Outcome of stapled hemorrhoidopexy versus doppler-guided hemorrhoidal artery ligation for grade III hemorrhoids.

PURPOSE: To evaluate the long-term results, early and late complication rates, and overall satisfaction of patients with grade III hemorrhoids treated by stapled hemorrhoidopexy (SH) or Doppler-guided hemorrhoidal artery ligation (DGHAL). METHODS: Operative and follow-up patients' data were prospectively collected for patients undergoing either SH or DGHAL by a single surgeon during a 2-year period. A retrospective comparison between patients' outcome operated by one of the two methods was made based on this data. Clinical data on postoperative pain, analgesic requirements, time to first bowel movement and functional recovery were collected at five postoperative follow-up visits (1 and 6 weeks, 6, 12, and 18 months). Data on patient satisfaction, recurrence of hemorrhoidal symptoms and further treatments were obtained by a standardized questionnaire that was conducted during the last visit 18 months postoperatively. RESULTS: A total of 63 patients underwent SH (aged 52 ± 3.2 years) and 51 patients underwent DGHAL (aged 50 ± 7.3 years). DGHAL patients experienced less postoperative pain as scored by pain during bowel movement (2.1 ± 1.4 vs. 5.5 ± 1.9 for SH), and required fewer analgesics postoperatively. Hospital stay, time to first bowel movement, and complete functional recovery were also significantly shorter for the DGHAL patients. Nine DGHAL patients (18%) suffered from persistent bleeding or prolapses and required additional treatment compared with 2 (3%) patients in the SH group. SH patients reported greater satisfaction compared with DGHAL patients at 1 year postoperatively. CONCLUSION: Both SH and DGHAL are safe procedures and have similar effectiveness for treating grade III hemorrhoids. DGHAL is less painful and provides earlier functional recovery, but is associated with higher recurrence rates and lower satisfaction rates compared with SH.

Detection of cancer cells in the axillary drainage using RT-PCR after operations for breast cancer.

The object of this study was to examine whether MUC-1 can be detected in the axillary lymphatic drainage of patients who have undergone conservative surgery for breast cancer and to assess the correlations between the presence of MUC-1 and prognostic factors in breast cancer. Sixty-eight women with invasive ductal carcinoma of the breast underwent wide local excision and axillary lymph node dissection. Axillary drains were inserted in all these cases, and the presence of MUC-1 and beta-actin was evaluated by RT-PCR in the lymphatic fluid collected after the operation. Prognostic factors included tumour size and grade, vascular and lymphatic invasion, clearance margins of the resected specimens and status of the axillary lymph nodes. RT-PCR assays for MUC-1 in the axillary fluid were positive in 17 patients (25%). The presence of MUC-1 was associated with increased tumour size and showed a positive correlation with axillary lymph node metastases and incomplete resection of the tumour. RT-PCR can disclose cancer cells in the axillary fluid after conservative surgery for breast cancer. The presence of MUC-1 in the axillary drainage may be associated with poor prognostic features, and its detection may have implications for therapy as it suggests that re-excision should be considered.

Benefits of radioimmunoguided surgery for pelvic recurrence.

AIM: Surgery for recurrent rectal cancer is usually traumatic and of questionable curative value. The use of radioimmunoguided surgery (RIGS) in enhancing the surgeon's assessment of the extent of disease in these patients was investigated. METHODS: Twenty-one patients diagnosed with recurrent pelvic cancer were operated using the RIGS(O)system. Preoperative assessment included CTs of chest, abdomen and pelvis as well as colonoscopy. Patients were injected with CC49, a monoclonal antibody (MoAb) labelled with 125I. Surgical exploration was followed by survey with the gamma-detecting probe. RESULTS: Surgical exploration identified eight intra-colorectal recurrences, nine extra-colonic pelvic recurrences and five extra-pelvic lymph node metastases. RIGS exploration confirmed all intra-colonic recurrences except for one (patient with no MoAb localization), identified 13 pelvic recurrences and 10 lymph node metastases. There were seven patients with occult findings (33%), resulting in a modified surgical procedure. Surgery included five abdomino-perineal resections, six low anterior resections, seven excisions of presacral tumour, eight total abdominal hysterectomy and bilateral salpingo-oophorectomy, one pelvic exenteration and one post-exenteration. There were no operative deaths. Eight patients had minor complications, and one patient had a major complication with reoperation due to urinary leak. The mean follow-up was 18 months. Ten patients died of disease. CONCLUSION: Although not curative, RIGS can help the surgeon in the decision-making process through better disease staging.

Immunoguided lymph node dissection in colorectal cancer: a new challenge?

Knowledge of lymphatic involvement in patients with colorectal cancer is important in surgery and in the postoperative decision-making process. Fifty-eight patients with recurrent colorectal cancer underwent operation with the RIGS/(Radioimmunoguided Surgery) technology. Preoperatively, patients were injected with 1 mg monoclonal antibody (MoAb) CC49 (anti-TAG-72-tumor-associated glycoprotein) labeled with 2 mCi of iodine 125. Traditional surgical exploration was followed by survey with a gamma-detecting probe. Localization of MoAb on tumor was noted in 54/58 patients (93%). Traditional exploration identified 117 suspected tumor sites. With RIGS, 177 suspected tumor sites were detected. In 17 of the 58 patients (27.5%), at least one occult tumor site identified by RIGS was confirmed by pathology with hematoxylin & eosin (H & E) staining. This finding resulted in 16 major changes in surgical plan. RIGS performance varied between lymphatic and non-lymphatic tissue, with a positive predictive value (PPV) of 95.6% and negative predictive value (NPV) of 90% in non-lymphoid tissue compared to PPV of 40% and NPV of 100% in lymphoid tissue. In patients with tumors that localize, no RIGS activity in lymph nodes signifies no tumor, while decisions based on RIGS activity in lymph nodes requires H & E confirmation. Using this guideline, additional information acquired by RIGS can help the surgeon in making an informed decision during surgery and in planning postoperative therapy.

Effects of intravenous gamma immunoglobulins treatment on severe peritonitis in rats.

BACKGROUND: Generalized purulent peritonitis is characterized by an early exposure of the immune system to a large number of bacterial antigens. The hypothesis that intravenous IgG treatment may improve the outcome of severe experimental peritonitis was studied. METHODS: Peritonitis was induced in rats by cecal ligation and perforation. Continuous intravenous fluid infusion, broad-spectrum antibiotics, and twenty-four hours treated forty rats after the induction of the disease they were re-operated and the perforated cecum was excised. Twenty of these animals received in addition specific rat IgG in two intravenous infusions (0.4 gr./kg), two and twenty four hours after the induction of peritonitis. RESULTS: Elevated WBC counts and mild metabolic acidosis was found one day after the induction of peritonitis. IgG treatment was associated with lower WBC counts in the following days and with higher pH than in the control group (p < 0.05 for both parameters). All peritoneal cultures and 90% of blood cultures were positive 24 hours after the initial operation. These rates decreased in the following days and in the IgG treatment rats the peritoneal cavity and blood were sterile earlier than in the control animals (p < 0.05). Serum IgG was depleted in the control animals within 48 hours after the induction of peritonitis, while in the IgG treated animals its levels were remarkably elevated. IgG administration significantly improved the survival, which was 70% in the IgG treatment rats as compared to 40% in the control rats. CONCLUSION: These results indicate that intravenous IgG has beneficial effects on severe experimental peritonitis.

Radioimmunoguided surgery for recurrent colorectal cancer manifested by isolated CEA elevation.

BACKGROUND: Carcinoembryonic antigen (CEA) is a sensitive marker for detecting recurrent colorectal carcinoma. An asymptomatic rise of CEA can precede by several months the detection of recurrent cancer by standard imaging modalities. Yet, surgeons are hesitant to operate solely on the basis of an observed increase in CEA. We investigated the ability of radioimmunoguided surgery to enhance the surgeon's capability of detecting intraabdominal disease in these patients. METHODS: Nineteen patients who underwent radioimmunoguided surgery for suspected tumor recurrence based solely on elevated CEA were included in the study. They underwent colonoscopy and CT of the abdomen and chest, all of which were negative. They then underwent scintigraphy scan with an anti-CEA monoclonal antibody (MoAb) labeled with (99m)Tc or Indium I-111. All patients were injected with the CC49 MoAb (an anti-TAG-72 tumor-associated glycoprotein) labeled with (125)I three weeks before surgery. During surgery, traditional exploration was followed by survey with a gamma-detecting probe. RESULTS: Traditional surgical exploration identified 26 recurrent tumors: 7 hepatic, 8 pelvic, 6 retroperitoneal, 3 colonic, 1 splenic, and 1 anastomotic. Radioimmunoguided surgical exploration confirmed all recurrent tumors and identified additional tumor sites in seven patients that resulted in changing the surgical plan. CEA scans correlated with intraabdominal findings in seven patients. Abdominal pathology did not correlate completely with the scans in three patients, and CEA scan results were undetermined in two patients. CONCLUSION: Patients with elevated CEA and no other findings should be operated upon without delay, and radioimmunoguided surgery should be used to enhance the surgeon's knowledge of the extent of disease.

Identification of lymph node metastases in recurrent colorectal cancer.

Lymph node metastases are an important prognostic prediction factor in patients with recurrent colorectal cancer, particularly those with liver metastasis. Fifty-six patients with recurrent colorectal cancer were operated by us using the RIGS (radioimmunoguided surgery) technology. Patients were injected with 1 mg monoclonal antibody (MoAb) CC49 labeled with 2 mCi 125I. In surgery, traditional exploration was followed by survey with a gamma-detecting probe. Sixty of 151 patients enrolled in the Neo2-14 Phase III study for recurrent colorectal cancer were diagnosed with liver metastases based on preoperative CT. In 17/56 patients (30%), RIGS identified at least one tumor site confirmed by pathology (H&E). This resulted in 16 major changes in surgical plan. RIGS performance varied between lymphatic and non-lymphatic tissue, with positive predictive value (PPV) of 100% and negative predictive value (NPV) of 94% for non-lymphoid tissue, compared to PPV of 46.5% and NPV of 100% for the lymphoid tissue. Thirty-five out of 60 patients were considered resectable after traditional evaluation. RIGS identified occult tumor in 10 of these patients (28.5%). 7/10 occult patients expired (70%), while only 7/25 of the non-occult patients expired (28%) (P = 0.046). In localizing patients, no RIGS activity in lymph nodes signifies no tumor, while H&E confirmation is needed for decisions based on RIGS activity in the lymph nodes. RIGS provides important staging information, identifying patients for whom surgery may be done with curative intent.

Photodynamic therapy of murine colon cancer and melanoma using systemic aminolevulinic acid as a photosensitizer.

BACKGROUND: Side effects of conventional photosensitizers, such as hematoporphyrins, are a limiting factor in the use of photodynamic therapy (PDT). We evaluated the effect of PDT on mice colon carcinoma and melanoma using systemic 5-aminolevulinic acid (ALA). IN VITRO STUDIES: CT26 colon carcinoma and B16 melanoma cells were incubated with ALA for 48 h. Subsequently, cells were subjected to photoradiation at 40, 60 and 100 J/cm2 and viability was assessed. In vivo studies: Balb/C mice were injected subcutaneously with 2x10(5) CT26 colon cancer cells and C57/Bl mice were injected subcutaneously with 2x10(5) melanoma cells. ALA 60 mg/kg was injected intra-peritoneally when tumors were visible. After 24 h mice were subjected to photoradiation (100 J/cm2). IN VITRO STUDIES: There was a significant decrease in the viability of treated cells as compared with non-treated tumor cells and with treated splenocytes (p<0.001). In vivo studies: PDT induced necrosis of both tumors. PDT also significantly prolonged the survival of the treated mice (p<0.05). CONCLUSIONS: Photodynamic therapy using systemic ALA as a photosensitizer was effective in treating mice colon cancer and melanoma in both in-vitro and in-vivo studies. Further pre-clinical and clinical studies are being conducted now.

Effect of photodynamic therapy on normal fibroblasts and colon anastomotic healing in mice.

Photodynamic therapy as an adjuvant modality to surgical resection of colon cancer is feasible provided that it does not affect healing of the anastomosis. The aim of this study was to evaluate the effects of photodynamic therapy on the viability of normal fibroblasts and on the healing process of colonic anastomosis in mice. Both in vitro and in vivo methods were employed. For in vitro study, 2 x 10(to the fifth power); human fibroblasts were incubated in triplicate with 5-aminolevulinic acid (2.5 microg/well) for 48 hours. Cells then underwent photoradiation at light doses of 50, 100, and 200 joules/cm(2) using a nonlaser light source. Viability was assessed by methylene blue dye exclusion. For in vivo studies, 60 mice were randomized into study and control groups and underwent laparotomy involving colonic anastomosis. The anastomosis underwent photodynamic therapy using 5-aminolevulinic acid (60 mg/kg) as a photosensitizer and a nonlaser light (40 joules/cm(2)). On postoperative days 1, 4, 7, 14, and 21, six mice were killed and subjected to bursting pressure and histologic examinations. Results of in vitro study showed pretreatment cell viability to be 96% to 99% in both groups. Photodynamic therapy caused no significant change in fibroblast viability at all light doses. Results of in vivo studies showed that the mean bursting pressure of both groups dropped to a low peak on day 4. Subsequently there was a gradual increase in bursting pressure along the examined time points (P <0. 001). There was no difference in bursting pressure between the two groups for all time points examined. It was concluded that photodynamic therapy has no effect on viability of normal human fibroblasts and no adverse effects on healing of colonic anastomosis.

Photodynamic therapy of cancer of the esophagus using systemic aminolevulinic acid and a non laser light source: a phase I/II study.

BACKGROUND: Surgery is the mainstay for the treatment of carcinoma of the esophagus and is also considered to be effective for palliation of dysphagia. Patients who are unfit for surgery represent a difficult therapeutic problem. The goal of the present study was to evaluate the effects of photodynamic therapy by using systemic administration of 5-aminolevulinic acid and a non laser light source on carcinoma of the esophagus. METHODS: Patients were given 60 mg/kg 5-aminolevulinic acid orally. Twenty-four hours later gastroscopy was performed. After initial localization of the tumor with the use of white light, the light source was switched to the red light band at 100 J/cm2 for 600 seconds. Gastroscopy was repeated at 48 hours and 7 days after the treatment. The degree of dysphagia was recorded before and 14 days after treatment. RESULTS: Five patients with advanced nonresectable tumors or who were unfit for surgery were treated. Two patients had squamous cell carcinoma of the mid-esophagus and three had adenocarcinoma of the distal esophagus. Mild self-limiting photosensitivity was noted in all patients. Liver and renal function tests as well as hemoglobin level and white blood cell count were not affected by the treatment. Improvement of dysphagia was observed in four patients who had pretreatment dysphagia. The patient with the early stage of disease continued to eat a normal diet. CONCLUSIONS: Photodynamic therapy with systemic aminolevulinic acid as a photosensitizer and a non laser light source is feasible and safe in advanced-stage esophageal cancer. It can be an effective modality for the relief of dysphagia in these patients.

Clinical applications of gamma-detection probes - radioguided surgery.

Radioguided surgery (RGS) is a surgical technique that enables the surgeon to identify tissue "marked" by a radionuclide before surgery, based on the tissue characteristics, the radioactive tracer and its carrying molecule, or the affinity of both. Thus, yet another tool has been added to the inspection and palpation traditionally used by the surgeon. Current clinical applications of radioguided surgery are: radioimmunoguided surgery (RIGS) for colon cancer, sentinel-node mapping for malignant melanoma (which has become state-of-the-art), sentinel-node mapping for breast, vulvar and penile cancer, and detection of parathyroid adenoma and bone tumour (such as osteid osteoma). Although the same gamma-detecting probe (GDP) may be used for all these applications, the carrier substance and the radionuclide differ. MoAb and peptides are used for RIGS, sulphur colloid for sentinel-node mapping, iodine-125 for RIGS, technetium-99m for sentinel node, parathyroid and bone. The mode of injection also differs, but there are some common principles of gamma-guided surgery. RIGS enables the surgeon to corroborate tumour existence, find occult metastases, and assess the margins of resection; this may result in a change on the surgical plan. Sentinel lymph-node (SLN) scintigraphy for melanoma guides the surgeon to find the involved lymph nodes for lymph-node dissection. SLN for breast cancer is being investigated with promising results. This procedure has also changed the outlook of lymph-node pathology by giving the pathologist designated tissue samples for more comprehensive examination. Gamma-guided surgery will result in more accurate and less unnecessary surgery, better pathology and, hopefully, in better patient survival.

Continuous intravenous octreotide treatment for acute experimental pancreatitis.

BACKGROUND: The efficacy of octreotide, the synthetic analogue of the hormone somatostatin, for the treatment of acute pancreatitis is controversial. Octreotide has been commonly administered in subcutaneous bolus injections; however, continuous intravenous infusion may be advantageous for acute conditions. METHODS: Acute experimental pancreatitis was induced in rats by intraparenchymal injections of 1 ml 10% sodium taurocholate, and octreotide (1 microg/kg/h, dissolved in physiological solution, intravenously was started 4 h later and continuously infused for 48 h. Physiological solution infusions, in identical volumes, were used in the controls. The following parameters were examined: mortality; macroscopic and histological damage; hematocrit; plasma pH; acid-base balance; serum glucose; calcium, and amylase. RESULTS: Octreotide treatment had a striking effect on mortality: 8.3 versus 91.6% in the treatment and control groups, respectively (p < 0.001). Octreotide also ameliorated pancreatic edema and intestinal dilatation, and had significant beneficial effects on histopathological damage and the biochemical alterations which are associated with acute pancreatitis. CONCLUSIONS: Continuous intravenous octreotide infusion is a potentially efficacious therapeutic method for acute pancreatitis.

Exposure of human peripheral blood mononuclear cells (PBMC) to hydrostatic pressure increases their proliferative response to phytohemagglutinin A (PHA) and anti-CD3 antibody.

In the present study we show that a brief exposure of human PBMC to hydrostatic pressure (HyP) increased their proliferative response to PHA and anti-CD3 antibody, assessed by DNA synthesis. The effect of HyP was most prominent at 400 atmospheres of HyP followed by 600 and 200 atmospheres. At any pressure level, the highest effect of HyP was noted when employing PHA and anti-CD3 antibody at 10(-2) dilution. When PBMC were exposed to 400 atmospheres HyP, maximal effect was achieved at 20 minutes of exposure. The highest effect of HyP on DNA synthesis was noted at 48 and 72 hours of incubation with PHA, when exposing cells to pressure for 20 minutes at 400 atmospheres. Exposure of PBMC under similar conditions for 40 minutes, caused an increase in DNA synthesis only at 48 hours incubation with PHA. These results demonstrate that exposure of human PBMC to HyP increases their proliferative response to different polyclonal activators. The possible mechanisms involved in this phenomenon are discussed.

[Photodynamic therapy for dysphagia due to esophageal carcinoma].

Surgery is the mainstay in the treatment of esophageal carcinoma and is effective for palliation of dysphagia. Patients unfit for surgery are difficult therapeutic problems. We evaluated photodynamic therapy for palliation of dysphagia in this condition. Patients were given 5-aminolevulinic acid, 60 mg/kg, orally and 24 hour later gastroscopy was performed during which red light illumination (100 j/cm2 for 600 seconds) was administered. This was repeated 48 hours later. The degree of dysphagia was recorded before and 14 days after treatment. 8 patients with an advanced non-resectable tumor, or who were unfit for surgery, were thus treated. 4 had squamous cell carcinoma of the mid-esophagus and 4 had adenocarcinoma of the lower esophagus. There was mild, self-limited photosensitivity in all. Liver and renal function tests and blood count were not affected by the treatment. Dysphagia was improved in all except 1 patient. A patient with early stage disease continued to eat a normal diet. We believe that photodynamic therapy with systemic aminolevulinic acid as a photosensitizer and a non-laser light source is feasible and safe in advanced esophageal cancer. It is an effective modality for relief of dysphagia in that condition.

Gamma probe-guided sentinel node biopsy--optimal timing for injection.

AIMS: We initiated a Phase I feasibility study using a gamma-detecting probe (GDP) and radiolabelled colloid to localize the sentinel lymph node (SLN) in breast cancer. The aim of the study was to establish the ideal timing for injection and examine any possible exclusion criteria for this method. METHODS: Thirty breast cancer patients diagnosed by fine needle aspiration (FNA) were included in this study. All were injected with 60 MBq rhenium colloid labelled with 99mTc (Tck-17). Scintigraphy was done 20 min, 2, 6 and 25 hours post-injection. Patients were then taken to surgery where they were injected with patent blue dye. During surgery, the SLN was located with a GDP (Neoprobe Model 1000). In 28 patients, the SLN was identified by scintigraphy 2 hours after injection, identical to the images seen after 24 hours. RESULTS: In all 28 patients, the SLN was found by the GDP during surgery. In 26 patients the SLN was dyed blue. The two patients with no SLN localization had received prior radiation. Pathology disclosed SLNs with metastases in seven patients. Two patients had a negative SLN but had an axillary lymph node replaced by tumour. CONCLUSIONS: Two to 24 hours prior to surgery is suitable timing for injection. Previous radiotherapy predicts failure for this procedure. Further studies are needed to find the exact false-negative rate of this method for breast cancer.

Management of breast fibroadenomas.

OBJECTIVE: To identify from the literature and clinical experience a rational approach to management of fibroadenomas of the breast. METHOD: Recent literature on detection, diagnosis, and natural history of fibroadenomas was reviewed. Experience with over 4,000 women evaluated in the breast clinic at the Tel-Aviv Medical Center contributed to the management strategies suggested by review of the literature. RESULTS: Fibroadenomas of the breast are common, accounting for 50% of all breast biopsies performed. Physical examination, sonography, and fine needle aspiration are effective in distinguishing fibroadenomas from breast cancer. Transformation from fibroadenoma to cancer is rare; regression or resolution is frequent, supporting conservative approaches to follow-up and management. CONCLUSION: Age-based algorithms that allow for conservative management and that limit excision to patients whose fibroadenomas fail to regress are presented.

Human tumor cells, modified by a novel pressure/crosslinking methodology, promote autologous lymphocyte proliferation and modulate cytokine secretion.

Hydrostatic pressure (P) combined with membrane protein crosslinking (CL) by adenosine dialdehyde (AdA) can render tumor cells immunogenic. We have recently shown that PCL treatment of murine tumor cells augmented the presentation of MHC-restricted tumor-associated antigens and enhanced cell-mediated immunity. In cancer patients inoculated with autologous PCL-modified tumor cells, a significant delayed-type hypersensitivity response was elicited. Since the balance between cell-mediated immunity and humoral immunity is reciprocally controlled by immunoregulatory cytokines, we have examined the proliferative response and cytokine secretion pattern in cultures of human peripheral blood mononuclear cells (PBMC) stimulated by autologous PCL-modified and unmodified tumor cells. These tumor cells were obtained from freshly resected tumor tissue of 16 patients with colon (8), lung (4) and renal (4) carcinomas. The results demonstrated that PCL-modified tumor cells promoted an increase in PBMC proliferation in 5 out of 8 (63%), 1 out of 4 (25%) and 4 out of 4 (100%) colon, lung and renal cell carcinomas. Fourteen of the above cultures were also analyzed for the secretion of interleukin-10 and interferon-gamma. Overall, a substantial decrease in IL-10 secretion was detected in 9 out of 14 (64%) cultures while a reciprocal increase in interferon-gamma secretion was noted in 8 out of 14 (57%) cultures. Our results confirmed that PCL-modified human tumor cells of different etiologies can modulate the pattern of cytokines released from stimulated autologous lymphocytes. Such a procedure could prove valuable in the production of autologous tumor vaccines.

Single-injection gamma probe-guided sentinel lymph node detection in 40 melanomatous lymphadenectomies.

The aim of the study was to evaluate single-injection gamma probe-guided sentinel lymph node (SLN) detection, applied in 40 melanomatous selective sentinel lymphadenectomies (SSLNDs). Thirty-four patients underwent preoperative lymphoscintigraphy, intraoperative SLN identification by a gamma-detecting probe and blue dye, and SLN sampling. The first 11 patients underwent formal lymphadenectomy. The following 23 patients underwent formal lymphadenectomy only when the SLN was involved with tumor. Evaluation included hematoxylin-eosin-stained slide microscopy, monoclonal antibodies to S-100 protein, and the melanoma-associated antigen HMB45. In all patients, single or multiple SLNs were identified by the gamma-detecting probe. However, only 82.5% of these specimens included blue-stained nodes. None of the non-SLN specimens were the exclusive site of metastases. Four patients had metastases in their SLN specimen without non-SLN involvement. We conclude that SSLND can be performed easily and precisely with the exclusive use of the gamma-detecting probe. A single injection is feasible, and decreases operating room contamination and patient discomfort.