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.

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.

Effects of anesthetics on water permeability and lipid metabolism in Acholeplasma laidlawii membranes.

The addition of tetracaine and diethyl ether to Acholeplasma laidlawii at concentrations commonly used for local anesthesia did not affect water permeability over the cell membrane, as measured by a pulsed magnetic field gradient NMR method. However, A. laidlawii changed its membrane lipid composition upon treatment with these anesthetics. Both tetracaine and diethyl ether addition resulted in a decrease in the molar ratio between the major membrane glucolipids, monoglucosyldiacylglycerol and diglucosyldiacylglycerol. The ratio between saturated and unsaturated acyl chains did not change. The results are in accordance with our proposal that A. laidlawii regulates its lipid composition in order to maintain optimal packing stability in the membrane (Wieslander, A., Christiansson, A., Rilfors. L. and Lindblom, G. (1980) Biochemistry 19, 3650--3655). Introduction of anesthetics into the hydrophobic region of a bilayer is likely to affect the lipid packing. A membrane which contains lipids like monoglucosyldiacylglycerol, which forms a reversed hexagonal phase, will be destabilized unless the amounts of such lipids are reduced. The membrane concentration of anesthetics was estimated to one molecule per 12--15 lipid molecules. The fact that A. laidlawii regulates its lipid composition as a response to these concentrations, despite their negligible effect on water permeability, indicates a high sensitivity of this regulatory system.

Spontaneous remission in Cushing's disease.

Four patients with proved Cushing's disease underwent spontaneous clinical and biochemical remission. They were part of an 11-patient group treated with methods that allowed spontaneous remission to be observed. Each patient was treated differently, one each with metyrapone tartrate, ketoconazole, bilateral adrenalectomy and adrenal autotransplantation, and no treatment. Spontaneous remission occurred 9 months to 5 years after diagnosis as evidenced by restoration of normal adrenal function occurring symptomatically in two patients and advent to hypoadrenalism with addisonian crisis in the two others. We conclude that spontaneous remission in Cushing's disease may not be a rare entity, although its actual incidence has yet to be established.

Locomotion through three-dimensional type I rat tail collagen. A modified mini-assay.

There is an increased application of three-dimensional type I rat tail collagen as an in vitro model for the peritumoral matrix in analysis of lymphocyte migration. The increased demand prompted us to modify the previous methods. We here describe our 'mini'-setup of the collagen model assay, which uses only 1/20 the amount of collagen medium and the number of cells used in the conventional assay. The modified assay was tested for optimal collagen concentration in gel for upward and downward migration, for locomotion from a collagen-gel bead into a collagen overlayer for demonstration of the effect of inhibitors and for differentiation between locomotory properties of lymphocyte subpopulations. The results verify that the mini-assay is an applicable in vitro model, easily read and amenable to limited blood samples such as those obtained from cancer patients, and reflects well known in vivo events.

Growth inhibition and induction of phenotypic alterations by L-histidinol in B16 mouse melanoma cells.

L-Histidinol, a histidine analog was recently shown to be an inducer of differentiation in the promyelocytic cell line HL-60. In the present study we show that L-histidinol inhibits the growth of B16 melanoma cells in vitro. Growth inhibition is accompanied by phenotypic alterations that include a marked increase in the activities of NADPH cytochrome c reductase and gamma glutamyl transpeptidase, lipid accumulation and cell enlargement. These phenotypic alterations are similar to those induced by other chemical inducers of differentiation in melanoma cells.

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.

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.

Sarcoma of the breast: implications for extent of therapy. The M. D. Anderson experience.

BACKGROUND: Sarcoma of the breast is a rare clinical entity for which there are no prospective data about extent of surgery indicated or role of multimodality therapy. The purpose of this study was to examine one of the largest single institutional experiences to shed light on these clinical issues. METHODS: This study retrospectively reviewed 60 cases of sarcoma of the breast (cystosarcoma phyllodes excluded). RESULTS: For the entire series there was a median overall survival time (OS) of 67 months and a disease-free survival period (DFS) of 18 months. Tumors smaller than 5 cm were associated with a better DFS (p < 0.04) and OS (p < 0.009). Patients with tumors less than 5 cm in diameter did equally well whether treated by wide local excision or mastectomy. Angiosarcoma histologic characteristics were associated with longer OS than stromal sarcoma (p = 0.017), malignant fibrous histiocytoma (p = 0.075), or fibrosarcoma (p = 0.08). Axillary dissections did not recover any nodal metastasis; moreover, treatment in 75% of the patients with negative nodes subsequently failed. Regional lymph node metastases were always and only in the context of disseminated disease. Adjuvant chemotherapy and/or radiotherapy was associated with prolonged DFS (p = 0.015). There was a trend toward improved local control with adjuvant radiotherapy (p = 0.14). CONCLUSIONS: Lesions less than 5 cm should be treated by breast-preserving wide local excision, and adjuvant radiotherapy should be considered for selected subgroups. For tumors 5 cm or larger, a more aggressive approach seems appropriate; consideration should be given to neoadjuvant chemoradiation followed by margin-negative surgery (if possible). There is no demonstrable staging or therapeutic role for routine axillary dissection.

Achievements of physical therapy in patients after modified radical mastectomy compared with quadrantectomy, axillary dissection, and radiation for carcinoma of the breast.

Flexion of the shoulder, abduction, and external rotation in 90 degrees abduction are impaired after operations for breast cancer. We compared postoperative range of motion in 27 patients who underwent modified radical mastectomy and 21 patients who underwent quadrantectomy with axillary dissection and radiation therapy. The patients in the quadrantectomy group demonstrated a significantly higher range of flexion on postoperative day 1 and the day of suture removal. After 3 months, all patients had regained their preoperative range of flexion, with no difference between the groups. The better compliance of the quadrantectomy group to physical therapy may indicate that they suffer less pain and require a briefer or less intensive course of physical therapy.

Diagnostic ultrasound of scrotum.

Ultrasound is a proved, safe diagnostic procedure. Its efficacy in the evaluation of 54 cases of scrotal pathology is reviewed. Ultrasound was 100 per cent accurate in the evaluation of hydroceles, hematoceles, and paratesticular masses, but less informative in testicular abscesses (80%) and epididymo-orchitis (77%).

Ureteral obstruction by shotgun pellet seven years after injury.

Ureteral obstruction by an extrinsic object is rare. We herein report a case of renal colic caused by a shotgun pellet lodged in the ureter seven years after the injury. Computerized tomography scan and antegrade pyelogram demonstration were obtained.

Biologic distinctions and therapeutic implications of sarcomatoid metaplasia of epithelial carcinoma of the breast.

BACKGROUND: Malignant sarcomatoid metaplasia of epithelial carcinoma of the breast (carcinosarcoma) is diagnosed at an annual rate of two cases per 107 women in the United States of America. It seems that these tumors behave differently than other carcinomas or sarcomas of the breast. STUDY DESIGN: The University of Texas M. D. Anderson Cancer Center experience (1947 to 1991) treating 50 patients (mean age of 50 years, range of 25 to 76 years) was retrospectively reviewed. The five-year overall survival and disease-free survival rates were compared and prognostic factors were identified. RESULTS: The overall survival rate of 43 percent was lower than had been expected for carcinoma of the breast. No patient with stage IV disease survived five years. Tumor size and stage at diagnosis had the strongest impact on outcome. The impact of axillary lymph node status on prognosis was less than expected. Hormonal receptor levels were positive in only 12.5 percent of the tumors tested. Mastectomy with adjuvant chemotherapy or radiotherapy, or both, was superior to mastectomy alone and to wide local excision with or without adjuvant therapy, particularly for patients with stage II disease. If complete surgical resection is possible, the surgical approach for treatment of recurrent disease is better than any other modality. CONCLUSIONS: Carcinosarcoma behave biologically differently than conventional carcinoma of the breast in that sarcomatoid characteristics dominate the clinical course. These biologic distinctions should direct the treatment toward a multimodality approach that includes mastectomy and sarcoma-oriented adjuvant chemotherapy and radiotherapy.

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.

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.

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.

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.

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.

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.

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.