Co-deposition of amyloidogenic immunoglobulin light and heavy chains in localized pulmonary amyloidosis.

Localized pulmonary amyloidosis is a rare condition whose pathogenesis is insufficiently understood. In the present study, we report a case of localized pulmonary amyloidosis associated with lung-restricted lymphoplasmacytoid lymphoma, monoclonal for immunoglobulin (Ig) G lambda (lambda). Biochemical microtechniques have been applied for extraction, purification, and characterization of amyloid proteins. Surprisingly, chemical analysis of these proteins revealed a not-previously-described case of combined deposits containing Ig fragments of gamma heavy chain (variable domain) and lambda light chain (constant domain). In view of the absence of circulating monoclonal Ig, this case supports the hypothesis that localized amyloid is formed by local plasmacytoid cells.

Hair growth induction by the Tellurium immunomodulator AS101: association with delayed terminal differentiation of follicular keratinocytes and ras-dependent up-regulation of KGF expression.

The synthetic immunomodulator AS101[ammonium trichloro(dioxoethylene-o,o')tellurate] was previously found to protect cancer patients from chemotherapy-induced bone marrow toxicity and alopecia. Here we show that AS101 induces hair growth in nude and normal mice. AS101 possesses the dual ability to both induce anagen and retard spontaneous catagen in the C57BL/6 mouse model. Anagen induced by AS101 is mediated by keratinocyte growth factor (KGF), as it is abrogated both in nude mice co-treated with AS101 plus neutralizing anti KGF antibodies and in AS101-treated transgenic mice expressing a dominant-negative KGF receptor transgene in basal keratinocytes. AS101 up-regulates KGF expression by activating the ras signaling pathway in cultured fibroblasts. AS101-induced delayed catagen is associated with inhibition of terminal differentiation marker expression both in nude and C57BL/6 mice epidermal follicular keratinocytes and in cultures of primary mouse follicular keratinocytes induced to differentiate. This activity is associated with relatively sustained elevation of p21waf. Delayed expression of terminal differentiation markers was not induced by AS101 in follicular keratinocytes from p21waf knockout mice. Because similar results were obtained with cultures of primary human keratinocytes and fibroblasts, preliminary case report studies revealed substantial hair growth when AS101 was topically applied on three adolescents who had remained alopeciac 1-2 years after chemotherapy. The results emphasize the unique mode of action of AS101 and highlight its potential clinical use for treating certain types of alopecia.

An improved technique for mitosis counting.

Mitosis counting remains one of the most valuable prognostic indicators in tumor pathology; however, as currently carried out it is time consuming and not reproducible. In this study, 6 different pathologists, using different microscopes, arrived at widely different mitotic counts on the same slide, ranging from 4 to 16. These differences were mainly due to the different field areas of the various microscopes used and the method used for counting and recording. In evaluating the most active 10 HPF, the count ranged from 10 to 19. Instead, when an average of 40 fields was recorded, the range was 4-11. Using the mitosis/volume index, which expresses the number of mitotic figures per mm2 of viable tumor, the counts ranged from 8 to 10, a marked improvement. However, this method is complicated and not "user-friendly.'' We suggest a variation of the technique by which a 2 mm2 rectangle is drawn on a cover slip and mounted under the microscope, centered on the most mitotically active area of the tumor. The mitoses in that area are counted (=n) and the percent of viable tumor (=x%) is estimated under low magnification. The number of mitoses per mm2 of viable tumor (cs-MAI) is then calculated according to the formula Cs-MAI=100n/2x. Using this modified method, the range of mitoses counted by the different observers was very narrow (9 to 11), and the time required for the counting was only 5-10 minutes.

In vitro and in vivo treatment of colon cancer by VIP antagonists.

Vasoactive intestinal peptide (VIP) is secreted from many cancer lines and VIP binding was observed in many tumors. We have shown before that VIP antagonists are potent inhibitors of neoplastic growth of neuroblastoma, lung and breast cancer cells in vitro. Here, the cultured colon cancer cell line HCT-15 that exhibited VIP receptor expression was treated with the VIP hybrid antagonist neurotensin(6-11)VIP(7-28). The antineoplastic activity was assessed by thymidine incorporation. Neurotensin(6-11)VIP(7-28) efficiently inhibited cancer growth with a maximal effect at nanomolar concentrations. Once the inhibitory properties of the VIP antagonist on colon cancer cells were established, the in vivo curative effects were analyzed. Sprague-Dawley rats were injected with azoxymethane (AOM) (15 mg/kg/week) for 2 weeks, providing artificial induction of colon tumors. The rats were then allocated into four experimental groups: (1) receiving no treatment; (2) receiving treatment with saline; (3, 4) receiving treatment with 10 or 20 microg of neurotensin(6-11)VIP(7-28), respectively. After 10 weeks of daily injections, rats were sacrificed and tumors assessed for stage, volume, location, differentiation and lymphocytic infiltrate. Embedded mucosa was assessed for dysplastic crypts. Results showed that the antagonist treatment reduced the tumor volume, staging, lymphocyte infiltrate and the number of dysplastic crypts. Thus, neurotensin(6-11)VIP(7-28) could serve as an effective cancer treatment and a preventing agent.

Prognostic value of Topoisomerase II in female breast cancer.

Topoisomerase II-alpha (Topo II-alpha) is a nuclear enzyme. Its expression rises rapidly at the end of the S to G2/M phase and falls after the mitotic process ends. We have studied the immunohistochemical expression of Topo II-alpha in breast cancer and its correlation with the menopausal state, tumor type, size, lymph node metastases, stage, and estrogen and progesterone positivity. Histological sections from 50 breast cancers were immunohistochemically stained for Topo II-alpha. The percent of positive cells at the area of highest staining was recorded as Topo index. The correlation between the course of disease, survival and Topo II-alpha index was statistically significant, p<0.001. High-grade tumors showed higher Topo II-alpha levels, than those of intermediate and low-grade, p<0.01. A significant association was found between estrogen receptors positivity and Topo II-alpha, p<0.05. A higher Topo II-alpha index indicates higher probability for recurrence of the disease and overall survival. Therefore, Topo II-alpha expression has a prognostic value in breast carcinoma.

Expression of protein kinase C isoenzymes in benign hyperplasia and carcinoma of prostate.

Protein kinase C family consists of 11 isoforms, classified into 3 categories according to their structure and mechanisms of activation. These isoenzymes are involved in processes, which maintain intracellular homeostasis. Alterations in activity, amount or distribution of protein kinase C (PKC) isoenzymes may cause cellular proliferation or induce apoptosis. We have studied and compared the expression levels of several PKC isoforms in benign prostatic hyperplasia (BPH) and prostate cancer (PCa). These are PKCs alpha (alpha), beta (beta), delta (delta), epsilon (epsilon), zeta (zeta), eta (eta), which have been detected as major isoforms in prostate tissue. Paraffin sections of 25 benign prostatic hyperplasia (BPH) and 25 of prostatic carcinoma (PCa) were examined for expression of PKC alpha, beta, delta, epsilon, zeta, and eta. Expression of PKC beta was examined in additional 3 BPH and 3 PCa using Western blot analysis. We found a significant high level of expression of PKC isoforms alpha, beta, epsilon and eta in PCa compared to BPH (p<0.01). Using backward logistic regression, we found changes in PKC epsilon expression to be most significant between malignant compared to benign tumor tissue specimens. Immunostaining for PKCs alpha, beta and eta in addition to PKC epsilon may aid in distinguishing between benign and malignant prostatic disease.

Cyclosporin A-induced hair growth in mice is associated with inhibition of hair follicle regression.

BACKGROUND: Cyclosporin A (CsA) often causes hair growth in transplant recipients. Our objectives were to evaluate the effect of CsA on follicular hair keratinocyte growth in nude mice by assessing their proliferation in vivo, and to assess the ability of CsA to prevent follicular keratinocyte apoptosis in vivo and chemotherapy-induced keratinocyte apoptosis in vitro. METHODS: Nude mice were fed various daily doses of CsA (10-100 mg/kg). Dorsal skin sections stained with hematoxylin and eosin, followed by immunostaining with 4-deoxybromouridine, were examined for determination of hair follicle number and hair follicle keratinocyte proliferation. Follicular keratinocytes were isolated and examined for apoptotic status. Apoptosis was induced in vitro in a keratinocyte cell line by 4-hydroperoxycyclophosphamide. The antiapoptotic effects of various CsA concentrations (0.1-5 microg/ml) were measured by annexin-V/propidium iodide binding. RESULTS: CsA caused a dose-dependent increase in the number of hair follicles but had no effect on follicular keratinocyte proliferation. Treatment with CsA decreased the number of apoptotic follicular keratinocytes. In vitro, there was a dose-dependent inhibition of the extent of early and late apoptosis of treated keratinocytes. CONCLUSION: CsA may induce hair growth by increasing the number of hair follicles and inhibiting apoptosis of follicular keratinocytes, thereby delaying hair follicle regression.

Significance of angiogenesis and microvascular invasion in renal cell carcinoma.

The aim of this study is to evaluate the relationship between tumor angiogenesis and microvascular invasion, and the subsequent development of metastatic disease in patients undergoing surgery for renal cell carcinoma (RCC). The study group consisted of 102 patients who underwent surgery for RCC between the years 1990 and 1997 in our institute with a mean follow up period of 81.3 months. Paraffin blocks were stained for Factor VIII - related antigen and CD34 which decorate endothelial cells in order to assess angiogenesis and microvascular invasion and their relevance for developing metastatic disease. When Factor VIII- related antigen staining was used we found that the microvessel count correlated with the development of metastatic disease with a mean count of 49.7 for patients with no evidence of disease and a mean count of 95.5 for patients who developed metastatic disease (p<0.05). We also found that microvascular invasion correlated with the development of metastatic disease. It was demonstrated in 55.5% of patients who developed metastatic disease versus 23.8% of patients with no evidence of disease with Factor VIII staining (p<0.05), and in 33.3% and 7.1%, respectively (p<0.05) with CD34 staining. This study suggest that demonstration of intense angiogenesis and micro-vascular invasion may be a predictor of a more aggressive tumor mandating closer follow up and consideration of adjuvant therapy.

The spectrum of laryngeal neoplasia: the pathologist's view.

Several types of neoplastic change with different prognostic implications typically involve the laryngeal squamous epithelium. The purpose of this review is to examine the spectrum of these changes, as well as their relationship to benign squamous epithelial proliferative states. Since these pathological changes are apt to occur in regions where the epithelial lining is typically squamous, it is important to recognize that the epithelium of the larynx varies from stratified squamous to respiratory-type, depending on the location. The lingual (anterior) surface of the epiglottis is lined by a stratified squamous type, while the laryngeal (posterior) surface is stratified squamous merging into respiratory-type. In the larynx, the supraglottic and infraglottic portions are a respiratory-type, which contrasts with the stratified squamous epithelium of the glottis. This typical distribution does show some degree of variability in those patches of squamous epithelium and is frequently seen within the respiratory-type epithelial regions. The junction between the two epithelial types may be abrupt or separated by a transitional zone.

The great auricular nerve; does it penetrate the parotid gland? An anatomical and microscopical study.

UNLABELLED: Conflicting opinions exist in the literature regarding the exact anatomical course of the great auricular nerve. The aim of this work was to study the pathway of its anterior branch and endings in relation to the parotid gland. MATERIAL AND METHODS: Thirty-seven specimens were dissected from 19 fresh adult cadavers and studied including the parotid gland at the region of the termination of the anterior branch of the nerve. The causes of death were not due to pathology in the parotid region. All the specimens were fixed in formaldehyde, serially cut, stained by haematoxylin and eosin, and examined by light microscope. RESULTS: In most of the glands (21/37 = 57%), there was no evidence of well-organized nerve fibres of the great auricular nerve inside the parotid gland. In a few (5/37 = 13%), nerve fibers were seen to penetrate the interlobular septa and in 30% of the cases (11/37) nerve bundles were found deep in the gland along side small ducts and close to thin-walled blood vessels. CONCLUSION: These findings prove that there are anatomical variations of the endings of the anterior branch of the great auricular nerve. The significance of nerve bundles deep in the gland along ducts and near vessels remains to be explored.

Attempts at suppression of amyloidogenesis in a mouse model by a variety of anti-inflammatory agents.

OBJECTIVE: The mainstay of AA amyloidosis prevention and treatment is suppression of inflammation. In the present study we have tried to determine the efficacy of a variety of anti-inflammatory agents at suppressing AA amyloidosis in a mouse model of the disease. METHODS: AA amyloidosis was induced in Swiss male mice using amyloid enhancing factor and AgNO(3). Suppression of amyloid formation was studied in comparison to saline, using i.p. injections of several non-steroidal anti-inflammatory agents, TNF-α inhibitors, interferon-α, leflunomide and a variety of chemotherapeutic agents, commonly used in the treatment of inflammatory illnesses such as methotrexate, azathioprine, chlorambucil and cyclophosphamide. The degree of splenic amyloid deposition was determined using Congo red staining of smears and a 5 grade scale. RESULTS: The alkylating agents, chlorambucil and cyclophosphamide, each resulted in a significant 88% reduction in amyloid deposition, yielded the most striking effect on amyloidogenesis suppression in the enhanced mouse model (p<0.0002). The non-steroidal anti-inflammatory agents tested varied widely in their ability to suppress amyloid formation in our mouse model, but only diflunisal was significantly effective, inducing a suppression of 57% (p=0.04). Other chemotherapeutic agents tested, methotrexate and azathioprine, yielded 32% and 27% suppression, which fell short of statistical significance. Surprisingly, the immunomodulatory agents etanercept, infliximab, leflunomide and interferon-α had insignificant effects on amyloid formation in this model. CONCLUSION: Our findings suggest that alkylating agents may have a role in the prevention of amyloidogenesis. Further testing of these agents in animal models and in the clinical setting is needed.

Suppression of amyloidogenesis in a mouse model by corticosteroid intervention.

Steroid treatment of amyloidosis was studied previously in human and murine models of reactive amyloidosis but with limited success and with conflicting results. To determine whether steroids may inhibit amyloidogenesis, and to study factors that may play a role in this effect, the authors induced amyloidosis in Swiss male mice, using the enhanced protocol with a single intravenous injection of amyloid-enhancing factor (AEF) and 3 successive daily subcutaneous AgNO(3) injections. Suppression of amyloid formation by various commonly used steroid preparations was evaluated from the amount of splenic amyloid, using the crush-and-smear technique. All steroid preparations examined were found to suppress amyloidogenesis but with differences between them in the degree and duration of inhibition. In general, hydrocortisone and dexamethasone had the highest suppressive effect, whereas methylprednisolone displayed lower activity for shorter duration. Single-dose experiments revealed that steroid effect is limited to the onset of amyloidogenesis. These experiments show that corticosteroids may significantly suppress amyloidogenesis but only briefly and, therefore, discourage a long-term and late use of steroid supplement in different anti-amyloid treatment protocols.

A new scoring system using multiple immunohistochemical markers for diagnosis of uterine smooth muscle tumors.

The diagnosis of uterine smooth muscle neoplasms by light microscopy is difficult. Multiple classification schemes have been proposed based on mitotic rate, nuclear atypia, and the presence or absence of necrosis. None of these classification systems has been entirely successful. This study was undertaken to evaluate the use of selected immunohistochemical and histochemical markers in differentiating these tumors, in addition to accepted morphologic criteria. Ten cases of each of the following: leiomyosarcomas (LMS), atypical leiomyomas (AL), cellular leiomyomas (CL) and usual leiomyomas (UL), were classically evaluated for histological diagnosis and were stained for Ki-67 (MIB-1), bcl- 2 and p53 using monoclonal antibodies and the avidin-biotin peroxidase method, and argyrophilic nucleolar organizer region (AgNORs). The number of stained cells was counted in the most positively stained region in a 4 mm2 square cover glass mounted on each slide. The mean value was calculated for each group of tumors. The data for Ki-67 (MIB- 1), bcl-2, p53 and AgNOR staining respectively, were significantly higher in LMS by comparison to UL, CL or AL. Because many singular cases had superimposed data being difficult to diagnose, a new scoring system for pathological evaluation was created. The results obtained by this scoring system suggest that immunohistochemical markers Ki-67 (MIB-1), bcl-2, p53 together with the AgNOR staining could be useful, by the scoring system, as an adjunct to the current accepted morphologic criteria in differentiating smooth muscle tumors of the uterus.

Abdominal and digestive system associations of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a hereditary episodic febrile syndrome that is expressed by acute spells of fever, painful manifestations in the abdomen, chest and joints, and slow development of nephropathic amyloidosis. Despite the recent cloning of the FMF gene (MEFV) and the identification of about 40 disease-related mutations, the diagnosis is still clinically dependent, and the pathogenesis and most of the clinical heterogeneity remain to be explained. Because episodic abdominal pain affects 95% of FMF patients, most of them are seen by gastroenterologists and undergo complete or partial abdominal imaging before the diagnosis is made. Focusing on recent advances in FMF, this article reviews both common and infrequent manifestations that a gastroenterologist may encounter during workups of FMF patients. These include episodic abdominal pain, paralytic or mechanical ileus, constipation, diarrhea, ascites, malabsorption, bowel infarction, and bleeding, arising directly from FMF or secondary to FMF common associations such as amyloidosis, vasculitides, inflammatory bowel disease, irritable bowel syndrome, or colchicine side effects. This article will help the gastroenterologist to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF.

Histological and scanning electron microscope examination of root canal after preparation with Er:YAG laser microprobe: a preliminary in vitro study.

OBJECTIVE: Until now, there has been no study that demonstrates the effectiveness of Er:YAG laser microprobes to clean and shape the root canal without using any mechanical instrumentation. MATERIALS AND METHODS: The study was conducted on 28 single-rooted extracted central incisors teeth with straight roots. Fourteen were mechanically prepared and served as the control group, and 14 were treated by Er:YAG laser only. From every group, half of the teeth were examined histiolgically and half by SEM. The instrument tested was an Er:YAG laser with microprobes 200-400 micro in diameter and 20 mm in length, coupled onto special handpieces, attached to the delivery fiber of an OPUS 20 Er:YAG laser. The Er:YAG laser was applied with the following parameters: wavelength 2.94 microm; pulse duration 400 msec; repetition rate 10 Hz; energy per pulse 140 mJ for the 400 micro microprobe and 90 mJ for the 200-micro microprobe. RESULTS: For the control group, histologically, large amounts of residual pulp tissue were found in the root canal cavity, and open tubules were seen in all the specimens; SEM examination showed very uniform root canal, from apical to cervical portion, high number of open tubules, and different levels of canal debridment. For the study group, histologically, no residual pulp tissue was found in the root canal cavity and open tubules were seen in all the specimens; SEM examination showed the root canal free of debris, removed smear layer, open dentinal tubules, and different levels of enlargement. CONCLUSION: Our results show that the Er:YAG laser special microprobes are effective in shaping, cleaning, and enlarging straight root canals faster and more efficiently then traditional methods.

Deleted in colorectal cancer protein expression as a possible predictor of response to adjuvant chemotherapy in colorectal cancer patients.

PURPOSE: The deleted in colorectal cancer (DCC) gene predicts a poor outcome for patients with colorectal carcinoma. This study was designed to investigate whether the expression of the DCC protein also can predict response to adjuvant chemotherapy. METHODS: The expression of DCC was evaluated immunohistochemically in 74 paraffin-embedded tumor samples from patients with Stage II (n = 41) and Stage III (n = 33) colorectal carcinomas. Follow-up time was at least 60 (median, 64) months. Follow-up was at least five years for all patients who are alive. End points of the study were recurrence of disease and death. Forty-eight patients received adjuvant therapy of 5-fluorouracil + levamisole; 28 were not treated. RESULTS: Fifty percent of tumors were deleted in colorectal cancer-positive (DCC+). Proportion of survival and disease-free survival were higher in the DCC+ patients (83 percent) than in deleted in colorectal cancer-negative (DCC-; 54 percent). In the DCC+ group, adjuvant treatment was a strong positive predictive factor for survival and disease-free survival. All DCC+ patients who received adjuvant chemotherapy (CHEMO+) are alive with no evidence of disease, whereas without chemotherapy (CHEMO-) only 54 percent are alive ( P = 0.0001). When stratification was performed by stage, patients in Stage II who were DCC+/CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO- survival rate was 75 percent and disease-free survival rate 62 percent ( P = 0.042). Patients in Stage III who were DCC+/ CHEMO+ had survival and disease-free survival of 100 percent, whereas in DCC+/CHEMO- both dropped to zero ( P = 0.0002). On the other hand, in the DCC- tumors, there was no statistical significant relationship between chemotherapy and survival or disease-free survival (DCC-/CHEMO- had 57 percent survival; DCC-/CHEMO+ had 52 percent survival). CONCLUSIONS: DCC is a prognostic factor for colorectal cancer. Positive expression of DCC identifies a subgroup of patients who respond favorably to adjuvant chemotherapy, which resulted in our cases, in 100 percent survival and disease-free survival rates. Without treatment, the survival rate of DCC+ patients dropped significantly. We suggest that DCC immunostaining should be performed routinely. All DCC+ patients should receive adjuvant chemotherapy. For DCC- tumors, a larger cohort of patients should be studied before definitive conclusions can be drawn; however, clinical trials of new drug combinations should focus on DCC- patients.

The expression of DCC protein in female breast cancer.

BACKGROUND: The deleted in colorectal cancer (DCC) gene has been shown to be frequently deleted or its expression reduced or absent in glioblastomas, colorectal, gastro-intestinal, pancreatic and prostatic tumors. In the present study, we investigated the expression of DCC in surgical specimen from 75 patients with primary breast cancer. METHODS: The expression of the DCC, estrogen receptors (ER), and progesterone receptors (PR) was studied in 75 surgical specimens of primary breast cancer using an immunohistochemical method. To evaluate the outcomes of the breast cancer patients, we followed up the patients during minimum of 10 years. RESULTS: Reduced or loss of expression of DCC was identified in 45 out of 75 samples. There were significant differences between cases without metastasis or local recurrences versus these with metastasis or local recurrences (p = 0.006), and between patients alive with no evidence of malignancy versus those with recurrence or dead of disease (p = 0.005). There were no significant differences between the DCC status and age, sex, tumor location, stage, grade, or proportion of patients who received adjuvant therapy. CONCLUSIONS: These findings suggest that a decrease in DCC expression may influence the prognosis of breast carcinoma patients.

Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention.

The role of IL-10 in experimental sepsis is controversial. The nontoxic immunomodulator, ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) has been previously shown to inhibit IL-10 expression at the transcriptional level. In this study, we show that in mice subjected to cecal ligation and puncture (CLP), treatment with AS101 12 h after, but not before, CLP significantly increased survival of septic mice. This was associated with a significant decrease in serum IL-10 and in IL-10 secretion by peritoneal macrophages 24-48 h after CLP. At that time, the ability of these cells to secrete TNF-alpha and IL-1beta was restored in AS101-treated mice. The increased survival of AS101-treated mice was due to the inhibition of IL-10, since cotreatment with murine rIL-10 abolished the protective activity of AS101. AS101 increased class II Ag expression on peritoneal macrophages, severely depressed in control mice, while it did not affect the expression of class I Ags. This was accompanied by a significant elevation in the level of IFN-gamma secreted by splenocytes. Moreover, AS101 ameliorated bacterial clearance in the peritoneum and blood and decreased severe multiple organ damage, as indicated by clinical chemistry. Furthermore, myeloperoxidase levels in the liver and lung of AS101-treated mice, an indirect means of determining the recruitment of neutrophils, were significantly decreased. We suggest that nontoxic agents such as AS101, with the capacity to inhibit IL-10 and stimulate macrophage functions, may have clinical potential in the treatment of sepsis, provided they are administered during the phase of sepsis characterized by immune suppression.

Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes.

One of the most common side effects of treatment with cyclosporin A (CsA) is hypertrichosis. This study shows that calcineurin activity is associated with hair keratinocyte differentiation in vivo, affecting nuclear factor of activated T cells (NFAT1) activity in these cells. Treatment of nude or C57BL/6 depilated normal mice with CsA inhibited the expression of keratinocyte terminal differentiation markers associated with catagen, along with the inhibition of calcineurin and NFAT1 nuclear translocation. This was associated with induction of hair growth in nude mice and retardation of spontaneous catagen induction in depilated normal mice. Furthermore, calcineurin inhibition blocked the expression of p21(waf/cip1) and p27(kip1), which are usually induced with differentiation. This was also associated with an increase in interleukin-1alpha expression (nude mice), a decrease in transforming growth factor-beta (nude and normal mice), and no change in keratinocyte growth factor expression in the skin. Retardation of catagen in CsA-treated mice was accompanied by significant alterations in apoptosis-related gene product expression in hair follicle keratinocytes. The ratio of the anti-apoptotic Bcl-2 to proapoptotic Bax expression increased, and expression of p53 and interleukin-1beta converting enzyme activity decreased. These data provide the first evidence that calcineurin is functionally active in follicular keratinocytes and that inhibition of the calcineurin-NFAT1 pathway in these cells in vivo by CsA enhances hair growth.

Laser surgery for the treatment of glottic carcinomas.

PURPOSE: The standard treatment for patients with early glottic carcinoma in Israel has been radiotherapy. In recent years, encouraging results with laryngo-microscopic carbon dioxide laser surgery as a treatment for early glottic carcinoma has changed our treatment strategy. We conducted a retrospective study to investigate the results of carbon dioxide laser excisional technique for early glottic carcinoma (T1, T2). MATERIALS AND METHODS: Twenty-six had squamous cell carcinoma (SCC), (21 patients with T1 and 5 patients with T2 lesions), 3 had carcinoma in situ, (CIS) and 3 had verrucous carcinoma (VC). RESULTS: All patients were free of disease after salvage treatment at the most recent follow-up. CONCLUSIONS: Careful patient selection with endoscopic staging and strict follow-up are essential to secure good results in the treatment of carbon dioxide laser for early laryngeal carcinoma.