[Clinical Significance of Total Pancreatectomy for Multiple Pancreatic Metastases from Renal Cancer].

With the progress of replacement therapy for pancreatic endocrine and exocrine functions, the indications for a total pancreatectomy are expanding, and reports of multiple pancreatic metastases of renal cancer are on the rise. In the present, we investigated the utility of a total pancreatectomy for multiple pancreatic metastases of renal cancer. The subjects were 8 patients who underwent a total pancreatectomy for multiple pancreatic metastases of renal cancer between 2012 and 2021. The median, postoperative observation period was 31(3-92)months. Six of 8 patients survived without cancer, and one survived with chemotherapy(pazopanib plus axitinib)plus radiation therapy(maintaining stable disease). The one, remaining patient died of hypoglycemia. Of the 8 patients, 4 survived for 2 years or more, and 2 survived for more than 5 years. Postoperative, support for endocrine and exocrine functions is indispensable, but a total pancreatectomy for multiple pancreatic metastases of renal cancer promises to be a viable treatment option owing to its favorable long-term prognosis.

[Multidisciplinary Treatment Aids Long-Term Stage â £ Pancreatic Cancer Survival-A Case Report].

A 56-year-old man presented at a local hospital with nausea, vomiting, epigastric pain, and white stool. CT scan showed hypovascular mass in pancreatic uncinate process and multiple peritoneal nodules. The diagnosis was stage Ⅳ pancreatic cancer(unresectable), and the patient underwent chemotherapy with GEM plus nab-PTX. He also claimed a severe cancer pain at presentation and was prescribed oxycodone 60 mg/day. After 43 months of chemotherapy, the duodenum was obstructed by tumor growth on CT scan, then he underwent duodenal stent placement. He eventually needed a total of 3 duodenal stenting for re-obstruction. He could keep adequate oral intake after the treatment. He also suffered from severe pain by progressed tumor, then underwent celiac plexus block and palliative radiation therapy(20 Gy/5 Fr). Afterwards his cancer pain has been under control. He underwent chemotherapy with FOLFIRINOX for next step. A patient with stage Ⅳ pancreatic cancer may survive for a long period with adequate QOL as a result of multidisciplinary treatment.

[Successful Surgical Resection of Expansive-Growth Acinar Cell Carcinoma-A Case Report].

Here, we report a case of successful surgical resection of expansive-growth acinar cell carcinoma. A 59-year-old man was referred to a local hospital with abdominal distention. CT revealed a large abdominal tumor. Subsequently, he was referred to our hospital. Physical examination showed a large tumor on his left upper abdomen without tenderness. CT revealed an enhanced 18 cm-sized expansive-growth tumor on the left flank, suggesting a primary pancreatic tumor. EUS-FNA yielded a diagnosis of adenocarcinoma. Imaging findings were not typical for pancreatic ductal carcinoma. We performed distal pancreatectomy with splenectomy, transverse colon resection, and proximal gastrectomy. Pathological findings revealed a tumor, measuring 19.5×16.5×15.5 cm, originating from the pancreatic body, positive for trypsin, chymotrypsin, and elastase, consistent with a diagnosis of acinar cell carcinoma, pT3, N0, M0. Four courses of adjuvant chemotherapy with S-1 were provided, and the patient is currently alive without recurrence for 10 months.

[A Case of Pulmonary Metastasis from Hilar Cholangiocarcinoma Treated by Stereotactic Body Radiotherapy].

We report a case of pulmonary metastasis from hilar cholangiocarcinoma successfully treated by stereotactic body radiotherapy. The patient was a 70-year-old woman who underwent extended left hemi-hepatectomy with bile duct reconstruction for hilar cholangiocarcinoma at the age of 67. Pathological diagnosis indicated a well-differentiated adenocarcinoma. We followed up the patient without adjuvant chemotherapy. Nineteen months after the initial resection, a solitary pulmonary metastasis was detected in the right upper lobe. The patient received gemcitabine plus cisplatin(GC)therapy. After 4 courses of GC therapy, the size of the pulmonary metastasis was unchanged. Therefore, we performed a thoracoscopic wedge resection. Pathological diagnosis indicated that the pulmonary metastasis originated from the cholangiocarcinoma. Fifteen months after the pulmonary resection, another solitary pulmonary metastasis was detected in the left lower lobe. As the patient refused further chemotherapy, we performed stereotactic body radiotherapy(SBRT)(50 Gy/4 Fr). An adverse event of Grade 1 radiation pneumonitis was observed. The metastasis disappeared after SBRT. Twenty-eight months after SBRT and 70 months after the initial surgery, the patient is alive without recurrence.

Combined thoraco-laparoscopic hepatectomy concomitant with resection of the diaphragm for solitary peritoneal seeding from cervical cancer: A case report.

Combined thoraco-laparoscopic resection can aid in precise resection of an invasive tumor of the diaphragm. A 44-year-old woman was referred to our department for resection of solitary peritoneal seeding from cervical cancer following systemic chemotherapy. The tumor was located in the right diaphragm with an ill-defined border of the liver. Combined thoraco-laparoscopic resection was proposed. Laparoscopy portrayed that the right diaphragm was partially attached to the liver, and the depth of tumor invasion to the diaphragm was ambiguous. Observation from the thoracic cavity indicated a white-colored distortion following the location of peritoneal seeding. Partial resection and repair of the diaphragm were made using the thoracoscopic-assisted approach, followed by laparoscopic hepatectomy. The postoperative course was uneventful, and pathological findings revealed that peritoneal metastases of the diaphragm and surgical margin was negative for cancer. Combined thoraco-laparoscopic resection can cover the drawbacks of each approach and is among the options for minimally invasive surgery for invasive tumor of the diaphragm.

Body-first approach of laparoscopic cholecystectomy for minimizing vasculobiliary injury: Initial experience.

INTRODUCTION: Vasculobiliary injury (VBI) is a rare but critical complication of laparoscopic cholecystectomy (Lap-C). Dividing first the gallbladder body and then the gallbladder neck from the gallbladder bed (the "body-first approach") may decrease the possibility of VBI. METHODS: The surgical outcome of 62 patients who underwent Lap-C with a body-first approach were evaluated. In this procedure, after serosal resection of the gallbladder, the gallbladder body is divided from the cystic plate; then the gallbladder neck and cystic duct are isolated. No connective tissue of the hepatic hilum is touched. RESULTS: A total of five patients had anatomical anomalies of the biliary tract that raised concerns of cholecystectomy. Furthermore, seven patients underwent subtotal cholecystectomy. No patients required conversion to open surgery, and none developed VBI or postoperative complications of Clavien-Dindo grade 3a or worse. CONCLUSION: The body-first approach may minimize the risk of VBI during Lap-C.

The outcome of a multidisciplinary approach incorporating neoadjuvant chemoradiotherapy with S1 for resectable pancreatic ductal adenocarcinoma.

Aim: This study was performed to evaluate the efficacy of a multidisciplinary approach incorporating neoadjuvant chemoradiotherapy with S1 (S1-NACRT) for resectable pancreatic ductal adenocarcinoma. Methods: The medical records of 132 patients who received S1-NACRT for resectable pancreatic ductal adenocarcinoma from 2010 to 2019 were reviewed. The S1-NACRT regimen consisted of S1 at a dose of 80-120 mg/body/day together with 1.8 Gy of radiation in 28 fractions. The patients were re-evaluated 4 weeks after S1-NACRT completion, and a pancreatectomy was then considered. Results: Adverse events of S1-NACRT ≥grade 3 occurred in 22.7% of the patients, and 1.5% discontinued therapy. Of the 112 patients who underwent a pancreatectomy, 109 underwent R0 resection. Adjuvant chemotherapy with relative dose intensity ≥50% was administered to 74.1% of the patients who underwent resection. The median overall survival of all patients was 47 months, and the median overall survival and recurrence-free survival of patients who underwent resection was 71 and 32 months, respectively. According to the multivariate analyses of prognostic factors for overall survival in patients who underwent resection, negative margin status (hazard ratio: 0.182; P = 0.006) and relative dose intensity of adjuvant chemotherapy ≥50% (hazard ratio 0.294; P < 0.001) were independent prognostic factors of overall survival. Conclusions: A multidisciplinary approach incorporating S1-NACRT for resectable pancreatic ductal adenocarcinoma demonstrated acceptable tolerability and good local control and resulted in comparable survival benefits.

Indocyanine green fluorescence navigation for hepatocellular carcinoma with bile duct tumor thrombus: a case report.

BACKGROUND: Bile duct tumor thrombus (BDTT) is one of the features of advanced hepatocellular carcinoma (HCC). In the resection of HCC with BDTT, it is important to detect the BDTT tip to decide the appropriate point of bile duct division. In this regard, the efficacy of indocyanine green (ICG) fluorescence navigation has been confirmed for the detection of HCC, whereas its utility for BDTT has not yet been reported. Herein, we describe our experience with right hepatectomy for HCC with BDTT using ICG fluorescence navigation. CASE PRESENTATION: A 72-year-old woman had experienced local recurrences of HCC after radiofrequency ablation, with BDTT reaching the confluence of the right anterior branch and posterior branch. Right hepatectomy was planned, and 2.5 mg of ICG was injected one day before surgery. After transection of the liver parenchyma, the right liver was connected with only the right hepatic duct. ICG fluorescence imaging visualized the tip of BDTT in the bile duct with clear contrast; the proximal side (hepatic side) of the right hepatic duct showed stronger fluorescence than the distal side (duodenal side). The bile duct was divided at the distal side of the BDTT border, and the tip of BDTT was recognized into the resected right hepatic duct without laceration. The patient had an uneventful postoperative course and currently lives without recurrences for 6 months. CONCLUSIONS: ICG fluorescence navigation assisted in the precise resection of the bile duct in HCC with BDTT.

Jejunal limb obstruction by a tumor thrombus from pancreatic metastasis of renal cell carcinoma: a case report.

BACKGROUND: Renal cell carcinoma (RCC) is a primary tumor with the highest frequency of pancreatic metastasis. Although surgical resection can improve the prognosis of some patients with pancreatic metastasis of RCC (PM-RCC), the role of palliative surgery remains unclear. Herein, we described a case of jejunal limb occlusion caused by a tumor thrombus arising from a PM-RCC which was treated by surgical resection. CASE PRESENTATION: A 75-year-old, male patient with metastatic RCC was admitted to our hospital with new-onset dysphagia and weight loss. Twenty years earlier he underwent a right nephrectomy with an adrenalectomy for the first surgical resection of RCC, and 12 years ago he underwent a left partial nephrectomy for metachronous primary RCC. Nine years later, multiple pancreatic metastases were detected. After discontinuing interferon therapy, he was followed up at his request without anticancer treatment. Multiple, pulmonary metastases developed 3 years ago, and resection of a brain metastasis was performed 6 months ago. He had also undergone a total gastrectomy with Roux-en Y reconstruction and splenectomy for gastric cancer 23 years ago. Computed tomography revealed a metastatic lesion in the pancreatic tail extending into the jejunal limb, which was obstructed by a tumor thrombus. Jejunal limb resection was performed concomitantly with a distal pancreatectomy as palliative surgery. The jejunal limb remnant was approximately 30 cm long and was re-anastomosed to the esophagus using a circular stapler. Blood perfusion at the anastomotic site was confirmed by indocyanine green fluorescence imaging. He was discharged on postoperative day 24 and was followed in the outpatient clinic. He achieved sufficient oral intake at 8 months postoperatively. CONCLUSIONS: PM-RCC can invade the gastrointestinal tract and cause tumor thrombus formation resulting in bowel occlusion requiring surgical intervention.

Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment.

BACKGROUND: The temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth. METHODS: C57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays. RESULTS: The distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth. CONCLUSIONS: Despite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

A patient with post-Fontan operation underwent left hepatectomy and caudate lobectomy for hepatocellular carcinoma: a case report.

BACKGROUND: The Fontan procedure has been widely accepted for children with single ventricle physiology and guarantees survival rates of approximately 80% at age 20 years. However, there have been cases of Fontan-associated liver disease (FALD) caused due to congestion, along with recent reports of the development of hepatocellular carcinoma (HCC) in younger patients with FALD. The literature consists of only five previous case reports of patients who underwent hepatectomy for HCC due to poorer cardiac function and liver cirrhosis caused due to congestion. CASE PRESENTATION: The patient was a 37-year-old woman who presented with epigastralgia. Computed tomography (CT) revealed a liver tumor, 8 cm in diameter, in the caudate lobe. Liver damage was A, with an indocyanine green retention rate of 6% at 15 min. The levels of alpha-fetoprotein (AFP) and protein induced by vitamin K antagonists-II (PIVKA-II) were elevated to 81,663 ng/ml (normal < 10 ng/ml) and 238 mAU/ml (normal < 40 mAU/ml), respectively. Left ventricular ejection fraction was 56%, and central venous pressure (CVP) was 12 mmHg. Left hepatectomy and caudate lobe resection were successfully performed in the reverse Trendelenburg position which reduced the CVP. The total operation duration was 450 min, with a total blood loss of 3200 ml. The patient's postoperative course was uneventful, and she is still alive 16 months after surgery. CONCLUSIONS: First left hepatectomy with caudate lobectomy during reverse Trendelenburg position which reduced the CVP was performed in a patient with HCC and FALD.

Inflammatory hepatocellular adenoma in a patient with Turner's syndrome: A case report.

INTRODUCTION: Hepatocellular adenoma (HCA) is a rare benign tumor and is related to the use of an oral contraceptive pill. Turner's syndrome requires various hormone replacement therapies, including the pill which is used as a female hormone replacement therapy. Herein we report a case of Turner's syndrome with HCA treated by liver segmentectomy. PRESENTATION OF CASE: A 36-year-old woman with Turner's syndrome was treated with oral contraceptive pills as a female hormone replacement therapy for 20 years. She presented with fatigue and liver tumor. Liver tumors in the posterior lobe measuring 60 mm and 10 mm in diameter were detected on CT; hence, she was referred to our department. Both the tumors showed high intensity in the arterial phase, iso-intensity in the portal and late phases, and low intensity in the hepatobiliary phase on Gb-EOB-MRI. She was diagnosed with multiple HCAs and underwent segmentectomy Section 7. Pathologically, both the tumors were diagnosed as HCAs, and inflammatory markers were detected by immunohistochemistry. Thirteen months postoperatively, she was doing well and there was no evidence of recurrence of HCA without the pill. DISCUSSION: There is only one report of HCA in patients with TS (Espat et al., 2000). We reported a case of multiple HCAs in a patient with TS underwent hepatectomy. CONCLUSION: With the use of the contraceptive pill as a long-term female hormone replacement therapy for Turner's syndrome, careful attention is required for HCA.

Cavo-atrial thrombectomy prior to hepatectomy for hepatocellular carcinoma with tumor thrombus in the right atrium: a case report.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumor thrombus (TT) in the right atrium is a critical condition. The general consensus is to perform hepatectomy prior to cavo-atrial thrombectomy because of the risk of uncontrollable bleeding during the liver transection after heparinization. However, sudden cardiac arrest due to the ball-valve effect and pulmonary embolism have been reported in cases of TT. Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium was successfully performed to prevent sudden cardiac arrest and pulmonary embolism. CASE PRESENTATION: Tumor thrombectomy under cardiopulmonary bypass with heparin and electrical ventricular fibrillation prior to hepatectomy was successfully performed to prevent sudden cardiac arrest or pulmonary embolism in a 75-year-old woman with a huge HCC and TT in the right atrium. After the neutralization of heparin, right hepatectomy with tumor thrombectomy in the inferior vena cava was performed. The total operation time was 9 h, and the total blood loss was 8200 mL. The patient's postoperative course was uneventful, and she was discharged 14 days after surgery. One year after surgery, she is alive with HCC recurrence in the lung. CONCLUSIONS: Cavo-atrial thrombectomy prior to hepatectomy for HCC with TT in the right atrium can be performed safely to prevent sudden cardiac arrest and pulmonary embolism by collaboration of cardiovascular surgeons and gastroenterological surgeons.

Depolarization-induced differentiation of PC12 cells is mediated by phospholipase D2 through the transcription factor CREB pathway.

The present study examined the role of phospholipase D2 (PLD2) in the regulation of depolarization-induced neurite outgrowth and the expression of growth-associated protein-43 (GAP-43) and synapsin I in rat pheochromocytoma (PC12) cells. Depolarization of PC12 cells with 50 mmol/L KCl increased neurite outgrowth and elevated mRNA and protein expression of GAP-43 and synapsin I. These increases were suppressed by inhibition of Ca2+-calmodulin-dependent protein kinase II (CaMKII), PLD, or mitogen-activated protein kinase kinase (MEK). Knockdown of PLD2 by small interfering RNA (siRNA) suppressed the depolarization-induced neurite outgrowth, and the increase in GAP-43 and synapsin I expression. Depolarization evoked a Ca2+ rise that activated various signaling enzymes and the cAMP response element-binding protein (CREB). Silencing CaMKIIdelta by siRNA blocked KCl-induced phosphorylation of proline-rich protein tyrosine kinase 2 (Pyk2), Src kinase, and extracellular signal-regulated kinase (ERK). Inhibition of Src or MEK abolished phosphorylation of ERK and CREB. Furthermore, phosphorylation of Pyk2, ERK, and CREB was suppressed by the PLD inhibitor, 1-butanol and transfection of PLD2 siRNA, whereas it was enhanced by over-expression of wild-type PLD2. Depolarization-induced PLD2 activation was suppressed by CaMKII and Src inhibitors, but not by MEK or protein kinase A inhibitors. These results suggest that the signaling pathway of depolarization-induced PLD2 activation was downstream of CaMKIIdelta and Src, and upstream of Pyk2(Y881) and ERK/CREB, but independent of the protein kinase A. This is the first demonstration that PLD2 activation is involved in GAP-43 and synapsin I expression during depolarization-induced neuronal differentiation in PC12 cells.

Induction of Tertiary Lymphoid Structures With Antitumor Function by a Lymph Node-Derived Stromal Cell Line.

Tertiary lymphoid structures (TLSs) associate with better prognosis in certain cancer types, but their underlying formation and immunological benefit remain to be determined. We established a mouse model of TLSs to study their contribution to antitumor immunity. Because the stroma in lymph nodes (sLN) participates in architectural support, lymphogenesis, and lymphocyte recruitment, we hypothesized that TLSs can be created by sLN. We selected a sLN line with fibroblast morphology that expressed sLN surface markers and lymphoid chemokines. The subcutaneous injection of the sLN line successfully induced TLSs that attracted infiltration of host immune cell subsets. Injection of MC38 tumor lysate-pulsed dendritic cells activated TLS-residing lymphocytes to demonstrate specific cytotoxicity. The presence of TLSs suppressed MC38 tumor growth in vivo by improving antitumor activity of tumor-infiltrating lymphocytes with downregulated immune checkpoint proteins (PD-1 and Tim-3). Future engineering of sLN lines may allow for further enhancements of TLS functions and immune cell compositions.

Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1.

Intralesional (IL) therapy is under investigation to treat dermal and subcutaneous metastatic cancer. Rose bengal (RB) is a staining agent that was originally used by ophthalmologists and in liver function studies. IL injection of RB has been shown to induce regression of injected and uninjected tumors in murine models and clinical trials. In this study, we have shown a mechanism of tumor-specific immune response induced by IL RB. In melanoma-bearing mice, IL RB induced regression of injected tumor and inhibited the growth of bystander lesions mediated by CD8+ T cells. IL RB resulted in necrosis of tumor cells and the release of High Mobility Group Box 1 (HMGB1), with increased dendritic cell (DC) infiltration into draining lymph nodes and the activation of tumor-specific T cells. Treatment of DC with tumor supernatants increased the ability of DCs to stimulate T cell proliferation, and blockade of HMGB1 in the supernatants suppressed DC activity. Additionally, increased HMGB1 levels were measured in the sera of melanoma patients treated with IL RB. These results support the role of IL RB to activate dendritic cells at the site of tumor necrosis for the induction of a systemic anti-tumor immune response.

Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation.

The relationship between sphingosine kinase (SPHK), cellular ceramide concentration and chemosensitivity was investigated in human colon cancer cell lines. Among nine colon cancer cell lines, SPHK1 and SPHK2 activity and protein expression was highest in RKO cells and lowest in HCT116 cells. A viability assay revealed that HCT116 cells were sensitive to the effects of oxaliplatin (l-OHP), whereas RKO cells were resistant to those of l-OHP. Treatment with 5microg/ml l-OHP induced a marked time-dependent increase in various ceramides (C16, C24, C24:1) in HCT116 cells but not in RKO cells, as indicated by liquid chromatography/mass spectrometry. The increase in ceramide and caspase activation induced by l-OHP in the sensitive HCT116 cells was abolished by pretreatment with a neutral sphingomyelinase inhibitor, suggesting that the ceramide formation was due to the activation of neutral, rather than acid, sphingomyelinase. In contrast, in l-OHP-resistant RKO cells, treatment with an SPHK inhibitor or SPHK1 and SPHK2 silencing by RNA interference suppressed cell viability and increased caspase activity and cellular ceramide formation after l-OHP treatment. The elevated ceramide formation induced by SPHK inhibition and l-OHP was inhibited by fumonisin B1 but not myriocin, suggesting that ceramide formation was through the salvage pathway. Endogenous phosphorylated Akt levels were much higher in the resistant RKO cells than in the sensitive HCT116 cells. Either SPHK1 or SPHK2 silencing in RKO cells decreased phosphorylated Akt levels and increased p53 and p21 protein levels as well as poly(ADP-ribose) polymerase cleavage in response to l-OHP treatment. These findings indicate that SPHK isoforms and neutral sphingomyelinase contribute to the regulation of chemosensitivity by controlling ceramide formation and the downstream Akt pathway in human colon cancer cells.