A case of metachronous oligo-hepatic and peritoneal metastases of pancreatic cancer with a favorable outcome after conversion surgery combined with perioperative sequential chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, and the prognosis for its recurrence after surgery is very poor. Here, we report a case of metachronous oligo-hepatic and peritoneal metastases in a patient who survived without recurrence for 3 years after conversion surgery combined with perioperative sequential chemotherapy using gemcitabine plus nab-paclitaxel (GnP) and modified FOLFIRINOX (mFOLFIRINOX). The patient was a 70-year-old man with pancreatic ductal carcinoma, classified as cT3N0M0, cStage IIA, who underwent a distal pancreatosplenectomy. At 1 year and 4 months later, two liver metastases and one peritoneal metastasis were detected. A systemic 9-month course of chemotherapy was administered with GnP and mFOLFIRINOX as the first- and second-line chemotherapeutic agents, respectively. The two liver metastases were judged as showing a partial response, but one dissemination was considered stable disease. After receiving informed consent from the patient, we performed resection of the disseminated tumor and lateral segmentectomy of the liver. Adjuvant chemotherapy using mFOLFIRINOX and GnP was administered for 10 months. The patient has now been alive for 5 years and 6 months after the initial pancreatosplenectomy, and 3 years and 3 months after the conversion surgery, without subsequent tumor recurrence. Thus, a multidisciplinary treatment approach including surgery and perioperative sequential chemotherapy using GnP and mFOLFIRINOX may be beneficial for treating metachronous oligo-hepatic and peritoneal metastases, depending on the patient's condition.

A case of granulocyte-colony-stimulating factor-producing gallbladder cancer with lymph node metastasis together with a literature review.

The granulocyte-colony-stimulating factor (G-CSF) glycoprotein stimulates precursor cell proliferation and differentiation in the bone marrow. Various G-CSF-producing tumors have been reported; they showed early progression and an extremely poor prognosis. Here, we report a case of G-CSF-producing gallbladder cancer with lymph node metastasis. In addition, we reviewed 30 previous case reports of G-CSF-producing gallbladder cancers to elucidate the characteristics and most appropriate treatment. During a routine visit to her local doctor for monitoring of diabetes and hypertension, a 68-year-old female was found to have an elevated white-blood-cell (WBC) count and C-reactive protein (CRP) level, and a gallbladder mass. Laboratory tests revealed a high serum G-CSF level, and imaging revealed a tumor of the gallbladder with regional lymphadenopathy. We diagnosed a G-CSF-producing gallbladder cancer and performed liver resection of segment IVa/V: regional lymph node dissection with extrahepatic bile duct resection. Pathologically, the tumor was a poorly differentiated squamous cell carcinoma. G-CSF immunostaining for tumor cells was positive. She is alive without recurrence at 16 months after surgery. If a patient exhibits a gallbladder tumor, with an elevated WBC count and CRP level but no symptoms of infection, a G-CSF-producing gallbladder cancer should be suspected; radical resection should be performed immediately after diagnosis.

Isolated caudate lobectomy using a modified hanging maneuver.

BACKGROUND: The caudate lobe is located deep in the dorsal portion of the liver. Complete resection is an extremely demanding surgery due to the limited surgical field, especially in cases with severe intra-abdominal complications. A major concern of isolated caudate lobectomy is the difficulty associated with securing the contralateral visual field during parenchymal transection. To overcome this issue, we present a new technique for isolated caudate lobectomy that uses a modified hanging maneuver. METHODS: We performed an anatomical isolated caudate lobectomy via the high dorsal resection technique using our new modified hanging maneuver in two patients with HCC in November and December 2019. RESULTS: Patient 1 was severely obese, so the upper abdominal cavity was occupied by a large amount of great omental fat, and fibrous adhesions were observed around the spleen. Patient 2 had undergone six preoperative treatments, and a high degree of adhesion was observed in the abdominal cavity around the liver. It was difficult to secure the surgical field due to severe abdominal complications in both cases. The total operation times in these two cases were 617 and 763 min, respectively, while the liver parenchymal dissection times of the caudate lobe were 96 and 108 min, respectively. The resection margin was negative in both patients (R0). Neither patient had any complications after surgery; both were discharged on postoperative day 14. CONCLUSION: Our modified hanging maneuver is useful, particularly in cases with a narrow surgical field due to severe adhesions, bulky tumors, and/or hypertrophy of the Spiegel lobe.

[A Case of Laparoscopic Surgery Performed for Lynch Syndrome in a Patient Who Developed Cecal Cancer and Uterine Carcinosarcoma Synchronously].

A 51-year-old woman was referred to our hospitalfor treatment of endometrialcancer. She had 3 family members with colorectal cancer in the first degree. She was also diagnosed with advanced cecal cancer based on a preoperative examination. She underwent laparoscopic surgery, modified radical hysterectomy, and bilateral salpingo-oophorectomy for endometrial cancer, and ileocecal resection for cecal cancer simultaneously. Pathological examination of the uterine tumor revealed carcinosarcoma with carcinomatous and sarcomatous components. Since she fulfilled 4 of the revised Bethesda criteria, we suspected Lynch syndrome. Immunohistochemical analysis of mismatch repair proteins demonstrated the loss of MSH2/MSH6 expression in both cecalcancer and uterine carcinosarcoma tissues. Genetic testing by direct sequencing revealed a pathogenic germ line mutation of MSH2 in codon 2245 of exon 14, and she was definitively diagnosed with Lynch syndrome. Laparoscopic surgery is less invasive and would be useful for Lynch syndrome patients potentially requiring multiple surgeries or risk- reduction surgery.

[A Case of Acute Afferent Loop Obstruction after Total Gastrectomy, Successfully Managed by Endoscopic Treatment].

The patient was a 76-year-old man who had 3 times previously undergone laparotomies, including distal gastrectomy with a Billroth Ⅰ operation. In the current case, a total gastrectomy, end-to-side esophagojejunostomy, and a Roux-en-Y anastomosis for adenocarcinoma of the remnant stomach were performed. On postoperative day (POD) 7, he complained of epigastralgia. Abdominal CT revealed a markedly dilated duodenum, and a diagnosis of acute afferent loop obstruction was made. Emergency endoscopy revealed edematous stenosis of the Y-anastomotic site. A nasal endoscope could not pass the stricture, but an endoscopic nasobiliary drainage (ENBD) catheter was successfully inserted into the duodenum. Epigastralgia decreased after drainage. Stenosis of the Y-anastomotic site was still observed 18 days after onset; therefore, we inserted 1 endoscopic retrograde biliary drainage (ERBD) tube, in addition to the ENBD catheter. Twenty-five days after onset, slight improvement of the stenosis was observed. By inserting 2 more ERBD tubes, the ENBD catheter could be removed. On day 28, abdominal CT revealed reduced dilatation of the duodenum. On day 29, oral intake was initiated, and the patient was discharged from the hospital on POD 66. During the early post-operative phase, the use of nasal endoscope drainage is an effective, minimally invasive, and safe procedure for decompression of the duodenum in afferent loop obstruction.

Human monocyte-derived dendritic cells pulsed with wild-type p53 protein efficiently induce CTLs against p53 overexpressing human cancer cells.

PURPOSE: Dendritic cells are the most potent antigen-presenting cells for initiating cellular immune responses. Dendritic cells are attractive immunoregulatory cells for cancer immunotherapy, and their efficacy has been investigated in clinical trials. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and p53-based immunization is an attractive approach to cancer immunotherapy because of the accumulation of p53 protein in malignant but not in normal cells. It has been shown that dendritic cells transduced with an adenoviral wild-type p53 (wt-p53) construct mediate the antitumor immune responses against p53-overexpressing tumor cells. We examined whether monocyte-derived human dendritic cells pulsed with the purified full-length wt-p53 protein were also capable of inducing the specific antitumor responses against p53-overexpressing tumors in vitro. EXPERIMENTAL DESIGN: Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from monocytes of HLA-A2- or HLA-A24-positive healthy individuals were pulsed with the purified p53 protein. Uptake of p53 protein by human dendritic cells was assessed by Western blotting and immunohistochemical staining using anti-p53 antibody. Induction of p53-specific CTL response was also evaluated by the cytotoxic assay against p53-overexpressing human tumor cells. RESULTS: Both Western blot and immunohistochemical analysis showed the accumulation of p53 protein in human immature dendritic cells. T cells obtained from HLA-A2- or HLA-A24-positive healthy donors were stimulated twice with p53 protein-pulsed dendritic cells and then applied to the cytotoxicity assay against p53-overexpressing target cells. The CTL activity was specific for p53-overexpressing tumor cells and MHC class I restricted. Moreover, the CTL activity generated by p53 protein-pulsed dendritic cells was nearly identical with that induced by adenoviral wt-p53-transduced dendritic cells. CONCLUSIONS: Our results indicate that monocyte-derived human dendritic cells pulsed with the wt-p53 protein could induce the specific antitumor effect against p53-overexpressing tumors and that this in vitro model offers a new and more simple approach to the development of p53-based immunotherapy.

Antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene.

PURPOSE: Dendritic cells (DCs) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and approximately 50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene. EXPERIMENTAL DESIGN: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice. RESULTS: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could be successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization. CONCLUSIONS: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.

Activation of caspase-3 and cleavage of Rb are associated with p16-mediated apoptosis in human non-small cell lung cancer cells.

The p16 tumor suppressor gene is frequently inactivated in human cancer tissues and cell lines. We previously reported that wild-type p16 expression from an adenovirus vector (Adv/p16) induced p53-dependent apoptotic cell death in non-small cell lung cancer (NSCLC) cell lines. Here we show the potential mechanism of apoptosis induced by Adv/p16 infection. Infection of human NSCLC cell line A549, which carries the wild-type p53 gene, with Adv/p16 resulted in activation of caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP), on day 3 of infection. The retinoblastoma (Rb) cell cycle regulator protein was also cleaved after activation of caspase-3; when the levels of Rb significantly diminished, apoptosis began. When A549 cells were pretreated with the caspase-inhibitory peptide N-acetyl-asp-Glu-Val-Asp-CHO (aldehyde) (Ac-DEVD-CHO), Adv/p16-mediated apoptosis and Rb cleavage were greatly inhibited. Furthermore, MDM2, a negative regulator of p53 expression was upregulated 3 days after Adv/p16 infection, and MDM2 was subsequently cleaved by caspase-3; MDM2 cleavage was inhibited by Ac-DEVD-CHO treatment. These data implied that cleavage of Rb, in addition to activation of caspase-3, represented a mechanism by which Adv/p16 induced apoptotic cell death in human NSCLC cells. Our results support the clinical relevance of Adv/p16 as a treatment for p16-null human NSCLC that express wild-type p53.