Metastatic Invasive Lobular Carcinoma of the Breast Presenting Peritoneal Metastasis with Bilateral Ureteral Obstruction.

The most common sites for recurrence of breast cancer are the lungs, liver, and bones. The frequency of peritoneal, gastrointestinal metastasis is significantly lower than those, and bilateral ureteral obstruction caused by peritoneal metastasis is relatively rare. A 66-year-old woman was referred to our hospital because of appetite loss and frequent urination. She was on adjuvant hormonal therapy for local recurrence of right breast cancer. She was diagnosed with bilateral ureteral obstruction due to extramural compression. Exploratory laparoscopy revealed omental cake and peritoneal nodules of which pathological examination showed peritoneal metastasis of invasive lobular carcinoma. Peritoneal metastases from breast cancer are unusual and consequently difficult to identify without non-invasive tools. Exploratory laparoscopy revealed that the cause of hydronephrosis in this case was peritoneal metastasis of invasive lobular carcinoma. Clinical history and histological study play a pivotal role in determining the correct diagnosis.

Giant Adrenal Myelolipoma in a Patient without Endocrine Disorder: A Case Report and a Review of the Literature.

We herein present a surgically treated case of huge adrenal myelolipoma. A 62-year-old woman presented to our surgical outpatient clinic with a retroperitoneal tumor. A clinical examination revealed an elastic soft, smooth-surfaced, painless, child-head-sized tumor with poor mobility, which was located in the left upper abdomen. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed an uneven tumor surrounding the stomach, spleen, pancreas, and left kidney, which was 20 × 18 × 10 cm in size. The retroperitoneal tumor was resected. The tumor was attached to the surrounding organs, including the pancreas, spleen, and left kidney, but had not directly invaded these organs. The tumor was yellow and elastic soft and covered with a thin film. The origin of the tumor was suggested to be the left adrenal gland. The weight of the excised tumor was 1500 g. The histopathological diagnosis was adrenal myelolipoma. The patient had an uneventful recovery and was discharged from the hospital on the thirteenth day after the operation. She has been followed up in our outpatient clinic.

Prognostic Significance of Mitochondrial Transcription Factor A Expression in Patients with Right- or Left-sided Colorectal Cancer.

BACKGROUND/AIM: Mitochondrial transcription factor A (mtTFA) is necessary for both the transcription and maintenance of mitochondrial DNA (mtDNA). The present study investigated the clinical significance of mtTFA in patients with right- and left-sided colorectal cancer (CRC). PATIENTS AND METHODS: Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-mtTFA antibody. The relationships among the mtTFA expression, clinicopathological factors and prognosis were evaluated. RESULTS: Thirty-five (60.3%) of 58 right-sided CRC patients and 82 (45.8%) of 179 left-sided CRC patients showed high mtTFA expression. The mtTFA expression significantly correlated with lymph node metastasis, distant metastasis, the TNM stage and lymphatic invasion in left-sided CRC patients and did not correlate with any factors in right-sided CRC patients. Univariate and multivariate analyses revealed the mtTFA expression to be a significant prognostic factor in left-sided CRC patients but not in right-sided CRC patients. CONCLUSION: These results suggest that a high mtTFA expression is a useful marker for tumor progression and a poor prognosis in left-sided CRC patients.

A novel transperitoneal abdominal wall nerve block for postoperative pain in laparoscopic colorectal surgery.

BACKGROUND: Although the laparoscopic approach reduces pain associated with abdominal surgery, postoperative pain remains a problem. Ultrasound-guided rectus sheath block and transversus abdominis plane block have become increasingly popular means of providing analgesia for laparoscopic surgery. METHODS: Ninety patients were enrolled in this study. A laparoscopic puncture needle was inserted via the port, and levobupivacaine was injected into the correct plane through the peritoneum. The patients' postoperative pain intensity was assessed using a numeric rating scale. The effects of laparoscopic nerve block versus percutaneous anesthesia were compared. RESULTS: This novel form of transperitoneal anesthesia did not jeopardize completion of the operative procedures. The percutaneous approach required more time for performance of the procedure than the transperitoneal technique. CONCLUSION: This new analgesia technique can become an optional postoperative treatment regimen for various laparoscopic abdominal surgeries. What we mainly want to suggest is that the transperitoneal approach has the advantage of a higher completion rate. A percutaneous technique is sometimes difficult with patients who have severe obesity and/or coagulation disorders. Additional studies are required to evaluate its benefits.

Novel technique of abdominal wall nerve block for laparoscopic colostomy: Rectus sheath block with transperitoneal approach.

A 62-year-old man who had acute rectal obstruction due to a large rectal cancer is presented. He underwent emergency laparoscopic colostomy. We used the laparoscopic puncture needle to inject analgesia with the novel transperitoneal approach. In this procedure, both ultrasound and laparoscopic images assisted with the accurate injection of analgesic to the correct layer. The combination of laparoscopic visualization and ultrasound imaging ensured infiltration of analgesic into the correct layer without causing damage to the bowel. Twenty-four hours postoperatively, the patient's pain intensity as assessed by the numeric rating scale was 0-1 during coughing, and a continuous intravenous analgesic was not needed. Colostomy is often necessary in colon obstruction. Epidural anesthesia for postoperative pain cannot be used in patients with a coagulation disorder. We report the use of a novel laparoscopic rectus sheath block for colostomy. There has been no literature described about the nerve block with transperitoneal approach. The laparoscopic rectus sheath block was performed safely and had enough analgesic efficacy for postoperative pain. This technique could be considered as an optional anesthetic regimen in acute situations.

Transperitoneal rectus sheath block and transversus abdominis plane block for laparoscopic inguinal hernia repair: A novel approach.

INTRODUCTION: A laparoscopic approach for inguinal hernia repair is now considered the gold standard. Laparoscopic surgery is associated with a significant reduction in postoperative pain. Epidural analgesia cannot be used in patients with perioperative anticoagulant therapy because of complications such as epidural hematoma. As such, regional anesthetic techniques, such as ultrasound-guided rectus sheath block and transversus abdominis plane block, have become increasingly popular. However, even these anesthetic techniques have potential complications, such as rectus sheath hematoma, if vessels are damaged. We report the use of a transperitoneal laparoscopic approach for rectus sheath block and transversus abdominis plane block as a novel anesthetic procedure. MATERIAL AND SURGICAL TECHNIQUE: An 81-year-old woman with direct inguinal hernia underwent laparoscopic transabdominal preperitoneal inguinal repair. Epidural anesthesia was not performed because anticoagulant therapy was administered. A Peti-needle™ was delivered through the port, and levobupivacaine was injected though the peritoneum. Surgery was performed successfully, and the anesthetic technique did not affect completion of the operative procedure. The patient was discharged without any complications. DISCUSSION: This technique was feasible, and the procedure was performed safely. Our novel analgesia technique has potential use as a standard postoperative regimen in various laparoscopic surgeries. Additional prospective studies to compare it with other techniques are required.

A Case of Advanced Descending Colon Cancer in an Adult Patient with Intestinal Malrotation.

This report presents an operative case of advanced descending colon cancer in an adult patient with intestinal malrotation. A 63-year-old Japanese male was suffering from left side abdominal pain, abdominal distension, and constipation. An endoscopic examination revealed an advanced tumor in the descending colon. Computed tomography (CT) of the abdomen revealed the thickening of the descending colon wall and superior mesenteric vein rotation. An opaque enema detected severe stenosis of the descending colon. An abdominal X-ray examination revealed the dilation of the colon and small intestine with niveau. At the insertion of an ileus tube, the C-loop of the duodenum was observed to be absent and the small intestine was located on the right side of the abdomen. After the decompression of the bowel contents, laparotomy was performed. Descending colon cancer was observed to have directly invaded the left side of the transverse colon. Left hemicolectomy, lymph node dissection, and appendectomy were performed. The patient had an uneventful recovery and was discharged from the hospital on the 16th day after surgery. This report presents a rare operative case of descending colon cancer in an adult patient with intestinal malrotation.

Postoperative megarectum in an adult patient with imperforate anus and rectourethral fistula.

This report presents a surgical case of postoperative megarectum in an adult patient with imperforate anus/anorectal malformations. A 71-year-old Japanese male presented with a mass in the lower abdomen which was 15 × 12 × 8 cm in diameter, edema in the right lower extremity, and frequent urination. He had undergone sigmoid loop colostomy for an imperforate anus as a newborn infant. At 28 years of age, the sigmoid loop colostomy was changed to sigmoid divided colostomy in the left lower abdomen. Computed tomography revealed a large cystic mass in the lower abdomen. Retrograde urethrography indicated a rectourethral fistula and megarectum with stones. A small laparotomy incision was created in the right lower abdomen, and the wall of the megarectum was identified. Approximately 2,300 mL of gray muddy fluid was identified and drained. A mucous fistula of the upper rectum was created in the right lower abdomen. This is an extremely rare case of postoperative megarectum in an adult patient with an imperforate anus and rectourethral fistula.

Hypersensitivity to aurora kinase inhibitors in cells resistant against platinum- containing anticancer agents.

The aurora kinases are serine/threonine kinases that are essential for mitosis and contribute to tumorigenesis. Therefore, aurora kinases hold promise for molecularly targeted therapy. In the present study, we demonstrated that aurora B kinase (AURKB) is overexpressed in both cisplatin- and oxaliplatin-resistant cells. Downregulation of AURKB sensitized cells to both cisplatin and oxaliplatin, but not to paclitaxel, 5-FU or hydrogen peroxide. Interestingly, we found that both cisplatin- and oxaliplatin-resistant cells were hypersensitive to the AURKB specific inhibitors, AZD1152 HQPA and ZM447439, suggesting that both cisplatin- and oxaliplatinresistant cells develop an addiction to AURKB. These data provide evidence that aurora kinase inhibitors can overcome both cisplatin and oxaliplatin resistance. Therefore, AURKB inhibitors could offer potential benefits if used after first-line platinum-based chemotherapy.

Short-term training of upper gastrointestinal endoscopy for resident doctors in Sotogahama Central Hospital in Aomori, Japan.

It is essential for young physicians in municipal hospitals to be familiar with the technique of upper gastrointestinal (GI) endoscopy. Endoscopy is an exciting subspecialty in primary care medicine. Endoscopic procedures are primarily performed by general physicians in Japan. However, a standardized strategy for teaching diagnostic GI endoscopy is still lacking, and there is not sufficient time for young physicians to effectively learn the upper GI endoscopy technique. To elucidate how young physicians can be trained in the skills of GI endoscopy in a short time period, we initiated a 12-week training course. Two young physicians performed upper GI endoscopies for outpatients and inpatients 2 or 3 days a week from April 2010 to March 2012. The total number of cases undergoing GI endoscopy during the training course in each year was 117 and 111, respectively. The young physicians were trained in this technique by the attending physician. The short-term training course included four phases. During these phases, the young physicians learned how to insert the endoscope through the nasal cavity or oral cavity into the esophageal inlet, how to pass the endoscope from the esophageal inlet into the duodenum, how to take pictures with the endoscope, and how to stain the gastric and duodenal mucosa and take mucosal biopsy samples. The young physicians experienced 20-30 cases in each phase. In week five, they performed endoscope insertion into the duodenum along the folds of the greater curvature of the stomach. They viewed the entire stomach and took pictures until week ten of the course. The pictures taken in week ten were of a better quality for examining the disease lesions than those taken in week six. In the last 2 weeks of the training course, the young physicians stained the gastric and duodenal mucosa and took mucosal biopsy samples. The short-term training course of 100-120 cases in 12 weeks was effective for teaching young physicians how to perform GI endoscopies independently.

Immunohistochemical characterization of non-epithelial cells in spiradenoma.

Spiradenoma is unique with respect to the presence of a large number of non-epithelial cells, including S100 protein(+) cells, most of which are presumably Langerhans cells, in the parenchyma as shown in the published work. However, the characterization of these non-epithelial cells to date is insufficient. Immunohistochemistry of CD1a, CD3, CD4, CD8, CD56, CD68, intercellular adhesion molecule-1 (ICAM-1), and HLA-DR, as well as double-immunofluorescence labeling of S100 protein/CD1a and CD1a/CD3, was performed using paraffin-embedded specimens from five cases of spiradenoma retrospectively. Non-epithelial cells evenly distributed throughout the parenchyma of spiradenoma primarily consisted of CD1a(+) Langerhans cells and CD3(+) T cells. ICAM-1 was expressed by epithelial cells and non-epithelial cells in the parenchyma. HLA-DR on the epithelial cells was limited to the focal area. In double-immunofluorescence labeling, approximately one-half of Langerhans cells were spatially related to T cells in the parenchyma, suggesting their functional interaction.

Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth.

Mitochondrial transcription factor A (mtTFA) is one of the high mobility group protein family and is required for both transcription from and maintenance of mitochondrial genomes. However, the roles of mtTFA have not been extensively studied in cancer cells. Here, we firstly reported the nuclear localization of mtTFA. The proportion of nuclear-localized mtTFA varied among different cancer cells. Some mtTFA binds tightly to the nuclear chromatin. DNA microarray and chromatin immunoprecipitation assays showed that mtTFA can regulate the expression of nuclear genes. Overexpression of mtTFA enhanced the growth of cancer cell lines, whereas downregulation of mtTFA inhibited their growth by regulating mtTFA target genes, such as baculoviral IAP repeat-containing 5 (BIRC5; also known as survivin). Knockdown of mtTFA expression induced p21-dependent G1 cell cycle arrest. These results imply that mtTFA functions in both nuclei and mitochondria to promote cell growth.

Forced Expression of ZNF143 Restrains Cancer Cell Growth.

We previously reported that the transcription factor Zinc Finger Protein 143 (ZNF143) regulates the expression of genes associated with cell cycle and cell division, and that downregulation of ZNF143 induces cell cycle arrest at G2/M. To assess the function of ZNF143 expression in the cell cycle, we established two cells with forced expression of ZNF143 derived from PC3 prostate cancer cell lines. These cell lines overexpress genes associated with cell cycle and cell division, such as polo-like kinase 1 (PLK1), aurora kinase B (AURKB) and some minichromosome maintenance complex components (MCM). However, the doubling time of cells with forced expression of ZNF143 was approximately twice as long as its control counterpart cell line. Analysis following serum starvation and re-seeding showed that PC3 cells were synchronized at G1 in the cell cycle. Also, ZNF143 expression fluctuated, and was at its lowest level in G2/M. However, PC3 cells with forced expression of ZNF143 synchronized at G2/M, and showed lack of cell cycle-dependent fluctuation of nuclear expression of MCM proteins. Furthermore, G2/M population of both cisplatin-resistant PCDP6 cells over-expressing ZNF143 (derived from PC3 cells) and cells with forced expression of ZNF143 was significantly higher than that of each counterpart, and the doubling time of PCDP6 cells is about 2.5 times longer than that of PC3 cells. These data suggested that fluctuations in ZNF143 expression are required both for gene expression associated with cell cycle and for cell division.

Role of ZNF143 in tumor growth through transcriptional regulation of DNA replication and cell-cycle-associated genes.

The cell cycle is strictly regulated by numerous mechanisms to ensure cell division. The transcriptional regulation of cell-cycle-related genes is poorly understood, with the exception of the E2F family that governs the cell cycle. Here, we show that a transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-associated genes and is highly expressed in multiple solid tumors. RNA-interference (RNAi)-mediated knockdown of ZNF143 showed that expression of 152 genes was downregulated in human prostate cancer PC3 cells. Among these ZNF143 targets, 41 genes (27%) were associated with cell cycle and DNA replication including cell division cycle 6 homolog (CDC6), polo-like kinase 1 (PLK1) and minichromosome maintenance complex component (MCM) DNA replication proteins. Furthermore, RNAi of ZNF143 induced apoptosis following G2/M cell cycle arrest. Cell growth of 10 lung cancer cell lines was significantly correlated with cellular expression of ZNF143. Our data suggest that ZNF143 might be a master regulator of the cell cycle. Our findings also indicate that ZNF143 is a member of the growing list of non-oncogenes that are promising cancer drug targets.

Y-box binding protein-1 is a novel molecular target for tumor vessels.

Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many reports indicate that YB-1 is highly expressed in tumor cells and is a marker for tumor aggressiveness and clinical prognosis. Here, we show clear evidence that YB-1 is expressed in the angiogenic endothelial cells of various tumors, such as glioblastoma, esophageal cancer, gastric cancer, colon cancer, and lung cancer, as well as in tumor cells. YB-1 was highly expressed in glomeruloid microvascular endothelial cells of brain tumors and microvessels in the desmoplastic region around multiple solid tumors. On the other hand, no or low YB-1 expression was observed in normal angiogenic endothelial cells from fetal kidney, newborn lung, and placenta. The endothelial cells in inflammatory regions of granulomas were also weakly labeled. Knockdown of YB-1 expression by small-interfering RNA induced G1 cell cycle arrest and inhibited the growth of human umbilical vein endothelial cells stimulated by growth factors. Taken together, YB-1 plays an important role in the growth of not only tumor cells but also tumor-associated endothelial cells, suggesting that YB-1 is a promising target for cancer therapy.

Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

Experimental treatment of ovarian cancers by adenovirus vectors combining receptor targeting and selective expression of tumor necrosis factor.

Ovarian cancer is the fourth most common cancer among women and existing treatment is not routinely curative. One new strategy for cancer therapy is the selective delivery of TNFalpha to tumors via adenovirus vectors. We have tested the combination of two modifications to adenovirus vectors designed to limit delivery to tumors, capsid modification and expression control. To target alpha(v)beta(3/5) integrin receptors that are highly expressed in tumor and sparsely expressed in the epithelial layer of peritoneum, we modified the capsid fiber and penton base to remove native receptor binding and incorporated an RGD-4C motif in the fiber knob (Ad.PB*F*RGD). This vector exhibits effective gene transfer in all of the alpha(v)beta(3/5)-positive ovarian cancer cells tested in vitro and in vivo. Importantly, the Ad.PB*F*RGD vector is able to transduce ovarian tumor nodules and avoid infecting the normal mesothelial cells that line the intraperitoneal space following intraperitoneal administration. To further increase selectivity, different promoters were incorporated into the capsid-modified vector to confer the expression of the hTNFalpha therapeutic gene. We analyzed both constitutive (CMV or RSV) and potentially tumor selective promoters (MUC-1, E2F or hTERT) in terms of efficacy, selectivity and safety. TNF-expressing Ad.PB*F*RGD vectors containing the MUC-1 promoter showed anti-tumor activity in two ovarian cancer xenograft models (Caov3 and Igr-ov1) with little evidence of toxicity or systemic TNF. The data indicate that combination of capsid modification and transcriptional regulation of expression is a promising strategy for development of a new ovarian cancer treatment.

Ablating CAR and integrin binding in adenovirus vectors reduces nontarget organ transduction and permits sustained bloodstream persistence following intraperitoneal administration.

To create tumor-targeted Ad vectors, ablation of native CAR and integrin receptor binding is crucial to enhance the specificity of tumor transduction. Toward this aim, we have previously created base vectors in which binding to CAR (single-ablated) or to both CAR and integrins (double-ablated) has been ablated. In this study, the biodistribution of the conventional (CAR and integrin binding intact), single-ablated, and double-ablated vectors was evaluated following intraperitoneal administration. The mesothelial lining of the peritoneal organs was the principle site of CAR-dependent gene transfer by the conventional vector. Surprisingly, the single-ablated vector strongly transduced the liver parenchyma rather than the mesothelium, while the double-ablated vector did not significantly transduce the parenchyma or mesothelium. The high level of parenchymal transduction by the single-ablated vector suggested that it efficiently entered the bloodstream from the peritoneal cavity. Consistent with this hypothesis, a large proportion of active particles distributed and persisted in the bloodstream following intraperitoneal administration of either the single- or the double-ablated vector. The above results suggest that the double-ablated vector backbone may not only significantly improve targeting to cancers located in the peritoneal cavity, but may also significantly improve targeting to metastatic tumors located throughout the body by virtue of its enhanced bloodstream persistence.