Repetitive antidotal treatment is crucial in eliminating eye pathology, respiratory toxicity and death following whole-body VX vapor exposure in freely moving rats.

Exposure to the chemical warfare nerve agent VX is extremely toxic, causing severe cholinergic symptoms. If not appropriately treated, death ultimately ensues. Based on our previously described whole-body vapor exposure system, we characterized in detail the clinical outcome, including respiratory dynamics, typical of whole-body exposure to lethal doses of VX vapor in freely moving rats. We further evaluated the efficacy of two different antidotal regimens, one comprising a single and the other repeated administration of antidotes, in countering the toxic effects of the exposure. We show that a 15 min exposure to air VX concentrations of 2.34-2.42 mg/m3 induced a late (15-30 min) onset of obvious cholinergic signs, which exacerbated over time, albeit without convulsions. Marked eye pathology was observed, characterized by pupil constriction to pinpoint, excessive lacrimation with red tears (chromodacryorrhea) and corneal damage. Respiratory distress was also evident, characterized by a three-fourfold increase in Penh values, an estimate of lung resistance, and by lung and diaphragm histological damage. A single administration of TAB (the oxime TMB-4, atropine and the anticholinergic and antiglutamatergic benactyzine) at the onset of clinical signs afforded only limited protection (66% survival), with clinical deterioration including weight loss, chromodacryorrhea, corneal damage, increased airway resistance and late death. In contrast, a combined therapy of TAB at the onset of clinical signs and repeated administration of atropine and toxogonin (ATOX) every 3-5 h, a maximum of five i.m. injections, led to 100% survival and a prompt recovery, accompanied by neither the above-described signs of eye pathology, nor by bronchoconstriction and respiratory distress. The necessity of recurrent treatments for successful elimination of VX vapor toxicity strongly supports continuous penetration of VX following termination of VX vapor exposure, most likely from a VX reservoir formed in the skin due to the exposure. This, combined with the above-described eye and respiratory pathology and absence of convulsions, are unique features of whole-body VX vapor exposure as compared to whole-body vapor exposure to other nerve agents, and should accordingly be considered when devising optimal countermeasures and medical protocols for treatment of VX vapor exposure.

WITHDRAWN: A comment on the application of statistical process control in the surgical arena.

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Carcinoma within solitary ductal papilloma of the breast.

BACKGROUND: Solitary ductal papilloma of the breast, traditionally considered a benign disorder, was recently found to have malignant potential, especially when associated with atypical ductal hyperplasia. METHODS: All patients diagnosed with solitary ductal papilloma at a tertiary medical center from 1994 to 2004 were identified by a database search. Background, clinical and pathological data were collected for those with a carcinoma within the papilloma, and their pathological specimens were revised. RESULTS: Of the 3849 breast biopsies performed in our medical center during the study period, 77 (2%) yielded a solitary ductal papilloma. In 12 cases (15.6% of all solitary ductal papillomas; 0.3% of all breast biopsies), a carcinoma was found within the papilloma. Ten were diagnosed as carcinoma in situ and 2 as microinvasive carcinoma. CONCLUSION: In the present series, the incidence of carcinoma within solitary ductal papilloma was 15.6%, indicating that solitary ductal papillomas have malignant potential. SUMMARY: Carcinoma within solitary ductal papilloma of the breast was found in 15.6% of all papillomas. This seems to indicate a malignant potential of papillomas and the need for surgical excision.

Radiation treatment for ductal carcinoma in situ (DCIS): is a boost to the tumor bed necessary?

The aim of the presented study was to evaluate the long-term outcome of breast-conserving surgery and radiation for the treatment of ductal carcinoma in situ (DCIS) and the role of the radiation boost to the tumor bed. The files of 75 women with DCIS treated by breast-conserving surgery followed by definitive radiation from 1988 to 1997 were reviewed for demographic data, prognostic variables, radiation dose, radiation boost, recurrence, and outcome. Total radiation dose was 5000 cGy delivered in 25 fractions. Twenty patients (26.7%) received an additional boost to the tumor bed of 1000 cGy in 5 fractions. Median follow-up time was 81.5 months (range, 22-145). Pearson correlation coefficient and its significance was calculated between the variables. Log rank test was used to analyze differences in local recurrence rates between patients who did or did not receive a boost, and a Cox regression model was fitted to the data to predict recurrence. Ten patients (13%) had local recurrence; one patient showed lymphatic spread. Histopathologic examination revealed DCIS in 6 cases (60%) and invasive duct carcinoma in 4 (40%)(one minimally invasive). The recurrence group included 3 of the 20 patients who received a radiation boost (15%) and 7 of the 55 who did not (12.7%) (p=0.7). Correlation analysis of patient characteristics, prognostic factors, and treatment was significant only between mastitis as the presenting symptom (n=4) and longer time to recurrence (p=0.02). The recurrence rate in the present study was similar to other series of conservative treatment for DCIS of the breast. No additional value was found for the radiation boost. Larger controlled randomized studies are needed to confirm these findings.

Sentinel-lymph-node biopsy (SLNB) for melanoma is not complication-free.

BACKGROUND AND AIM: Sentinel lymph node biopsy (SLNB) is reportedly associated with insignificant morbidity. The study aims at documenting SLNB-related complications and identifying possible risk factors. METHOD: Data of all melanoma patients who underwent SLNB in our medical center (1994-2002) were analysed. Procedure-related complications were recorded. RESULTS: Three hundred and nine lymphatic basins of 250 patients were explored for SLNB. Overall complication rate was 20%. Sensory morbidity was significantly associated with axillary SLNB (p=0.04) and was more prevalent in younger patients. The use of blue dye alone or combined with a hand-held gamma probe had no statistically significant impact on the identification rate. There were six false-negatives (2.3%), for an overall false-negative rate of 18%. A positive sentinel node was significantly associated with shortened overall survival (p=0.04). CONCLUSION: Wound complications are more frequent than usually reported. Sensory morbidity occurs mostly in the axilla. Neck SLNB is associated with the highest rate of identification failure. Patient age, basin location, and number of excised nodes may serve as prognostic factors of morbidity.

Failure of sentinel node identification following neo-adjuvant chemo-radiotherapy for locally advanced squamous cell carcinoma of the vulva.

A case of a 70-year-old patient with advanced local vulvar cancer is presented. Treatment with neo-adjuvant chemo-radiotherapy for two courses was administered and two weeks after completion of treatment the patient underwent wide local excision with bilateral inguino-femoral lymph node dissection through three separate incisions. Two methods for the evaluation of sentinel nodes--lymphoscintigraphy and intraoperative gamma hand-held probe and blue dye injection, did not detect any sentinel node on either side. Groin-node dissection revealed 23 negative nodes. It is our hypothesis that the non-visualization of sentinel nodes in this patient was due to post-irradiation damage to the lymph channels.

Locomotion of lymphocytes towards melanoma cells treated with tumor necrosis factor in a syngeneic in vitro model.

Tumor necrosis factor (TNF) causes cell necrosis in vivo by damaging the endothelium of the neovasculature. However, its mechanism of action is not well understood. We hypothesized that TNF affects the tumor microenvironment even before neovascularization occurs, thereby increasing lymphocyte locomotion through the peritumoral matrix, a crucial step in tumor cell killing. The effect of TNF on lymphocytes was tested with the type I rat-tail collagen mini-assay in peripheral blood lymphocytes (PBL) from normal donors, a non-migratory PBL cell line (HPB), and a C3H mice splenic lymphocytes. Melanoma cell line (k1735p) was treated with TNFalpha/TNFbeta 10 or 20 pg/microl. The syngeneic splenic lymphocytes were layered on top of the collagen, and their migration into the collagen towards the tumor cells was assessed. Tumor cell viability was evaluated before and after TNF treatment. Paired two-tailed Student's t-test was used for statistical analysis. TNFalpha and TNFbeta had no significant direct effect on locomotion of PBL or HPB. Lymphocyte locomotion was inhibited in the presence of untreated melanoma cells in 7 of 9 assays (statistically significant in four), and it was significantly increased towards TNFalpha- or beta-treated melanoma cells, compared to untreated condition, in 7 of 9 assays (p=0.05 to p=0.0001). The number of viable tumor cells was not significantly different before and after treatment. In conclusion, treatment of tumor cells with TNFalpha or TNFbeta significantly enhances lymphocyte locomotion through the matrix. The effect of TNF is not the result of a direct influence on the lymphocytes, and is not associated with a decrease in the number of viable tumor cells. These findings suggest that TNF interaction with the cell microenvironment induces a change in lymphocyte locomotion.

Surgery for abdominal metastases of cutaneous melanoma.

The objective of this study was to support our hypothesis that surgical resection of abdominal metastases of melanoma, regardless of symptomatology, could provide prolonged palliation and improved survival. We performed a retrospective chart review at M.D. Anderson Cancer Center. A series of 251 melanoma patients (stages I, II, or III at registration) who developed intraabdominal metastases during follow-up were studied. Altogether, 96 patients underwent 119 laparotomies; 51 underwent endoscopic or percutaneous procedures; and 116 patients were treated medically. Surgery was associated with a median survival of 11 months, significantly longer than that with other treatment (p < 0.001). Tumor was extirpated during 37% of the first laparotomies, and in an additional 33% very good palliation was achieved with incomplete resection. Tumor extirpation was associated with 10-month symptom-free survival (SFS), significantly longer than that with any other approach (p < 0.0001). In the nonsurgically treated patients, good palliation was achieved in 8% to 17% of patients with no complete response. The median SFS after surgery was 5 months, but 23% of patients were symptom-free more than 12 months; 87 patients with minimal symptoms; and 72 severely symptomatic patients underwent surgery. Complete resection was feasible in 42% and 34%, respectively. Surgery was associated with 12 months median survival in both groups. There was a significant survival benefit from surgery in patients with gastrointestinal (GI) tract metastases in contrast to those who had non-GI metastases. For the 96 surgically treated patients, a time interval of more than 4 years between diagnosis of the primary lesion and the abdominal recurrence predicted decreased risk of death (p = 0.038). The 30-day postoperative complication and mortality rates were 19.0% and 3.3%, respectively. Complete surgical resection of melanoma metastases in the abdomen is associated with median and symptom-free survival benefits. Symptomatic and asymptomatic patients benefit equally, especially if abdominal metastases appear more than 4 years after the initial diagnosis and do not involve non-GI viscera. Less than complete resection can provide durable palliation.

Topical Biafine and Lipiderm for the prevention of radiation dermatitis: a randomized prospective trial.

We evaluated the effects of Biafine and Lipiderm ointments in preventing radiation dermatitis. The study population included 74 patients after conservative surgery for early breast carcinoma who were referred for adjuvant external beam irradiation. Patients were randomized to receive Biafine or Lipiderm or no treatment. Both study preparations were applied twice daily, starting 10 days before onset of radiotherapy and continuing until 10 days after its completion. The skin treatment was upgraded, if clinically necessary, to steroids (grade 3), antibiotics (grade 4), or pause in therapy (grade 5). Success of treatment was evaluated according to the maximal level of skin treatment, the number of gaps in radiation therapy, the impression of the patients and the subjective skin reaction, and scores of the study nurse and radiotherapist. The three groups were comparable for all clinical features, except for a lower mean age of the Biafine group. Comparative analysis of the results showed no advantage for either preparation compared to the control arm other than maximal treatment level required for a skin reaction (mean 1.7 and 1.6 vs. 2.2), which did not reach statistical significance (p=0.145). Nevertheless, 86% of the patients in both the Biafine and Lipiderm arms expressed satisfaction with the respective ointments. In conclusion, neither Biafine nor Lipiderm seems to have a radioprotective effect.

Laryngeal carcinoma--epidemiological and clinical features: experience of the Rabin Medical Center in Israel.

We sought to compare the epidemiological and clinical features of patients with carcinoma of the larynx treated at a major Israeli tertiary facility with other series in the literature. The charts of 361 consecutive patients from 1974 to 1995 were reviewed. Our population was distinguished from other series by a low rate of alcohol abuse (12%), high incidence of second malignancies in sites other than the upper aerodigestive tract (53%) and high rate of early-stage tumors (82%). Overall 5-year survival and local control rates were 88% and 85%, respectively. Our study suggests that the low alcohol consumption and high proportion of early-stage tumors at diagnosis, characteristic of the Israeli population of patients with laryngeal carcinoma, may explain, in part, the relatively high survival and local control rates.

Standard and nonstandard applications of sentinel node-guided melanoma surgery.

Identification and histologic study of the sentinel node (SN) is an acceptable, yet not firmly established, guide for treating intermediate-thickness melanoma. This study widens the range of applications of this technique. We included 97 patients with intermediate-thickness melanoma lesions or lesions for which there is no standard treatment. Fifty-six underwent preoperative lymphoscintigraphy, and all underwent intraoperative lymphatic mapping (IOLM) using blue dye, followed by frozen section study and total node processing by serial sections. Elective lymph node dissection was performed in cases of metastasis to the sentinel node or technical failures with high risk. Four categories were defined: (A) intermediate-thickness lesions (mean 2.27 mm) (n = 45); (B) thin lesions (mean 1.14 mm) with risk factors of regional failure (n = 27); (C) lesion thickness close to but more than 4 mm (n = 10); and (D) lesions of undetermined thickness (n = 15). Median follow-up was 30 months (range 13-51 months). Intraoperative lymphatic mapping successfully identified the sentinel node (SN) in 93% of basins explored. Metastases were detected in 11 SNs. There were three lymph basin recurrences in patients with previously negative SNs, all salvaged by therapeutic lymph basin dissection and are NED (no evidence of disease). Two SN(+) patients had systemic recurrences; one died of his disease, and the other is alive with disease. One SN(-) patient died NED owing to other cause. This technique spared 83% of category A patients from lymph node dissection. It allowed better staging and better decision making for treatment in categories B and D; and it prevented early regional recurrences in category C patients. Intraoperative lymphatic mapping with SN guidance is a novel, lo

Applicability of the sentinel node technique to Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) resembles malignant melanoma in several ways. Both are cutaneous lesions of the same embryonic origin. Both have an unpredictable biologic behavior, early regional lymph node involvement, early distant metastases, and high recurrence rate. OBJECTIVE: To apply the sentinel node technique described for melanoma to MCC in light of the common biologic features of these two tumors. METHODS: Preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and sentinel node biopsy and frozen section histology were performed to guide the surgical treatment of three patients with MCC. RESULTS: Application of this approach in patients with MCC is feasible, reproducible, and seems reliable. CONCLUSION: The use of the sentinel node technique for MCC will reduce the number of unnecessary lymphadenectomies, will enable identification of microscopic metastases to lymph nodes, and will improve the stratification and accrual of patients into adjuvant treatment protocols. It may even lead to a survival benefit.

Role of radiotherapy in sarcoma of the breast--a retrospective review of the M.D. Anderson experience.

BACKGROUND: The role of adjuvant radiotherapy for sarcoma of the breast, based on local extension of disease and patterns of failure, remains undefined because of the rarity of the disease presentation. METHODS: Fifty-nine cases of soft tissue sarcoma of the breast were retrospectively reviewed. Cystosarcoma phylloides was excluded from analysis. Surgical intervention consisted of segmental resection (n = 16) or mastectomy (n = 38); five patients underwent excisional biopsy. Adjuvant radiotherapy was administered in four patients following segmental resection and in 13 patients after mastectomy. Doses totaled 50 Gy in the majority of patients, and conventional criteria and radiotherapy techniques for adjuvant breast irradiation were used. RESULTS: None of the dissected axillary nodes contained metastatic tumor on pathologic review. Patterns of failure were evaluated. Tumor size (P < 0.03) and surgical margins (P < 0.002) were predictive of local failure (LF). Due to limited patient numbers, no statistical significance was identified with any treatment modality. Following mastectomy alone, LF occurred in 13 patients (34%) versus the 13% rate of LF with mastectomy and radiotherapy (P = NS). Distant metastases developed concurrently with the two local failures in the group that underwent mastectomy and radiation. After segmental mastectomy, LF occurred in 3 cases (25%) concurrent with distant metastases: no LF were noted after segmental mastectomy and radiation (P = 0.27). For all treatment groups, local recurrences were characterized as multiple and involved the chest wall. Local failure occurred in 60% of patients with positive surgical margins who did not receive adjuvant irradiation. Irrespective of surgical margins, over 75% of local recurrences developed among patients treated by surgery alone. CONCLUSIONS: The role of radiotherapy for breast sarcoma remains undefined due to the rarity of this disease presentation. This retrospective review failed to demonstrate a statistical benefit for the administration of adjuvant irradiation in sarcoma of the breast, probably because of limited patient numbers. Because large tumor size and positive surgical margins incur a higher risk for LF, radiotherapy is probably indicated in these cases. Axillary dissection obligates the radiotherapist to treat the axilla in order to include all tissues in the surgical bed, and should be avoided to reduce potential treatment related morbidity. Established therapeutic principles and techniques used for both soft tissue sarcoma and breast cancer should continue to be applied.

Toxicity of adjuvant high-dose interferon-alpha-2b in patients with cutaneous melanoma at high risk of recurrence.

Interferon-alpha-2b (INF-alpha-2b) has been approved by the FDA as adjuvant treatment for patients with melanoma at high risk of recurrence. INF-alpha-2b is administered at 20 MU/m2/day IV, 5 days per week for 4 weeks, and then 10 MU/m2/day SC, three times weekly for 48 weeks. We investigated the toxicity of this protocol in 30 patients between June 1996 and February 1998. An intensive toxicity evaluation program was developed to monitor side effects. During both induction and maintenance phases, 60% of patients required a dose delay and/or reduction. Twenty percent were unable to complete the treatment plan, and 53% tolerated at least 80% of the scheduled dose. The frequently reported toxicity during induction included constitutional symptoms, myelosuppression, and hepatotoxicity. All were reversible on cessation of treatment or dose modification. During maintenance, toxicity included thyroid dysfunction, hypertriglyceridemia, retinopathy and a combination of mood disturbances, memory loss, cognitive slowing and impaired executive function. Administration of high-dose INF-alpha-2b is feasible, with close patient monitoring.

Sentinel-node guided lymph-node dissection for merkel cell carcinoma.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumour. Treatment is still debatable. Merkel cell carcinoma resembles malignant melanoma in its cutaneous presentation and its embryonic origin; both have unpredictable biological behaviour, early regional lymph node involvement, early distant metastases and a high recurrence rate. In light of these common features, we used pre-operative lymphoscintigraphy, intraoperative lymph-node mapping and sentinel-node biopsy-a well-described technique for the treatment of melanoma-in a 60-year-old man with Merkel cell carcinoma in the right buttock. Following frozen section identification of a metastatic first-order sentinel node, radical right groin dissection was performed. All the other lymph nodes in this basin proved to be disease-free, including the second-order sentinel node and Cloquet node. The patient is now being treated with adjuvant chemotherapy and radiotherapy. This case shows that sentinel-node guided dissection is applicable to Merkel cell carcinoma.

Usefulness of serological determinations of soluble 53 kDa protein in follow-up of melanoma patients.

The role of the soluble 53 kDa antigen (s53) determinations in follow-up of melanoma patient was studied. high performance liquid chromatography (HPLC) was used to measure serum levels of s53 antigen after its partial isolation on gel fiberglass (GFG) affinity chromatography columns. Two main proteins were isolated from these columns as representatives of soluble tumor-associated antigens (TAA) with molecular masses of 64 and 53 kDa. In a Western immunoblot analysis, the 53 kDa protein exhibited a strong positive reaction to the commercial p53 antibody. HPLC isolated both antigens with individual variations and significant differences in their concentrations in patients from different groups. The presence of metastases was manifested by a significant increase in the serum levels of both isolated TAA. This finding is in accordance with our previous observations on the role of the soluble 53 kDa protein in the development of colon and uterine cancers. We conclude that the determination of the serum level of the s53 antigen is of diagnostic significance in the monitoring of melanoma patients.

Tailoring treatment for classical Kaposi's sarcoma: comprehensive clinical guidelines.

Classical Kaposi's sarcoma (CKS) is a rare indolent proliferative disease which is particularly prevalent among Jews of Ashkenazi and Mediterranean origin. To define guidelines for its comprehensive management, we conducted a retrospective analysis of 123 patients, focusing mainly on treatment modalities. The CKS-related mortality was 4% (5 patients). Of the 39 patients for whom observation only was the primary approach, 15 (38%) remained progression-free for 1-83 months (median, 4 months). Twenty-nine of the 52 (56%) patients who underwent surgery as the primary approach remained recurrence-free for 1-162 months (median, 15 months). Radiotherapy achieved an objective response in 74 courses (85%), including 50 (58%) complete responses. Symptomatic relief was reported in 95% of the patients. Vinblastine (27 series) achieved an objective response in 73% of series, including 22% complete responses. Multivariate analysis of time to progression with observation alone identified immunosuppression as the only significant independent factor that predicted disease progression. Our study suggests that observation alone may be sufficient for immunocompetent asymptomatic patients; symptomatic resectable lesions are suitable for simple excision; and more advanced disease or unresectable lesions require radiotherapy. If disease is extensive or the other approaches fail, chemotherapy is appropriate. Tailoring the treatment for CKS is an integrative process, requiring good understanding of the role of each available modality in the different clinical disease settings.

Role of radiation therapy in the management of cutaneous malignant melanoma.

Traditionally, cutaneous malignant melanoma is regarded as a radioresistant tumor. Recently, however, an increasing number of clinical studies have refuted this notion. The authors examined the role of radiation therapy in the palliative and/or adjuvant treatment of cutaneous malignant melanoma. The records of 69 patients with cutaneous malignant melanoma were reviewed. Twenty-five patients with extensive regional lymph node involvement received adjuvant radiation therapy after primary surgical treatment, and the remainder received palliative radiation therapy. The therapeutic significance of fraction size was analyzed. In the palliative radiation therapy group, the response rate was 52% with a fraction size < or = 300 cGy and 35% with a larger fraction size (p > 0.05, NS). Local regional control rates after adjuvant radiation therapy using conventional fractionation and larger fraction size were 87% and 82%, respectively (p > 0.05, NS). Radiation therapy is effective in the management of cutaneous malignant melanoma. It plays an important role in the palliation of metastatic disease and as an adjuvant treatment. No advantage in using a large fraction size over conventional dose schedules was found.

Cancer of the anus (review).

Cancers of the anus differ in their histology, anatomical location, response to therapy and prognosis. Epidermoid cancers have turned out to be one of the tumors most responsive to multimodality treatment, for which radical surgery is no longer the primary modality of choice.