrence after Radical Surgery following Neoadjuvant Chemoradiation Therapy(NACRT)with Pathological Complete Response(pCR)].

A 71-year-old woman was diagnosed with a tumor in the pancreatic head on CT imaging, which was performed as a close examination of an exacerbation of diabetes mellitus. The pancreatic tumor was diagnosed as resectable pancreatic cancer, and after preoperative adjuvant chemoradiotherapy, pancreatoduodenectomy was performed as a radical surgery. There were no residual tumor cells in the resected specimen histopathologically, and the patient was judged to have a pathological complete response(pCR). Six months of postoperative adjuvant chemotherapy was administered, but peritoneal recurrence was observed at 20 months postoperatively, and the patient is currently undergoing treatment for recurrence. There have been other reports of recurrence even after pCR was achieved with preoperative treatment, so it is important to follow up carefully, keeping in mind that pancreatic cancer is a latent systemic disease.

How is transfusion-associated graft-versus-host disease similar to, yet different from, organ transplantation-associated graft-versus-host disease?

Graft-versus-host disease (GVHD) is a rare, usually fatal complication following blood transfusion or organ transplantation, namely transfusion-associated GVHD (TA-GVHD) and organ transplantation-associated GVHD (OA-GVHD). The dominant mechanism of GVHD is exposure to viable donor lymphocytes that are not recognized as foreign by, but able to respond to, the recipient. The clinical features and relative risk factors of either TA-GVHD or OA-GVHD are yet to be fully understood. The current review article aims to discuss and summarize the similarities and differences between TA-GVHD and OA-GVHD to gain a deeper understanding of the pathogenesis. It is evident that the shared human leukocyte antigens (HLA) between donor and recipient and immunocompromised status of the recipient are the two main risk factors for the development of both TA-GVHD and OA-GVHD. In particular, the homozygous donor with donor-dominant one-way matching at the three loci HLA-A, -B, and -DR has a high risk of developing GVHD following liver transplantation, and such donors should be excluded to prevent it. However, the development of GVHD is thought to be related to a combination of several risk factors, and the contribution of each risk factor remains unknown. Further studies are warranted to determine the important contributing factors that lead to an accurate prediction of GVHD development.

What is the optimal surgical treatment for hepatocellular carcinoma beyond the debate between anatomical versus non-anatomical resection?

The optimal type of hepatectomy for hepatocellular carcinoma (HCC)-anatomical or non-anatomical resection-remains controversial despite numerous comparative studies. There are common fundamental issues in published studies comparing anatomical resection with non-anatomical resection: (1) confounding by indication, (2) setting primary outcomes, and (3) a lack of a clear definition of non-anatomical resection. This degrades the quality of the comparison of the two types of surgery. To measure the therapeutic effect of hepatectomy, it is essential to understand the accumulated knowledge underlying these issues, such as the mechanism of hepatocellular carcinoma spread, tumor blood flow drainage theory, and the three patterns of hepatocellular carcinoma recurrence: (1) local intrahepatic metastasis, (2) systemic metastasis, and (3) multicentric carcinogenesis recurrence. Based on evidence that the incidence of local intrahepatic metastasis was so low it was almost negligible, the therapeutic effect of anatomical resection on the oncological survival was determined to be similar to that of non-anatomical resection. Recent research progress demonstrating the clinical impact of subclinical dissemination of HCC after surgery may stimulate new debate on the optimal surgical treatment for HCC beyond the comparison of anatomical and non-anatomical resection.

Predicting Post-Hepatectomy Liver Failure Using Intra-Operative Measurement of Indocyanine Green Clearance in Anatomical Hepatectomy.

BACKGROUND: Prediction of post-hepatectomy liver failure (PHLF) based on remnant liver function reserve is important for successful hepatectomy. The aim of this study was to investigate whether intraoperative indocyanine green (ICG) clearance in a future remnant liver was a predictor of PHLF. METHODS: This prospective study enrolled 31 consecutive patients who underwent anatomical hepatectomy between June 2016 and August 2019. Intraoperative ICG plasma disappearance rate (ICG-PDR) and ICG retention rate at 15 min (ICG-R15) were measured after clamping the selective hepatic inflow to the liver to be resected. The discriminative performance of the ICG-associated variables for the prediction of PHLF grade B/C was evaluated by receiver operator curve (ROC) analysis. RESULTS: Of the operations performed, 87.1% were major hepatectomy. PHLF Grade B/C was observed in eight patients (25.8%) with no mortality. The concordance indices of intraoperative ICG-PDR and ICG-PDR for predicting PHLF were 0.834 (95% CI, 0.69-0.98) and 0.834 (95% CI, 0.69-0.98), respectively. A subgroup analysis of patients with preoperative biliary drainage (BD) (n = 17) showed that the concordance indices of intraoperative ICG-PDR increased to 0.923 (95% CI, 0.79-1.00). CONCLUSIONS: Intraoperative ICG clearance in the remnant liver was a promising predictor for PHLF in patients undergoing anatomical hepatectomy, especially in patients with BD.

Accuracy comparison of MR elastography and biological markers in detecting liver fibrosis and predicting postoperative ascites.

BACKGROUND: This retrospective study aimed to compare the discriminative performance between magnetic resonance elastography (MRE) and biological markers in detecting liver fibrosis and in predicting postoperative ascites (PA). METHODS: We enrolled 77 patients consecutively who underwent hepatectomy between March 2017 and June 2019. Liver fibrosis was histopathologically graded using the METAVIR scoring system as reference. Discriminative performance of non-invasive assessments in detecting different stages of liver fibrosis and predicting PA was evaluated by receiver-operator curve analysis. RESULTS: The concordance indices (C-indices) for MRE and biological markers for detecting significant fibrosis (≥F2) and cirrhosis (F4) were: MRE, 0.84 and 0.86; Wisteria floribunda agglutinin + Mac-2 binding protein (WM2BP), 0.63 and 0.71; Hyaluronic acid (HA), 0.72 and 0.75; 7 S-type 4 collagen (T4C), 0.61 and 0.66; APRI, 0.76 and 0.83; and Fib-4, 0.75 and 0.76. Univariable logistic analysis for predicting PA showed that C-indices were 0.751 (p = 0.007), 0.798 (p = 0.106), 0.771 (p = 0.050), 0.674 (p = 0.855), 0.655 (p = 0.263), and 0.560 (p = 0.640) for MRE, WM2BP, Fib-4, HA, APRI, and T4C, respectively. CONCLUSION: MRE has a higher diagnostic performance than biological markers in detecting the stages of liver fibrosis and is a predictor for PA after hepatectomy.

[FOLFIRINOX for Locally Advanced and Recurrent Pancreatic Cancer with UGT1A1 *6 and or UGT1A1*28 Polymorphisms-A Report of Two Cases].

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

Utility of magnetic resonance elastography for predicting ascites in patients with chronic liver disease.

OBJECTIVE: This study aimed to evaluate the utility of magnetic resonance elastography (MRE) as a non-invasive method for predicting ascites in patients with chronic liver disease (CLD). METHODS: A total of 208 CLD patients underwent MRE to measure liver stiffness (LS) at our institution from March 2013 to June 2015. We evaluated the diagnostic performance of MRE for predicting the presence of ascites using receiver-operating characteristic (ROC) curve analysis and compared the performance with that of serum fibrosis markers. Multivariate logistic regression analysis was performed to identify factors associated with the presence of ascites. The cumulative incidence of ascites was examined in patients without ascites at baseline. The pathological stage of liver fibrosis was evaluated in 81 CLD patients using histopathologic diagnosis. RESULTS: Of the 208 patients, 41 had ascites. The optimal cut-off LS value for the presence of ascites was 6.0 kPa (area under the ROC curve = 0.87). The area under the ROC curve for the presence of ascites was significantly higher for MRE than that for fibrosis markers. Multivariate analysis revealed that LS >6.0 kPa is an independent risk factor for the presence of ascites. The cumulative incidence of ascites was significantly higher among those with LS values >6.0 kPa. There was significantly greater diagnostic accuracy for liver fibrosis stage ≥4 with MRE than that with fibrosis markers. CONCLUSIONS: Compared with serum fibrosis markers, MRE has higher diagnostic performance in predicting the presence of ascites. MRE-based LS has the potential to predict the presence of ascites in CLD patients.

[A Case of Long-Term Survival of the Pancreatic Tail Cancer with the Concomitant Small Liver Metastasis].

We hereby report a case of long-term survival of the pancreatic tail cancer with a synchronous small liver metastasis. A 62- year-old male with pancreatic tail cancer was incidentally diagnosed with single tiny metastasis in the left medial section of the liver duringthe distal pancreatectomy. The lesion was also resected together with primary lesion. Since then, systemic chemotherapies such as gemcitabine(GEM)plus S-1 combination therapy, GEM alone therapy and S-1 alone therapy had been given to escape from recurrence. However, the recurrences were found in the liver at 21 months after surgery. Left hepatectomy was performed for metastatic lesions. Afterwards, proton radiation therapy was twice performed for the metastatic lesions in the liver which were unable to be removed by surgery alone. Partial resection of transverse colon was also needed to be performed for the bowel obstruction caused by recurrence on the surgical margin of the liver. Systemic chemotherapies includingS -1 therapy, FOLFIRINOX therapy and GEM plus nab-paclitaxel therapy have been continued throughout his entire treatment history after recurrence. He has been keepingin good physical condition with these multidisciplinary therapies, even though 51 months have passed since the first evidence of liver metastasis was diagnosed.

[A Case of Long-Term Survival of Metastatic and Recurrent Duodenal Gastrointestinal Stromal Tumor Treated with Multimodality Managements].

We hereby report a case of long-term survival of metastatic and recurrent duodenal gastrointestinal stromal tumor(GIST) treated with multimodality managements. A 59-year-old man was diagnosed with duodenal GIST and underwent surgical resection of a primary lesion of the duodenum. Since the pathological findings on mitotic rate indicated its high risk of recurrence, the systemic treatment by imatinib mesylate was given shortly after the surgery. Six months later, metastatic lesions being considered to be imatinib-resistant were observed in the remnant liver. Since there were no other drugs available for GISTs in clinic at that time, surgery of central bisegmentectomy with partial resection of the liver was performed to eliminate all metastatic lesions. However, recurrences had been repeatedly diagnosed afterward. In response to them, four more surgery for recurrent liver or peritoneal tumors, two transcatheter arterial chemoembolizations(TACE)and one radiofrequency ablation(RFA)were performed on the basis of its resectability. Sunitinib malate had been given since it was approved for imatinib-resistant GISTs in clinic. Eventually, as long as 99 months had passed since we observed the first evidence of the resistance to imatinib mesylate when he died from the GIST.

M1 macrophage infiltrations and histological changes in the liver after portal vein embolization using fibrinogen and OK432 in the rat.

The mechanism of anti-tumor effect of transarterial Immuno-Embolization (TIE) using OK-432 has not been well elucidated. In this study, we aimed to investigate the tissue injury and immune response after portal venous embolization (PVE) with/without OK-432. Embolic materials (L group: lipiodol, LF group: lipiodol+fibrinogen, LO group: lipiodol+OK-432, LFO group: lipiodol+fibrinogen+OK-432) were administered via the right portal vein in Wistar rats. The histological findings in LFO group demonstrated liver damage with severe architectural changes. The concentrations of CD68(+) cells were observed in a time-dependent manner; it was significantly increased in the LO group on day 1 and in the LFO group on day 3. CD68(+)CD163(-) macrophages significantly increased in the LFO group on day 7 (P<0.05). In conclusion, PVE with fibrinogen and OK-432 markedly increased the CD68(+)CD163(-) infiltrating macrophages around the peri-portal area in the liver. This novel technique could be applied as immune-enhanced chemo-embolization of liver tumors.

INITIAL EXPERIENCE OF THE ENZALUTAMIDE TREATMENT FOR CASTRATION-RESISTANT PROSTATE CANCER.

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naïve achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.

[A Case of Axillary Lymph Node Metastases from Distal Bile Duct Cancer].

A 67-year-old man suffered from obstructive jaundice due to distal bile duct cancer. He underwent surgery after percutaneous biliary drainage and did not received adjuvant chemotherapy afterwards. Two years after surgery, some subcutaneous nodules were detected in the left axilla and the lateral chest on enhanced CT imaging. The nodules were diagnosed as metachronous distant metastases from bile duct cancer based on pathological findings. He was treated postoperatively with S-1 and new lesions have not been detected during the 3 months after the surgery. Surgical intervention in combination with chemotherapy might be beneficial in selected patients with recurrent bile duct cancer.

[A Case of AFP and PIVKA- II Producing Gastric Cancer Presenting with Metachronous Multiple Liver Metastases].

A 55-year old man underwent distal gastrectomy with lymphadenectomy for gastric cancer(T1N0M0, Stage I A). Six months after the radical operation, he presented with multiple liver metastases. Based on immunohistochemical examination, he was diagnosed with AFP-producing gastric cancer and metachronous liver metastases. He underwent a surgery to remove the liver metastases. Two months after the surgery, recurrent tumors were found in the lung and remnant liver. He received chemotherapy(S-1/CDDP and CPT-11/CDDP)for the recurrent tumor and lived for 15 months after the surgical intervention.

Reduced expression of dermcidin, a peptide active against propionibacterium acnes, in sweat of patients with acne vulgaris.

Dermcidin (DCD), an antimicrobial peptide with a broad spectrum of activity against bacteria such as Propionibacterum acnes, is expressed constitutively in sweat in the absence of stimulation due to injury or inflammation. The aim of this study was to determine the relationship between DCD expression and acne vulgaris associated with P. acnes. The antimicrobial activity of recombinant full-length DCD (50 µg/ml) was 97% against Escherichia coli and 100% against Staphylococcus aureus. Antimicrobial activity against P. acnes ranged from 68% at 50 µg/ml DCD to 83% at 270 µg/ml DCD. DCD concentration in sweat from patients with acne vulgaris (median 9.8 µg/ml, range 6.9-95.3 µg/ml) was significantly lower than in healthy subjects (median 136.7 µg/ml, range 45.4-201.6 µg/ml) (p = 0.001). DCD demonstrated concentration-dependent, but partial, microbicidal activity against P. acnes. These results suggest that reduced DCD concentration in sweat in patients with inflammatory acne may permit proliferation of P. acnes in pilosebaceous units, resulting in progression of inflammatory acne.

[A CASE OF PROSTATE CANCER WITH UNUSUAL PATTERN OF RECURRENCE AFTER RADIOTHERAPY].

An 82-year-old man underwent radiotherapy (brachytherapy, external beam radiotherapy) for prostate cancer, followed approximately five years later by endocrine therapy for biochemical recurrence, which controlled the prostate-specific antigen (PSA) level. His later admission due to severe gross hematuria and dysuria is described. Computed tomography and magnetic resonance imaging findings revealed a cystic tumor continuous with the prostate between the prostate and rectum, and this tumor was thought to be the cause of the hematuria and dysuria. Transrectal biopsy and transurethral resection of the prostate were performed for pathological diagnosis and improvement of dysuria. The pathological diagnosis was remnant prostate cancer, and the cystic tumor was thought to have developed as a result of prostate cancer recurrence. Although chemotherapy using docetaxel was considered postoperatively, the patient refused this treatment. Even though the PSA level was under control, the patient's condition progressed rapidly, with onset of pulmonary and cervical lymph node metastases within a short period of time, and the patient subsequently died.

[Surgical Resection for a Metachronous Liver Metastasis of an Esophagogastric Junction Adenocarcinoma].

The patient was a 56-year-old man with advanced esophagogastric junction cancer. He received neoadjuvant chemotherapy with 5-FU plus CDDP followed by lower esophagectomy and total gastrectomy via the left thoracoabdominal approach in October 2011. Pathological examination revealed EGJ adenocarcinoma (ypT4aN1M0, Stage ⅢA, Japanese Classification of Gastric Carcinoma ver.14), and histological analysis indicated Grade 0 (no change). Adjuvant chemotherapy with S-1 was administered. Nevertheless, 6 months after the operation, a solitary hepatic metastasis (f: 32 mm) was detected in S7 of the liver. The patient underwent proton beam irradiation of the liver metastasis, resulting in a complete response, and he was followed up without any chemotherapy. However, 21 months after the irradiation, regrowth of the previous lesion with FDG re-accumulation was noted. Given the absence of any neoplasms other than the liver metastasis, right hepatic lobectomy was performed. Pathological examination revealed a small cluster of viable tumor cells surrounded by extensive fibrotic tissue (Grade 2). At 45 months after the initial operation (10 months after the liver lobectomy), the patient is living without any signs of recurrence. Surgical resection for liver metastasis of EGJ cancer may be feasible after careful selection.

[A case of two re-resections for peritoneal recurrence of pancreatic cancer].

A 63-year-old man underwent subtotal stomach-preserving pancreaticoduodenectomy and intraoperative radiation therapy for pancreatic head cancer (Stage IVa, JPS). Subsequently, he received adjuvant chemotherapy including gemcitabine (GEM). A peritoneal recurrence appeared adjacent to the right colon and the lower pole of the right kidney. He received chemotherapy including S-1 and GEM+S-1. Since the recurrent lesions were localized, he underwent resection for the recurrence lesions 2 years and 9 months after surgery. The resection was R1, and re-recurrence appeared in the lower pole of the right kidney. After chemotherapy and chemoradiotherapy, he underwent re-resection for the recurrence 4 years and 3 months after the first surgery. Three months after re-resection, multiple liver metastases appeared in the bilateral lobes. Reoperation can be one of the multidisciplinary management options for local recurrence of pancreatic cancer under specific conditions.

Predicting surgical outcomes of acute diffuse peritonitis: Updated risk models based on real-world clinical data.

Aim: The existing predictive risk models for the surgical outcome of acute diffused peritonitis (ADP) need renovation by adding relevant variables such as ADP's definition or causative etiology to pursue outstanding data collection reflecting the real world. We aimed to revise the risk models predicting mortality and morbidities of ADP using the latest Japanese Nationwide Clinical Database (NCD) variable set. Methods: Clinical dataset of ADP patients who underwent surgery, and registered in the NCD between 2016 and 2019, were used to develop a risk model for surgical outcomes. The primary outcome was perioperative mortality. Results: After data cleanup, 45 379 surgical cases for ADP were derived for analysis. The perioperative and 30-day mortality were 10.6% and 7.2%, respectively. The prediction models have been created for the mortality and 10 morbidities associated with the mortality. The top five relevant predictors for perioperative mortality were age >80, advanced cancer with multiple metastases, platelet count of <50 000/mL, serum albumin of <2.0 g/dL, and unknown ADP site. The C-indices of perioperative and 30-day mortality were 0.859 and 0.857, respectively. The predicted value calculated with the risk models for mortality was highly fitted with the actual probability from the lower to the higher risk groups. Conclusions: Risk models for postoperative mortality and morbidities with good predictive performance and reliability were revised and validated using the recent real-world clinical dataset. These models help to predict ADP surgical outcomes accurately and are available for clinical settings.