Minimally Invasive Treatment for Advanced Hemorrhoids.

Hemorrhoids, the most common anorectal disease, give rise to symptoms such as bleeding, prolapse, and pruritus. The treatment for advanced hemorrhoids (Grade III or IV) is gradually shifting toward minimally invasive procedures. These procedures focus on reduction of blood flow in hemorrhoids. Conventional hemorrhoidectomy (CH), also known as Milligan-Morgan or Ferguson hemorrhoidectomy, is considered as the standard treatment for Grade III and IV hemorrhoids because it achieves the lowest recurrence rate. Over the years, alternative minimally invasive techniques such as stapled hemorrhoidopexy and transanal hemorrhoidal dearterialization (THD) have been developed. A new, effective sclerosant, aluminum potassium sulfate and tannic acid (ALTA), has been developed in Japan and has been used for all grades of hemorrhoids; however, its effectiveness declines over time. Other minimally invasive, nonsurgical procedures, including rubber band ligation, endoscopic injection sclerotherapy, and infrared coagulation, have also been performed for Grade III hemorrhoids. Those minimally invasive treatments improve bleeding and prolapse and are highly recommended for patients who are unfit for CH. THD with mucopexy or ALTA sclerotherapy has also been performed for Grade IV hemorrhoids. However, the recurrence rate after ALTA sclerotherapy for Grade IV hemorrhoids was higher than that for Grade III lesions in our case study. In conclusion, minimally invasive treatments are a valid alternative for patients with advanced hemorrhoids after clear explanation of recurrence rates and possible complications.

Discovery and structure optimization of a novel corn herbicide, tolpyralate.

Tolpyralate, a new selective postemergence herbicide developed for the weed control in corn, possesses a unique chemical structure with a 1-alkoxyethyl methyl carbonate group on the N-ethyl pyrazole moiety. This compound shows high herbicidal activity against many weed species, including glyphosate-resistant Amaranthus tuberculatus. Tolpyralate targets 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), which is involved in the tyrosine degradation pathway. Inhibition of the enzyme destroys the chlorophyll, thereby killing the susceptible weeds. Details of tolpyralate discovery, structure optimization, and biological activities are described.

Aluminum potassium sulfate and tannic acid sclerotherapy for Goligher Grades II and III hemorrhoids: Results from a multicenter study.

AIM: To show that aluminum potassium sulfate and tannic acid (ALTA) sclerotherapy has a high success rate for Grade II and III hemorrhoids. METHODS: This study was based on the clinical data of 604 patients with hemorrhoids who underwent ALTA sclerotherapy between January 2009 and February 2015. The objective of this study was to assess the efficacy of this treatment for Grades II and III hemorrhoids. Preoperative and postoperative symptoms, complications and success rate were all assessed retrospectively. Follow-up consisted of a simple questionnaire, physical examination and an anoscopy. Patients were followed-up at one day, one week, two weeks, one month, one year, two years, three years, four years and five years after the ALTA sclerotherapy. RESULTS: One hundred and sixty-nine patients were diagnosed with Grade II hemorrhoids and 435 patients were diagnosed with Grade III hemorrhoids. The one year, three year and five year cumulative success rates of ALTA sclerotherapy for Grades II and III hemorrhoids were 95.9% and 93.1%; 89.3% and 83.7%; and 89.3% and 78.2%, respectively. No significant differences were observed in the cumulative success rates after ALTA sclerotherapy between Grades II and III hemorrhoids (P = 0.09). There were forty-seven post-operative complications (low grade fever; anal pain; urinary retention; rectal ulcer; and others). No serious or life-threatening complications occurred and all cases improved through conservative treatment. At univariate analysis there were no predictive factors of failure. CONCLUSION: ALTA sclerotherapy has had a high success rate for Grade II and III hemorrhoids during five years of post-operative treatment. However, additional studies are needed to evaluate the efficacy of this ALTA sclerotherapy in the management of hemorrhoidal disease.

ALTA injection sclerosing therapy:non-excisional treatment of internal hemorrhoids.

BACKGROUND/AIMS: Aluminum potassium sulfate and tannic acid (ALTA) is a new sclerosing therapy for internal hemorrhoids. This injection therapy is a four-step direct injection sclerosing procedure intended to shrink and harden internal hemorrhoids to eliminate hemorrhoidal prolapse and bleeding. The aim of this study was to assess the short term efficacy of this treatment. METHODOLOGY: The procedure was conducted using a four-step injection process under perianal local anesthesia. The entry point for the four-step injection of ALTA is the submucosa of the superior pole, the submucosa in the central part, the mucous lamina propria in the central part and the submucosa at the inferior pole of hemorrhoid. RESULTS: From January 2009 to March 2010, we performed the ALTA sclerosing therapy on 28 patients (14 men and 14 women; mean age, 64.6 years), including 5 second-degree, 16 third-degree and 7 fourth-degree hemorrhoids. There were 6 postoperative complications (2 cases of low grade fever, 2 anal pains, 1 necrosis at injection site and 1 perianal dermatitis). All symptoms of prolapse or bleeding disappeared after 29 postoperative days. There were 3 recurrent cases (10.7%). CONCLUSIONS: ALTA sclerosing therapy is a useful and less invasive treatment for internal hemorrhoids.

Evaluation of procedure of laparoscopic para-aortic lymph node biopsy: comparison between transperitoneal approach and extraperitoneal approach.

In gastrointestinal laparoscopic surgery, paraaortic lymphadenectomy is usually performed using a transperitoneal approach (TP), and the use of an extraperitoneal approach (EP) has been scarcely reported. Biopsy of the para-aortic lymph nodes was performed using TP with 3 ports on the patient with esophageal cancer, and EP lymphnode biopsy was performed with 4 ports with malignant lymphoma. The effect of TP vs. EP was evaluated regarding the intraoperative and postoperative complications. TP was difficult for massive biopsy, 1.5cm sized several lymph nodes along the common hepatic artery were biopsied. On the other hand, using EP a 5cm sized paraaortic lymph node was successfully performed. There was no difference between TP and EP in intraoperative blood loss and operation time, respectively, but EP showed great advantage with respect to postoperative complications and length of administration in hospital. Laparoscopic biopsy of para-aortic lymph nodes using EP is a useful method compared with the TP.

HPV infection in an HIV-positive patient with primary squamous cell carcinoma of rectum.

Primary squamous cell carcinoma (SCC) of the colorectum is a rare malignancy of unknown etiology and pathogenesis. We report a case of primary SCC of the rectum. A 55-year-old man with a rectal tumor and human immunodeficiency virus (HIV) infection was referred to our hospital. Histopathology of biopsy specimens showed characteristics of SCC. We diagnosed the patient as having primary moderately differentiated SCC of the rectum according to the criteria proposed by Cooper. Human papillomavirus (HPV) DNA was amplified by polymerase chain reaction analysis of unfixed tumor biopsy specimens. In addition, no p53 overexpression or nuclear staining of retinoblastoma protein (Rb) was observed in neoplastic cells by immunohistochemical staining. We suggest from our case that HPV infection following the inactivation of the cellular tumor suppressor Rb and the immune suppression induced by HIV infection play an etiologic role in the pathogenesis of rectal SCC, consistent with the well-established concept of HPV-associated anal carcinogenesis.

Sonic hedgehog relates to colorectal carcinogenesis.

AIM: The activation of Hedgehog signaling, which is critical to normal mammalian gastrointestinal development, is implicated in the development of various tumors, including colorectal cancer. In the pancreas, a precursor lesion overexpresses the Sonic hedgehog (Shh) when compared with normal tissue and cancer. The present study was designed to investigate Shh related protein expression in hyperplastic polyps and the adenoma-carcinoma sequence in the colon and rectum. METHODS: Seventeen hyperplastic polyps, 24 adenomas of the colon, 69 adenocarcinomas (31 well-differentiated, 38 moderately-differentiated), and 30 normal colon samples were used in the study. We checked the expression of Shh, both patched (Ptch) and smoothened (Smo), by immunohistochemistry and compared the expression rate of each group. RESULTS: Almost all adenomas, 22 of 23 (96%), expressed Shh. In other groups, 4 of 17 hyperplastic polyps (24%), 7 of 31 well-differentiated adenocarcinomas (23%), 13 of 38 moderately-differentiated adenocarcinomas (34%) and none of the 30 normal samples expressed Shh. The rate of expression in Ptch and Smo gradually increased in accordance with tumor progression. CONCLUSION: This result indicates that Shh-related carcinogenesis and Shh expression may be a trigger for the adenoma-carcinoma sequence. This study suggests a potential therapeutic target of hedgehog blockade in carcinogenesis.

A new classification system for liver metastases from colorectal cancer in Japanese multicenter analysis.

BACKGROUND/AIMS: Although numerous authors have reported various prognostic factors for liver metastases from colorectal cancer, there is not yet a general classification. METHODOLOGY: A total of 478 colorectal cancer patients from 18 institutes were studied. Prognostic factors were investigated using univariate and multivariate analyses. RESULTS: Independent prognostic factors for colorectal liver metastases were number of liver metastases, size of the largest liver metastases, mesenteric lymph node metastases (pN0/1: < or =3 lesions, pN2: > or =4 lesions), and extrahepatic metastases (EM0: absence of extrahepatic metastasis, EM1: presence of extrahepatic metastases). We defined the following classification system; Stage A: HT1 (< or =4 lesions and < or =5cm) and pN0/1, Stage B: HT2 (> or =5 lesions or >5cm) and pN0/1, or HT1 and pN2, Stage C: HT2 and pN2, HT3 (> or =5 lesions and >5cm) with any pN, or any HT and any pN with EM1. Five-year survival rates were 53.5% for Stage A patients, 25.4% for Stage B patients, and 5.8% for Stage C patients. Median survival time was 70.4 months, 31.4 months, and 17.2 months, respectively. CONCLUSIONS: Our classification was advocated to evaluate prognoses for liver metastases from colorectal cancer. It can help guide decision making in terms of liver resection and assessing patient prognosis.

Kampo medicine "Dai-kenchu-to" prevents bacterial translocation in rats.

Kampo medicine "Dai-kenchu-to" (DKT) has been used for treatment of ileus. The aim of this study was to evaluate the role of DKT on the bacterial translocation (BT) model in rats. Rats were divided into the following four groups: group 1, receiving only water, and groups 2, 3, and 4, receiving 100, 300, and 1,000 mg/kg/day of DKT. Rats were sacrificed 6 days after the beginning of the fast, and then the mesenteric lymph node was cultured. Inflammatory cytokines, intestinal integrity, and apoptosis were assessed. Incidence of BT in groups 3 (33%) and 4 (16%) was lower than in group 1 (66%). Interferon-gamma expression in groups 2, 3, and 4 was significantly lower than in group 1. Villous height and number of villus in groups 2, 3, and 4 were significantly taller and greater than in group 1. Apoptotic index in groups 2, 3, and 4 was significantly lower than in group 1. This is the first evidence that DKT prevents BT by reducing inflammatory reaction and maintaining intestinal integrity.

p53 and MIB-1 expression of esophageal carcinoma concominant with achalasia.

Achalasia, insufficient relaxation of the lower esophageal sphincter (LES) causes the retention and stasis of food and secretions, chronic hyperplastic esophagitis and eventual malignant transformation. p53 alternation has been suggested to play an important role in the malignant transformation. A 53-year-old man was endoscopically followed up for esophageal achalasia for seven years, and endoscopy revealed an ulcerative region in the upper thoracic esophagus, and histopathologically the biopsy specimens showed moderately differentiated squamous cell carcinoma. In resected specimens, p53 staining was strong and diffuse in the tumor and MIB-1 immunoreactivity was strong and patchy in the tumor and the basal layer of squamous mucosa of the esophagus. No staining for either immunostains was noted in normal esophageal mucosa. It is necessary for patients with esophageal achalasia to be followed-up with endoscopy, and that p53 and MIB-1 immunostaining of biopsy specimens should be performed to detect pre-cancerous lesions.

Pyrimidine nucleoside phosphorylase and dihydropyrimidine dihydrogenase activities as predictive factors for the efficacy of doxifluridine together with mitomycin C as adjuvant chemotherapy in primary colorectal cancer.

BACKGROUND/AIMS: Pyrimidine Nucleoside Phosphorylase (PyNPase) converts 5'-deoxy-5-fluorouridine (5'-DFUR, doxifluridine) to 5-fluorouracil (5-FU). While this reaction is taking place Dihydropyrimidine Dihydrogenase (DPD) catalyzes 5-FU to inactive molecules. Mitomycin C (MMC) elevates the PyNPase level in tumor cells. METHODOLOGY: We investigated 17 colorectal cancer patients' PyNPase and DPD activities in tumor and normal tissues using an enzyme-linked immunosorbent assay (ELISA) to assess their clinical significance as indicators for selecting colorectal cancer patients for 5'-DFUR together with MMC as adjuvant chemotherapy. RESULTS: Six of 17 patients developed experienced a recurrence. Tumor DPD activity of the 6 patients who had a recurrence were higher than those of the 11 patients with no recurrence (p = 0.047). On the other hand, there were no significant differences in both the PyNPase and the PyNPase/DPD (P/D) ratio between the group with recurrence and the group without recurrence. For survival analyses, we designed the cut-off value of tumor PyNPase, DPD and P/D ratio as their median value and classified patients into a higher group and a lower group, but there were no significant differences between the groups. CONCLUSIONS: The DPD activity in the tumor may be a useful indicator for selecting patients likely respond to 5'-DFUR together with MMC as adjuvant chemotherapy. If tumor DPD is high, we had better select a different anticancer drug.

Usefulness of local excision for early lower rectal cancer.

BACKGROUND/AIMS: The purpose of this study was to examine the long-term results of transanal excision compared with major surgery for lower rectal cancer. METHODOLOGY: This retrospective study included 14 patients with early rectal cancer within 8cm from the anal verge treated by local excision in the period from January 1991 to December 2000, and 16 patients treated by major surgery in the period from January 1996 to December 2000. We evaluated the prognosis or anorectal or urinary function of these patients. RESULTS: Six of the patients had additional treatments which included additional resection or adju vant chemotherapy. None of these patients had macroscopic tumor remnants (R2). With the exception of one patient who died of heart disease, all of the patients survived without metastasis. Anorectal and urinary function maintained a good status. CONCLUSIONS: Local excision for early rectal cancer (Tis N0 M0) brought an excellent outcome, and maintained good anorectal and urinary function. We recommend local excision for the early rectal cancer patients.

Squamous cell carcinoma of the descending colon: report of a case and literature review.

It is very rare that squamous cell carcinoma (SCC) arises from colorectal epithelium. An 89-year-old man was treated in 2001 with chief complaints of anorexia, abdominal pain, and low grade fever. The histological diagnosis as SCC was determined by biopsy during a colonoscopy. We diagnosed primary SCC of the colon because except in the colon no malignant lesions were found by systemic CT. Surgical complete resection was performed. However, he died three months after surgical resection because of hepatic metastasis and cachexia. The prognosis of this disease seems to be worse than that of adenocarcinoma.

Poorly differentiated neuroendocrine cell carcinoma of the rectum: report of a case and literal review.

A 56-year-old man was admitted to our hospital because of anal bleeding. Colonoscopy and barium enema revealed type 4 tumor in the rectum. Biopsy revealed poorly differentiated adenocarcinoma. Low anterior resection with total mesorectal excision and lymph node dissection was performed. In immunohistochemical staining, chromogranin A and synaptophysin were positive at major lesion, and CEA were focal positive. The resected tumor was diagnosed pathologically as neuroendocrine cell carcinoma. The Ki-67 labeling index (LI) was 87.8%, so proliferative activity and potential malignancy was very high. Multiple metastatic tumors appeared in pelvis and lung eight months after operation. Treatment for neuroendocrine cell carcinoma of the rectum was controversial. Surgical resection and adjuvant chemotherapy might be one of the methods for gastrointestinal neruroendocrine cell carcinoma.

Accumulation profile of frameshift mutations during development and progression of colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.

PURPOSE: Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined. This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer. METHODS: Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes. RESULTS: The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency (94-100 percent) in all pathologic stages, and mutation of the MARCKS gene also was high (94 percent) in Dukes B and C cancers. These frequencies were higher than the frequency of TGFbetaRII gene inactivation (64-88 percent). Mutations of the hMSH3, TCF4, CASP5, RIZ, RAD50, and MBD4 genes were comparatively frequent (>35 percent) in all stages. Frequencies of inactivation of the MARCKS, BAX, IGFIIR, and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer (P < 0.05). The number of accumulated frameshift mutations was larger in Dukes B and C cancers (9.4) than in Dukes A cancer (6.8) (P = 0.003). CONCLUSIONS: The present data suggest that the disruption of the transforming growth factor-beta super-family signaling pathway by the alteration of the ACVR2 and/or TGFbetaRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer. Moreover, the further accumulation of alterations in the MARCKS, BAX, IGFIIR, and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.

N(1),N(12)-Diacetylspermine as a sensitive and specific novel marker for early- and late-stage colorectal and breast cancers.

PURPOSE: N(1),N(12)-diacetylspermine (DiAcSpm) in the urine of colorectal and breast cancer patients was examined to establish its usefulness as a novel diagnostic tool for detecting these cancers at clinically early stages. EXPERIMENTAL DESIGN: Urine samples from 248 colon cancer patients and 83 breast cancer patients as well as 51 patients with benign gastrointestinal diseases treated in Tokyo Metropolitan Komagome Hospital during the period of August 1999 to January 2004 were collected. DiAcSpm was analyzed by ELISA and its sensitivity for malignant conditions was compared with that of serum carcinoembryonic antigen (CEA), CA19-9, and CA15-3. RESULTS: The sensitivity of urinary DiAcSpm for colon cancer patients (n = 248) was 75.8% (mean +/- 2 SD for 52 healthy controls as a cutoff value), which was markedly higher than the sensitivities of serum CEA (39.5%, P < 0.0001) and CA19-9 (14.1%, P < 0.0001). DiAcSpm was elevated in 60% of tumor-node-metastasis cancer stage 0 + I patients, whereas only 10% (P < 0.0001) and 5% (P < 0.0001) of these patients were CEA- and CA19-9-positive, respectively. The sensitivity of urinary DiAcSpm for 83 cases of breast cancer (60.2%) was higher than the sensitivities of CEA (37.3%, P = 0.0032) and CA15-3 (37.3%, P = 0.0032). DiAcSpm was elevated in 28% of tumor-node-metastasis stage I + II patients, whereas only 3% (P = 0.0064) and 0% (P = 0.001) of these patients were CEA- and CA15-3-positive, respectively. CONCLUSION: The observations indicate that urinary DiAcSpm is a more sensitive marker than CEA, CA19-9, and CA15-3 and that it can efficiently detect colorectal and breast cancers at early stages.

[Biomarkers for neoplasmas in digestive organs].

This review is concerned with the usefulness and the problem of biomarkers for cancer of digestive organs. Carcinoembryonic antigen (CEA) is a most popular and useful tumor marker for cancer of digestive organs. Squamous cell carcinoma (SCC) antigen and CYFRA have been reported as a useful tumor marker for esophageal cancer. CEA and CA 19-9 are a good prognostic factor in gastric cancer patients. The post-operative increase of serum CEA can be a predictive marker for the patients of colorectal cancer. Development of a radioimmunoassay for highly sensitive detection of tumor markers, they are considered to be useful for monitoring after treatment. But are not useful for the early diagnosis. The diagnosis of hepatocellular carcinoma (HCC) is based mainly on serological markers, such as alpha-fetoprotein and PIVKA-II. The two are useful complementary markers of HCC because they do not correlate with each other. But the problem of the false-positive rate for the patients with chronic hepatitis or liver cirrhosis is still remained. A typical marker of pancreatic and bile duct cancer is carbohydrate antigen, but the sensitivity of these markers is only 50%. Recent molecular biological analysis may be used as effective biomarkers in the diagnosis, prognosis, therapy, and risk assessment of digestive cancer.

[The significance of urine di-acetyl spermine level as a cancer marker for colorectal cancer].

We analyzed the significance of the measurement of urine di-acetyl spermine (DiAcSpm) as a cancer marker for colorectal cancer treatment. We measured both the urine DiAcSpm(ELISA, normal range: 0-0.25 mumol/creatinine) and serum CEA (normal range: 0-5.0 ng/ml) of preoperative and postoperative colorectal cancer patients every month. We compared the positive rate from the cancer stage and the power of prognostic prediction. We divided the colorectal cancer patients into 4 groups: Group A: both levels were high; Group B: only the CEA level was high; Group C: only the DiAcSpm level was high; Group D: both levels were within a normal range. The positive rates of DiAcSpm and CEA from cancer staging were as follows: Stage 0: 62% and 9.5%, Stage I: 60% and 10%, Stage II: 70% and 42%, Stage III: 82% and 47%, and Stage IV: 88% and 63%, respectively. There was a significant difference (p < 0.0001) between both levels, especially for early-stage cases. The two-year survival rate was 0% in Group A, 100% in Group B, 72.7% in Group C and 100% in Group D. The difference among the 4 groups was significant (p < 0.0001). This showed that urine DiAcSpm predicted the prognosis after colorectal cancer surgery more exactly than serum CEA.

Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins.

INTRODUCTION: Pancreatic cancer is one of the major causes of cancer-related deaths in industrialized countries. It is known that pancreatic cancer is resistant to chemotherapy and that cancer cells are surrounded by extracellular matrix (ECM) proteins including collagen I, collagen IV, fibronectin, and laminin. AIMS: To examine the role of ECM proteins in acquired resistance to anticancer drugs and proliferation regulation in pancreatic cancers. METHODOLOGY AND RESULTS: We used an in vitro model of ECM-induced chemoresistance and cell proliferation of cancer cell lines (MIA PaCa-2, PANC-1, and Capan-1) with 3 different malignancy grades and found that resistance to cytotoxic drugs and proliferation regulation was dependent on ECM proteins. Pancreatic cancer cell lines, especially MIA PaCa-2 cells, adhering to any of the ECM proteins showed decreased cytotoxicity of anticancer drugs, except for gemcitabine. PANC-1 and Capan-1 cells adhering to fibronectin, collagen I, and collagen IV proliferated more than the controls. CONCLUSION: ECM proteins have important roles in acquired resistance to anticancer drugs and cell proliferation regulation of pancreatic cancer cells. Therefore, the expression of ECM proteins in pancreatic cancer specimens could provide valuable information to aid anticancer drug cytotoxicity, and gemcitabine would be useful for treatment of patients with pancreatic cancer.

[The present and future of home care chemotherapy for patients with advanced and recurrent colorectal cancer].

PURPOSE: If the chemotherapy at home is as effective as the chemotherapy at an outpatient clinic, QOL of the patients will be improved. In this paper the future of chemotherapy at home was clarified from the outcome of the chemotherapy for advanced and recurrent colorectal cancer. METHOD: Hepatic arterial infusion chemotherapy (HAI) (5-FU 2,000 mg/w, continuous infusion for 7 days, n=123) for unresectable liver metastases and FL chemotherapy (5 FU 1,500 mg + l-LV 375 mg/w, continuous systemic chemotherapy for 7 days, n=32) for extra hepatic recurrence were carried out at home by a portable pump system every other week. RESULTS: The response rates were 61.2% in HAI and 18.8% in FL. MST were 14.7 months in HAI and 10.8 months in FL. It was important to establish a surveillance network system to continue the chemotherapy at home. CONCLUSIONS: It was suggested that the chemotherapy at home was effective and to maintain the patient's QOL as one of the options.