[A Case of Laparoscopic Whole Layer Cholecystectomy for Elevated Lesion Suspected Biliary Cancer].

A case of attempted laparoscopic cholecystectomy for elevated lesion which was clearly early biliary cancer. Laparoscopic cholecystectomy has become popular as a minimally invasive surgical method, and is the primary choice for benign diseases. However for cases of suspected biliary cancer, open cholecystectomy, rather than laparoscopic, is recommended according to medical guidelines. The reason for this is that in cases of damage to the gallbladder, bile spillage to the abdominal cavity may occur, leading to port site recurrence and peritoneal recurrence. In addition, for invasion depth exceeding ss, or in cases of RAS cancer, the cancer may become exposed on the resected surface and remain. Hypothetically though, if the gallbladder is resected by total layer resection, RAS cancer can be removed. At this time, we performed a laparoscopic whole layer cholecystectomy for elevated lesion. We would like to report this case along with some bibliographic considerations.

[A case of mature intestinal malrotation with cecal volvulus].

We report an uncommon case of an elderly patient with cecal volvulus caused by intestinal malrotation. We performed lower gastrointestinal endoscopy on an 84-year-old man with a chief complaint of abdominal distention and fever. However, emergency surgery had to be performed because intestinal perforation had occurred. The patient had cecal volvulus associated with incomplete rotation of the intestine. Subsequently, the patient developed multiple organ failure and died 2 days after the surgery. Despite its low incidence, we believe that the possibility of intestinal malrotation should be considered in elderly patients who present with abdominal distention for which the definitive diagnosis cannot be easily obtained.

[A Two-Stage Right Hemicolectomy Case in Which the First Surgery Was Laparoscopic Ileocecal Resection Based on Preoperative Diagnosis of Acute Appendicitis].

We report a case oftwo -stage right hemicolectomy in which the first surgery performed was laparoscopic ileocecal resection based on the preoperative diagnosis ofacute appendicitis. The second surgery was performed based on pathological diagnosis ofadvanced cecal cancer accompanied by appendicitis. A 49-year-old woman came to our hospital with a chief complaint of abdominal pain in the lower quadrant for 1 week. Blood test results indicated an inflammatory response, with white blood cells at 10,000/mL and C-reactive protein of1 7.5mg/dL. Abdominal computed tomography showed a swollen appendix and increased uptake in adipose tissue around the appendix. The patient was diagnosed with acute appendicitis, and emergency laparoscopic surgery was performed. Because the cecum wall was thickened and formed an inflammatory mass, ileocecal resection was performed. The pathological diagnosis was advanced cecal cancer accompanied by appendicitis, with metastasis to lymph node No. 201; thus, right hemicolectomy and D3 dissection were performed 14 days after the first surgery. No tumor was found in additional resected tissues. The final diagnosis was cecal cancer: adenocarcinoma tub1, SE, N1, M0, Stage III a. The patient received adjuvant chemotherapy with XELOX and remains relapse free. Acute appendicitis is induced by certain mechanisms that cause appendiceal obstruction. Unlike young patients, middle-aged and elderly patients rarely develop acute appendicitis because ofa tumor causing appendiceal obstruction, which often makes preoperative or perioperative diagnosis difficult. The presence of cancer, such as cecal cancer, should be considered when appendicitis is accompanied by severe inflammation in elderly patients.

A Case of Streptozocin Monotherapy for Unresectable Duodenal Neuroendocrine Tumor G2.

BACKGROUND: Duodenal neuroendocrine tumors (NET) are rare, and few reports have demonstrated the effectiveness of chemotherapy for duodenal NET, with not many other treatment options available. Here, we present a case of unresectable duodenal NET G2 that was effectively treated with streptozocin (STZ) monotherapy. We also perform a literature review. CASE SUMMARY: A 57-year-old man presented with multiple lymph node metastasis, liver metastasis, and bone metastasis that occurred after the primary resection of the duodenal NET G2. His long-term survival was obtained; the duration of stable disease exceeded 1 year and 6 months following STZ monotherapy. In addition, his CA 19-9 levels, which previously were increasing, normalized following treatment. CONCLUSION: To our knowledge, no study has reported the effectiveness of STZ monotherapy for duodenal NET. Our findings demonstrate that for unresectable duodenal NETs, STZ should be first administered as a high volume/single dose to stabilize the disease. However, if the disease progresses, a combination therapy may be effective in obtaining a long-term prognosis of the patient. Furthermore, CA19-9 levels may be an effective factor for determining the therapeutic effect of STZ in NET with other metastases.

Induction of peptide-specific immune response in patients with primary malignant melanoma of the esophagus after immunotherapy using dendritic cells pulsed with MAGE peptides.

Primary malignant melanoma of the esophagus (PMME) is a very rare disease with an extremely poor prognosis. Surgery is currently considered its best treatment, while any other measures are ineffective. We studied the effect of active specific immunotherapy using monocyte-derived dendritic cells (DCs) pulsed with the epitope peptides of melanoma-associated antigens (MAGE-1, MAGE-3) in patients with PMME after surgery, for the first time. The patient received passive immunotherapy with lymphokine-activated killer cells concomitantly. Two HLA-A24-positive patients with PMME were treated. Both patients initially received radical esophagectomy with regional lymphadenectomy, followed by adjuvant chemotherapy with dacarbazine, nimustine, vincristine and interferon-alpha. In the case 1 patient, active specific immunotherapy was used to treat a large abdominal lymph node metastasis that became obvious 21 months after surgery. The disease remained stable for 5 months, and the patient survived for 12 months after the initiation of immunotherapy. In the case 2 patient, immunotherapy was tried as post-operative adjuvant treatment after adjuvant chemotherapy. There was no tumor recurrence for 16 months after the immunotherapy. As of 49 months after esophagectomy, the patient is still alive. In both patients, the ability of peripheral lymphocytes to produce IFN-gamma in vitro in response to peptide stimulation was significantly enhanced and delayed-type hypersensitivity skin test response to MAGE-3 peptide was turned positive after immunotherapy. In conclusion, active specific immunotherapy for PMME with the use of DCs and MAGE peptides was safe and capable of inducing peptide-specific immune responses. This case report warrants further clinical evaluation of this immunotherapy for PMME.

Mature dendritic cells generated from patient-derived peripheral blood monocytes in one-step culture using streptococcal preparation OK-432 exert an enhanced antigen-presenting capacity.

Dendritic cells (DCs) have been shown to be potent in inducing cytotoxic T cell (CTL) response leading to the efficient anti-tumor effect in active immunotherapy. Myeloid DCs are conventionally generated from human peripheral blood monocytes in the presence of interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). Streptococcal preparation OK-432, which is known to be a multiple cytokine inducer, has been extensively studied as to its maturation effects on immature DCs using an in vitro culture system. The purpose of this study was to examine whether it could be possible to generate mature DCs directly from peripheral monocytes using OK-432. We specifically focused on the possibility that recombinant cytokines, which are considered to be essential for in vitro DC generation, could be substituted by OK-432. Human peripheral monocytes, which were obtained from patients with advanced cancer, were cultured with IL-4 and OK-432 for 7 days. Cultured cells were compared with DCs generated in the presence of IL-4 and GM-CSF with or without OK-432 with regard to the surface phenotype as well as the antigen-presenting capacity. As a result, the culture of monocytes in the presence of IL-4 followed by the addition of OK-432 on day 4 (IL-4/OK-DC) induced cells with a fully mature DC phenotype. Functional assays also demonstrated that IL-4/OK-DCs had a strong antigen-presenting capacity determined by their enhanced antigen-specific CTL response and exerted a Th1-type T cell response which is critical for the induction of anti-tumor response. In conclusion, human peripheral blood monocytes cultured in the presence of IL-4 and OK-432 without exogenous GM-CSF demonstrated a fully mature DC phenotype and strong antigen-presenting capacity. This one-step culture protocol allows us to generate fully mature DCs directly from monocytes in 7 days and thus, this protocol can be applicable for DC-based anti-tumor immunotherapy.

Potassium oxonate, an enzyme inhibitor compounded in S-1, reduces the suppression of antitumor immunity induced by 5-fluorouracil.

S-1 is an oral formulation combining tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. We examined whether Oxo reduces the immunosuppression induced by 5-fluorouracil (5-FU) in the rat. The body weight of rats treated with S-1 (FT + CDHP + Oxo) for seven consecutive days was significantly higher than that of rats treated with a combination of FT plus CDHP (FT + CDHP) for a similar period. The number of peripheral leukocytes was significantly higher in the S-1-treated rats (S-1 group) than that in the FT + CDHP-treated rats (FT + CDHP group). There was no apparent difference between the two treated groups in phenotypic changes of CD3-, CD45-, CD4-, or CD8-positive cells from the spleen or mesenteric lymph nodes. However, the natural killer activities of both spleen cells and mesenteric lymph node cells were significantly higher in the S-1 group than in the FT + CDHP group. Interleukin (IL)-2 production by spleen cells stimulated with concanavalin A was significantly lower in the FT + CDHP group than in the S-1 group. Although IL-2 production by mesenteric lymph node cells in the S-1 group was lower than that in untreated rats, it was higher than that in the FT + CDHP group. These findings suggest that Oxo in S-1 may reduce the suppression of antitumor immunity induced by 5-FU.

A new strategy using autologous dendritic cells and lymphokine-activated killer cells for cancer immunotherapy: efficient maturation of DCs by co-culture with LAK cells in vitro.

Among a variety of antigen presenting cells (APCs), accumulating results support that the mature dendritic cell (DC) has the potential to induce efficient cytotoxic T lymphocyte (CTL) responses in the context of peptide-based immunotherapy. DCs have been known to assume the mature form by signaling through the CD40-CD40 ligand (CD40L) interaction, which may be provided by activated CD4+ T cells expressing abundant CD40L molecules on their surfaces. Here, we report that DCs generated from peripheral blood monocytes obtained from patients with advanced cancer exhibit a mature phenotype after co-culturing with autologous lymphokine-activated killer (LAK) cells generated by the stimulation of peripheral blood mononuclear cells with anti-CD3 monoclonal antibody (mAb) and interleukin (IL)-2. Part of this process appeared to be dependent on the expression of CD40L on the surface of LAK cells, although it was also suggested that some other humoral factors produced by LAK cells may be involved in this effect as well. DCs derived from the donors, of which LAK cells demonstrated a higher Th1/Th2 ratio upon activation determined by the intracellular detection of interferon-gamma and IL-4, showed more efficient maturation upon co-culture with LAK cells than DCs from donors with a low Th1/Th2 ratio. Importantly, these matured DCs induced a two-times stronger antigen-presenting capacity measured by an allo-reactive mixed lymphocytes reaction assay as compared to immature DCs. These results imply the use of the combination of DCs and LAK cells for immunotherapy against cancer.

Intraoperative pathological investigation of recurrent nerve nodal metastasis can guide the decision whether to perform cervical lymph node dissection in thoracic esophageal cancer.

Three-field lymph node dissection has been widely used to treat thoracic esophageal cancer, but is very invasive and can cause serious complications. Whether cervical lymph node dissection should be performed in all patients with thoracic esophageal cancer remains controversial. We pathologically examined the recurrent nerve lymph nodes during surgery in patients with thoracic esophageal cancer to determine the presence or absence of lymph node involvement. In patients without recurrent nerve nodal involvement, cervical lymph node dissection was not performed. Treatment outcomes were analyzed to evaluate whether intraoperative pathological investigation was a useful procedure. Among 71 patients with thoracic esophageal cancer who underwent 3-field lymph node dissection, the rate of cervical lymph node metastasis was 40.9% in patients with recurrent nerve nodal metastasis on intraoperative pathological investigation, as compared with 10.2% in patients without recurrent nerve nodal metastasis (p=0.007). Multiple logistic-regression analysis showed that recurrent nerve nodal metastasis was a strong predictor of cervical lymph node metastasis (odds ratio, 2.98; 95% confidence interval, 1.139-7.775; p=0.03). Among 41 patients who underwent intraoperative pathological investigation, 10 had recurrent nerve nodal metastasis and underwent cervical lymph node dissection. Two of these patients had histological evidence of cervical lymph node metastasis. The remaining 31 patients had no recurrent nerve nodal metastasis on intraoperative pathological examination and therefore did not receive cervical lymph node dissection. None of these patients had cervical lymph node recurrence on follow-up. We compared patients who underwent intraoperative pathological investigation with those who underwent conventional 3-field lymph node dissection (without performing intraoperative pathological investigation). The rates of cervical lymph node recurrence were similar among the groups (2.6% vs. 6.7%), but the 3-year survival rate was significantly higher in the patients who underwent intraoperative pathological dissection (83.3%) than in those who underwent 3-field dissection (57.2%; p<0.05). Although this was a retrospective study, our results suggest that outcomes of patients undergoing cervical lymph node dissection according to the results of intraoperative pathological investigation are at least as good as those in patients undergoing 3-field lymph node dissection. We conclude that intraoperative pathological investigation of recurrent nerve nodal metastasis is useful for determining whether cervical lymph node dissection should be performed in patients with thoracic esophageal cancer.

Long-term administration of low-dose cisplatin plus 5-fluorouracil prolongs the postoperative survival of patients with esophageal cancer.

To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.