A pilot study evaluating the efficacy of a fully acetylated poly-N-acetyl glucosamine membrane formulation as a topical hemostatic agent.

BACKGROUND: Topical hemostatic agents are frequently needed for control of intraoperative bleeding. Currently available topical products each have potential drawbacks, making a more effective topical hemostatic agent desirable. This study was performed to evaluate the effectiveness of a particular formulation of a newly available polysaccharide polymer, poly-N-acetyl glucosamine (p-GlcNAc), as a topical hemostatic agent for use in the operating room. Swine splenic incision and splenic capsular stripping hemorrhage models were initially used, with a subsequent pilot human study then performed. METHODS: For the swine splenic incision model, anesthetized immature female Yorkshire white swine had a 3 x 8 mm incision created on the spleen. One of 3 agents (p-GlcNAc membrane, oxidized cellulose, or absorbable collagen) was sequentially applied to individual wounds and digitally compressed for 20 seconds. The wound was observed without pressure for 2 minutes. Up to 8 wounds per animal were created in 7 animals. For the swine splenic capsular stripping model a 2 x 2 cm area of capsular stripping on the surface of the spleen to a depth of 3 mm was created. Either p-GlcNAc membrane or oxidized cellulose was applied and digitally compressed for 60 seconds, followed by observation without pressure for 2 minutes. Six wounds per animal were created in 2 animals. If bleeding persisted in either model, a new cycle of compression was applied. These steps were repeated until hemostasis was achieved. No change in hemodynamics or coagulation factors was observed in either model. Subsequently, 10 consecutive patients undergoing elective small-bowel surgery were enrolled on pilot study. A 5 x 3 x 3 mm cruciate incision was created midway between the mesenteric and antimesenteric borders of the small bowel. Either p-GlcNAc membrane formulation or oxidized cellulose was applied (the sequence alternated per patient) with a 400-mg weight used for even, direct pressure. A second cruciate incision was then created on the contralateral side of the bowel to evaluate the second material. The number of applications required for hemostasis was assessed. Hemodynamics, small-bowel pathologic condition, and hematologic parameters were evaluated. RESULTS: The p-GlcNAc membrane required fewer cycles of compression in the swine splenic incision model to achieve hemostasis than either absorbable collagen or oxidized cellulose (1.25 vs 2.58 and 3.41, respectively; P < .01) and caused more effective immediate cessation of bleeding (79% for p-GlcNAc vs 17% for both absorbable collagen and oxidized cellulose). With the more traumatic splenic capsular stripping model, p-GlcNAc required fewer cycles of compression to achieve hemostasis than oxidized cellulose (average, 2.5 versus 6.8 respectively; P < .01) and was able to achieve hemostasis with greater efficacy (50%) in 2 applications than did oxidized cellulose (0%; P < .01). When used in the human pilot study, p-GlcNAc membranes required fewer cycles of compression than oxidized cellulose (2.5 vs 5.4, respectively; P < .002), was able to stop bleeding with greater efficacy in 1 cycle of compression (50% vs 0%, respectively; P < .01), and ultimately accomplished hemostasis in 80% of the cases as opposed to 20%. CONCLUSIONS: On the basis of its greater hemostatic efficacy as compared with collagen or oxidized cellulose-based products, p-GlcNAc holds promise as an effective topical hemostatic agent and deserves further evaluation.

Detection of occult breast cancer micrometastases in axillary lymph nodes using a multimarker reverse transcriptase-polymerase chain reaction panel.

BACKGROUND: Axillary lymph node status in breast cancer patients remains the single most important predictor of outcomes. Current methods of histopathologic analysis may be inadequate because 30% of node-negative patients recur. The purpose of this study was to test the hypothesis that a multigene reverse transcriptase-polymerase chain reaction (RT-PCR) panel provides a more sensitive method to detect axillary lymph node metastases than routine pathologic examination. STUDY DESIGN: Sixty-one consecutive breast cancer patients were evaluated, with nine normal control patients. Nodes > 1 cm were bisected for histopathologic and RT-PCR analysis. Nodal tissue was homogenized, and total RNA was converted into cDNA with reverse transcriptase. Reverse transcriptase-polymerase chain reaction analysis was performed with primers specific for keratin-19, c-myc, prolactin inducible protein (PIP), and beta-actin using ethidium bromide gel electrophoresis. Reverse transcriptase-polymerase chain reaction positive/ pathology negative axillary lymph nodes were reevaluated using step sectioning and immunohistochemical staining. RESULTS: Thirty-seven patients had pathologically negative axillary lymph nodes, of which 15 (40%) were positive by RT-PCR analysis. Two RT-PCR negative results (one probably from tissue processing error and the other secondary to sampling error) among the 24 histologically positive specimens were detected (8%). The number of patients in each pathologic stage was 26 patients in stage I; 18, stage IIA; 7, stage IIB; 7, stage IIIA; 3, stage IIIB; and 0 patients in stage IV. By RT-PCR staging, 8 of 26 patients went from stage I to IIA (30%), and 7 of 18 from stage IIA to IIB (39%). Of the RT-PCR positive individuals who were stage I by pathologic analysis, 100% were found to be c-myc positive, 0% keratin-19 positive, and 0% PIP positive; for stage IIIB patients these markers were 50%, 100%, and 100% respectively. Additionally, an increasing number of positive markers per specimen appeared to correlate with larger primary tumor size (p < 0.01) and decreased predicted 5-year survival (r = 0.950, p < 0.002). CONCLUSIONS: Multimarker RT-PCR analysis appears to be a readily available and highly sensitive method for the detection of axillary lymph node micrometastases. Longterm followup of RT-PCR positive patients will be required to determine its clinical relevance. If validated as a predictor of disease recurrence, this method would provide a powerful complement to routine histopathologic analysis of axillary lymph nodes.

Melanoma thickness and histology predict sentinel lymph node status.

BACKGROUND: It remains unclear which patients with melanoma will benefit most from lymphatic mapping and sentinel lymphadenectomy. The purpose of this study is to determine whether primary melanoma histopathologic features could be applied to predict sentinel node status. METHODS: One hundred twelve patients underwent sentinel node biopsy between May 1995 and August 1999. Reported histologic features were assessed for predictive value by univariate and multivariate logistic regression. RESULTS: The sentinel node was located successfully in 105 of the 112 patients (94%). Twenty-one of these 105 patients (20%) had sentinel nodes that were positive for metastatic disease. Multivariate analyses revealed that tumor thickness greater than 1.5 mm (P = 0.01), ulceration (P <0.01), and lymphovascular invasion (P = 0.05) predicted the presence of micrometastases. CONCLUSIONS: The presence of unfavorable histopathology such as ulceration and lymphovascular invasion may identify a group of patients with thin melanomas who would benefit from sentinel lymphadenectomy.

CEA--a concept worth exploring.

We believe patients who have elevated CEA levels before resectioning procedures and who also have documented cancer of the gastrointestinal tract, with a subsequent drop in normal CEA levels postoperatively, should have sequential monthly determinations of colonic embryonal antigens. If there is an increase in levels of concentration, there is at that time justification for surgical intervention. The earlier the detection of elevated colonic embryonic antigen is accomplished, the better are the odds for a successful surgical resection of recurrent disease. The values of the CEA studies define slopes which can identify local recurrence and liver metastasis. For these slope values, it is necessary that the CEA level be drawn regularly. We consider this a promising real clinical advance in that it permits for better utilization of the two significant therapeutic modalities we have for the treatment of cancer of the gastrointestinal tract, namely resectional surgery and radiation therapy. CEA determinations have false positives and limited specificity. It is unfortunate that adult tissues express fetal antigens under conditions wherein there are bursts of cellular activity. This should not diminish the significance of tumor-embryo cross reactivity. This reactivity phenomenon is, in the words of Sir Peter Medawar, "a now well attested empirical fact," and this observation is "profoundly interesting and potentially important." The eventual significance of this fact may well transcend current use of the CEA in the diagnosis of recurrent cancer of the gastrointestinal tract.

Another cause of nipple discharge. Mammary duct ectasia with periductal mastitis.

Mammary duct ectasia with periductal mastitis is a distinct, benign form of breast pathology that is different from fibrocystic disease of the breast. There are no known increased risk factors for developing breast cancer from this entity. The treatment is local surgical excision which relieves symptoms and does not significantly alter the appearance of the breast.

Radiation enteritis.

As the population receiving radiation therapy grows, so does the incidence of chronic radiation enteritis. A review of the pathology of chronic radiation enteritis reveals fibrosis, endarteritis, edema, fragility, perforation, and partial obstruction. Conservative management of patients with this disease is common. Because the obstruction is only partial, decompression is easily achieved with nasogastric suction and parenteral support. The patient is then often discharged on a liquid-to-soft diet. This therapeutic strategy does nothing for the underlying pathology. The problem, sooner or later, will return with the patient further depleted by the chronic radiation enteritis. We think surgical intervention is appropriate when the diagnosis of chronic radiation enteritis is assumed. The surgery in relation to this disease is high risk with a 30% mortality and 100% expensive morbidity. Early intervention seems to decrease these figures. All anastomoses, if possible, should be outside the irradiated area. Trapped pelvic loops of intestine should be left in place and a bypass procedure with decompressing enterostomies accomplished. The surgery should be performed by a surgeon with extensive experience with all kinds of bowel obstruction as well as experience in performing surgery in radiated tissue.

Stereotactic core biopsy of the breast: results of one-year follow-up of 101 patients.

Stereotactic core biopsy (SCB) is being used as a cost-effective alternative to needle localized biopsy (NLB). However, an area of concern is the potential for sampling error, with sparse surgical data available concerning follow-up and failure rates. We therefore reviewed our results in patients undergoing SCB for mammographically detected breast abnormalities. Between January 1994 and February 1995, 128 patients underwent SCB. Average age was 56.4 years. Nine patients (7.0%) had histologic evidence of malignancy, with 111 (86.7%) benign diagnoses requiring no further initial intervention. Eight patients (6.3%) proceeded directly to NLB, five because of technical failure of SCB and three because of suspicious initial histology. One of the latter patients had ductal carcinoma in situ. The remaining 111 SCB patients were evaluated at 6 months and 1 year by mammographic and physical examination. Ten patients were lost to follow-up. Of the remaining 101 patients, 98 (97%) had stable mammograms and normal physical examinations. Three patients (3.9%) required subsequent NLB due to progression of the mammographic lesion. Two cases were histologically benign, and 1 patient had ductal carcinoma in situ adjacent to the previous SCB biopsy site. An additional patient underwent NLB for a new radiographic abnormality at a separate location in the ipsilateral breast, which was invasive ductal carcinoma. SCB appears to be an effective alternative to NLB for the majority of patients deemed eligible. Careful mammographic follow-up is warranted for these patients given the small, but real, possibility of sampling error.

Efficacy of reverse transcriptase-polymerase chain reaction screening for micrometastic disease in axillary lymph nodes of breast cancer patients.

Pathologic examination of axillary lymph nodes (ALNs) may miss micrometastases in 30 per cent of breast cancer patients. We have developed a multimarker reverse transcriptase-polymerase chain reaction (RT-PCR)-based screening method that detects histopathologically positive ALNs with a 5 per cent false-negative rate. The purpose of this study was to compare this RT-PCR methodology with histopathology with regard to sensitivity and cost. Pathologically negative ALNs from 35 breast cancer patients were re-evaluated by a single pathologist in a blinded fashion using serial sectioning with immunohistochemical staining. Histopathologic results were then compared with those of RT-PCR. Cost analysis was performed based on standard charges for these methods. RT-PCR identified micrometastases in 14 of 35 pathologically negative nodes. Serial sectioning and immunohistochemical staining identified micrometastases in two cases, with RT-PCR positive for one of these. The charge per specimen for performing routine histopathologic examination was $380, serial sectioning and immunohistochemical staining $787, and RT-PCR $125. RT-PCR appears to be more sensitive at detecting ALN micrometastasis than histopathologic examination even with serial sectioning and immunohistochemical staining. If micrometastatic breast cancer detected by RT-PCR proves to be clinically relevant, it could be a more effective screening methodology with significant cost savings as compared to currently available pathologic examinations.

Radiofrequency thermotherapy, local chemotherapy, and arterial occlusion in the treatment of nonresectable cancer.

Localized radiofrequency thermotherapy (RFTT) has been effective by itself in debulking cancers but has not accomplished total eradication by itself. Occlusion of the regional artery supplying the tumor drastically reduces the arterial pressure distal to occlusion and further impairs tumor blood flow leading to an accentuation of the temperature differentiation achieved by the normal tissue and tumor. Radiofrequency thermotherapy with vascular occlusion is combined with direct injection of an effective chemotherapeutic agent into the tumor. Radiofrequency thermotherapy is performed after injection of chemotherapy using bleomycin and mitomycin C for squamous cell cancers and Adriamycin and mitomycin C for adenocarcinoma. There are no adverse systemic responses to the small dose of chemotherapy used and the combination therapy is effective in destroying the tumor.

Recent advances and controversies in the management of Hodgkin's disease.

Sifting the preceding factors, which may weigh for or against routine laparotomy and splenectomy as a staging procedure in Hodgkin's disease, we advocate that one be sure the diagnosis and histologic classification are confirmed by an experienced hematologic pathologist, that complete clinical studies for clinical staging with the exception of the lymphangiogram be performed, and that a laparotomy and splenectomy be performed in appropriate centers for clinical Stages I through III and unconfirmed Stage IV patients unless some contraindication is present. The subdiaphragmatic nodal areas should not be irradiated without evidence of the presence of disease in these areas. A minimum of 4,000 rads of supervoltage therapy should be delivered to the areas known to be involved with Hodgkin's disease plus the neighboring lymph node areas, using total nodal irradiation only on definite indication but not prophylactically.

Villous tumors of the rectum: excision by the posterior approach.

Villous tumors of the rectum require complete excision for accurate histologic diagnosis. The posterior rectotomy approach of Kraske is presented and described in detail as an excellent method for use in the surgical managment of these lesions. The technic is simple and postoperative morbidity minimal. The procedure is curative for benign lesions and does not interfere with further radical resection of malignant lesions.

Lobular carcinoma in situ.

Lobular carcinoma in situ remains controversial in nomenclature, histology, and therapy. The original description and therapeutic recommendations remain a significant contribution to better control of breast cancer. We believe the sophistication of mammography, not available at the time of the earliest therapeutic recommendations, provides the clinician with a valuable and accurate new diagnostic tool for this disease. The risk factors from this disease entity have been well outlined by McDivitt [1] and others. We believe the patient should permitted to participate in the therapeutic decision after proper education about the risk factors of cancer in the ipsilateral and contralateral breast. Patients have requested bilateral mastectomies; some of these patients then wanted plastic reconstruction. Many others, however, have no such interest. The properly informed and responsible patient who elects to have close observation, with mammograms every six months, we feel has elected an acceptable clinical strategy for this disease.