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BACKGROUND Soft tissue sarcomas (STS) account for less than 1% of all malignant tumours but present a significant diagnostic and therapeutic challenge since there are more than 50 histological subtypes.1 The clinical course of a sarcoma cannot be predicted by histologic typing alone but must be accompanied by grading and staging. Sarcomas with high metastatic potential can be picked out by histologic grading which is a cheap and simple method. One widely used and most reproducible grading system is French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) based on a score obtained by evaluating tumour differentiation, mitotic rate and amount of tumour necrosis.2 Histologic grading is the mainstay in predicting prognosis of STS especially in centres where facilities for more sophisticated methods are not available. Hence this study was undertaken to assess the effectiveness of the FNCLCC grading system in the prognostication of STS in our patient population. Aims and Objectives 1. To grade soft tissue sarcomas according to the FNCLCC system. 2. To study the association between grade and survival of soft tissue sarcomas in the patient population. MATERIALS AND METHODS The cases selected were adult patients with soft tissue sarcomas whose excision specimens were received in the Department of Pathology, Medical College, Thiruvananthapuram during a 3-year period for diagnosis. Histopathology slides of these tumours were retrieved and graded according to the FNCLCC system. The patients were followed up for 5 years. Overall and diseasefree survival rates were estimated. The data was analysed with the help of computer software SPSS. RESULTS Of the 110 cases of soft tissue sarcoma reviewed, 27.3% were low grade, 49% intermediate grade and 23.7% high grade. Follow up was available only for 70 patients with STS. The prognostic factors found significant in univariate analysis were histologic grade, necrosis and mitosis. But by multivariate analysis only histologic grade and necrosis were found to be independent prognostic factors. CONCLUSION Histologic grading of soft tissue sarcomas definitely influences the survival of patients and it should be routinely mentioned while reporting soft tissue sarcomas. FNCLCC grading system may be modified giving more importance to necrosis.

A 66-year-old man on hormonal therapy with prostate cancer was referred for Ga-PSMA PET/CT scan for biochemical recurrence. Ga-PSMA PET/CT scan detected moderate heterogeneous tracer concentration in bilateral breast parenchyma, in addition to the abnormal tracer concentration in enlarged prostate gland, right external iliac lymph node, and sclerotic lesion in L4 vertebra. On clinical examination, he was found to have bilateral gynecomastia. Abnormal concentration of Ga-PSMA in breast cancer is now well known, and in this context, it is important to know that tracer localization can occur in gynecomastia as well, as evidenced in this case.

Objective To evaluate the feasibility of using Ga PSMA-11 PET/CT for imaging brain lesions and its comparison with F-FDG. Methods Ten patients with brain lesions were included in the study. Five patients were treated cases of glioblastoma with suspected recurrence. F-FDG and Ga PSMA-11 brain scans were done for these patients. Five patients were sent for assessing the nature (primary lesion/metastasis) of space occupying lesion in brain. They underwent whole body F-FDG PET/CT scan and a primary site elsewhere in the body was ruled out. Subsequently they underwent Ga PSMA-11 brain PET/CT imaging. Target to background ratios (TBR) for the brain lesions were calculated using contralateral cerebellar uptake as background. Results In five treated cases of glioblastoma with suspected recurrence the findings of Ga PSMA-11 PET/CT showed good correlation with that of F-FDG PET/CT scan. Compared to the F-FDG, Ga PSMA-11 PET/CT showed better visualization of the recurrent lesion (presence/absence) owing to its significantly high TBR. Among the five cases evaluated for lesion characterization glioma and atypical meningioma patients showed higher SUVmax in the lesion with Ga PSMA-11 than with F-FDG and converse in cases of lymphoma. TBR was better with Ga PSMA PET/CT in all cases. Conclusion Ga PSMA-11 PET/CT brain imaging is a potentially useful imaging tool in the evaluation of brain lesions. Absence of physiological uptake of Ga PSMA-11 in the normal brain parenchyma results in high TBR values and consequently better visualization of metabolically active disease in brain.

Summary Background Pemetrexed maintenance therapy significantly improved overall survival and progression-free survival compared with placebo, and had a good safety profile in a phase 3 placebo-controlled study in patients with advanced non-small-cell lung cancer (NSCLC). Results for quality of life, symptom palliation, and tolerability are presented here. Methods After four cycles of platinum-based induction therapy, 663 patients with stage IIIB or stage IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (in a 2:1 ratio) from March 15, 2005, to July 20, 2007, using the Pocock and Simon minimisation method to receive pemetrexed (500 mg/m 2 every 21 days; n=441) or placebo (n=222) plus best supportive care until disease progression. The primary efficacy data have been reported previously. Patients completed the Lung Cancer Symptom Scale (LCSS) at baseline, after each cycle, and post-discontinuation. Worsening of symptoms was defined as an increase of 15 mm or more from baseline on a 100 mm scale for each LCSS item. The primary outcome for these quality-of-life analyses was time to worsening of symptoms, analysed for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings Baseline characteristics, including LCSS scores, were well balanced between groups. Baseline LCSS scores were low, indicating low symptom burden for patients without disease progression after completion of first-line treatment. Longer time to worsening was recorded for pain (hazard ratio [HR] 0·76, 95% CI 0·59–0·99; p=0·041) and haemoptysis (HR 0·58, 95% CI 0·34–0·97; p=0·038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4·3 mm vs 0·2 mm; p=0·028). Rates of resource use were statistically higher for pemetrexed than for placebo: admissions to hospital for drug-related adverse events (19 [4%] vs none; p=0·001), transfusions (42 [10%] vs seven [3%]; p=0·003), and erythropoiesis-stimulating agents (26 [6%] vs four [2%]; p=0·017). Interpretation Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy. Funding Eli Lilly.

Summary Background The focal goal of this study is to identify optimal accumulation periods for ALA-induced PpIX in different healthy anatomical sites of human oral cavity and different types of abnormal mucosa to improve the accuracy of the clinical applications such as photodiagnosis and tissue grading. Materials and methods Laser-induced fluorescence (LIF) emission spectra, with excitation at 404 nm from a diode laser, were recorded with a miniature fiber-optics spectrometer from 13 anatomical sites of oral mucosa in 15 healthy volunteers and 30 suspicious sites in 15 patients after topical application of 0.4% 5-ALA solution for 15 min. The optimal accumulation time in different anatomical sites of healthy subjects and abnormal tissues were determined by studying the temporal variation in normalized fluorescence intensities (NFI) at 635, 685 and 705 nm. Results and discussions In masticatory anatomical locations such as (gingival and hard palate) and in lining mucosa (inner lip, soft palate, floor of mouth, transition to floor of mouth, alveolus and ventral tongue) except vermillion border of lip (VBL) of healthy subjects (designated as group I), it was observed that optimum time for maximum accumulation of PpIX is 90 min. In comparison, for lateral side of tongue (LST) and dorsal side of tongue (DST) tissues (designated as group II), maximum accumulation of PpIX was observed in 150 min of ALA application. For diverse grade lesions of group I mucosa in patients, maximum accumulation of PpIX was observed in 90 min, whereas, in group II mucosa the optimum accumulation time was 150 min as in the case of healthy mucosa. Further, between different grades oral mucosa, maximum variation in NFI take place at these optimal time periods. Conclusions The determination of the optimum accumulation time of ALA in oral mucosa based on NFI helps to improve the diagnostic contrast and accuracy of oral cancer diagnosis, and to plan appropriate timing for ensuing PDT.

Laser-induced autofluorescence (LIAF) and diffuse reflection spectroscopy (DRS) are two emerging noninvasive optical tools that have shown immense potential to detect oral cavity pre-cancer. In a recent study, we have used spectral ratio reference standards (SRRS) of LIAF intensity ratios F500/F635, F500/F685, and F500/F705 for grading of tissues belonging to sites other than dorsal side of tongue (DST), lateral side of tongue (LST), and vermillion border of lip (VBL) that exhibited similar spectral shape for normal and abnormal tissues. This led to dismal diagnostic accuracies, and for the three LIAF-SRRS, normal tissue values were often misclassified as squamous cell carcinoma (SCC), which means that the true negatives were being wrongly identified as true positives. This study examines the applicability of the site-specific diffuse reflection spectral intensity ratio (R545/R575) of the oxygenated hemoglobin bands to classify different DST lesions and compares the results obtained with those obtained using LIAF-SRRS. DRS-SRRS of R545/R575 differentiated benign hyperplastic DST tissues from normal tissue with a sensitivity of 86% and specificity of 80%, which were indistinguishable using LIAF-SRRS. Further, in distinguishing hyperplastic tissues from premalignant dysplastic lesions, DRS-SRRS gave a sensitivity of 90% and a specificity of 86%, as compared to sensitivity of 89% and specificity of 72% shown by the three LIAF-SRRS together. The diagnostic accuracy and statistical adequacy of the two techniques were assessed by receiver operating characteristic curve (ROC-Curve) analysis. Three LIAF ratios gave a low overall ROC area under curve (ROC-AUCs) of 0.521, whereas the DR ratio (R545/R575) has shown an improved accuracy of 0.970 in differentiating different tissue types. While distinguishing hyperplastic from dysplastic tissues, the DR ratio gave a higher discrimination accuracy of 0.9. Based on these findings, it can be concluded that the DRS-SRRS technique by virtue of its low cost and higher diagnostic accuracies could be a viable alternate to LIAF-SRRS for in vivo screening of tongue pre-cancers and grading of different tissue types.

Summary Background Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed—an antifolate antineoplastic agent—in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m 2 , day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B 12 , folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months [95% CI 4·1–4·7] vs 2·6 months [1·7–2·8]; hazard ratio [HR] 0·50, 95% CI 0·42–0·61, p vs 10·6 months [8·7–12·0]; HR 0·79, 0·65–0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p vs one [1%], p=0·001) and neutropenia (13 [3%] vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0·0001). Interpretation Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding Eli Lilly.

Background and Objectives: Low survival rate of individuals with oral cancer emphasize the significance of early detection and treatment. Optical spectroscopic techniques are under various stages of development for diagnosis of epithelial neoplasm. This study evaluates the potential of a multivariate statistical algorithm to classify oral mucosa from autofluorescence spectral features recorded in vivo. Study Design/Methods: Autofluorescence spectra were recorded in a clinical trial from 15 healthy volunteers and 34 patients with diode laser excitation (404 nm) and preprocessed by normalization, mean-scaling and its combination. Linear discriminant analysis (LDA) based on leaveone-out (LOO) method of cross validation was performed on spectral data for tissue characterization. The sensitivity and specificity were determined for different lesion pairs from the scatter plot of discriminant function scores. Results: Autofluorescence spectra of healthy volunteers consists of a broad emission at 500 nm that is characteristic of endogenous fluorophores, whereas in malignant lesions three additional peaks are observed at 635, 685, and 705 nm due to the accumulation of porphyrins in oral lesions. It was observed that classification design based on discriminant function scores obtained by LDA-LOO method was able to differentiate pre-malignant dysplasia from squamous cell carcinoma (SCC), benign hyperplasia from dysplasia and hyperplasia from normal with overall sensitivities of 86%, 78%, and 92%, and specificities of 90%, 100%, and 100%, respectively. Conclusions: The application of LDA-LOO method on the autofluorescence spectra recorded during a clinical trial in patients was found suitable to discriminate oral mucosal alterations during tissue transformation towards malignancy with improved diagnostic accuracies. Lasers Surg. Med. 41:345–352, 2009. 2009 Wiley-Liss, Inc.

Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. As the incidence of lung cancer is known to differ according to ethnicity, we have conducted a case-control study of 146 South Indian lung cancer patients along with 146 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of lung cancer in our population. The current weight of evidence from our study indicated that the frequency of CYP1A1 MspI homozygous variant alleles was significantly higher in cases (OR = 3.178). We observed a considerable difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR = 2.472, 95% CI: 1.191-5.094, P = 0.014). There was no relative risk in GSTM1 null genotype when analysed singly (P = 0.453). Considering genotype combinations, risk of lung cancer increased remarkably significantly in individuals having one variant allele of CYP1A1, GSTM1, or GSTT1, suggesting gene-gene interactions. Rare genotypic combinations (such as CYP1A1 wild GSTM1 or GSTT1 either null; CYP1A1 variant both GSTM1 and GSTT1 present; CYP1A1 variant GSTM1 or GSTT1 either null), were at higher risk compared to the reference group. Moreover, patients who had smoked20 pack years and harboured the CYP1A1 variant allele or the GSTT1 null genotype also had a significant risk of lung cancer. Hence our study-the first to analyse a South Indian population-suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.

Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. To explore the contribution of BRCA1 mutations to hereditary breast cancer among Indian women, we examined the coding sequence of the BRCA1 gene in 14 breast cancer patients with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation sensitive gel electrophoresis (CSGE) followed by sequencing. Three mutations (21%) in the BRCA1 gene were identified. Two of them are novel mutations of which one is a missense mutation in exon 7 near the RING finger domain, while the other is a one base pair deletion in exon 11 which results in protein truncation. The third mutation, 185 delAG, has been previously described in Ashkenazi Jewish families. To our knowledge this is the first report of a study of germline BRCA1 mutation analysis in familial breast cancer in India. Our data from 14 different families suggests a lower prevalence but definite involvement of germline mutations in the BRCA1 gene among Indian women with breast cancer and a family history of breast cancer.

Recent evidence has emphasized the importance of programmed cell death or apoptosis in the maintenance of tissue homeostasis and pathogenesis of tumors. This study, analyzed in breast cancer, investigates the significance of apoptosis in relation to the expression of p53 and bcl-2 proteins, tissue proliferation defined by Ki-67 expression, hormone receptors and tumor grade. The extent of apoptosis was defined by morphological criteria and the TUNEL (Tdt-mediated dUTP biotin nick end labelling) assay. Immunocytochemistry was performed for p53, bcl-2, estrogen receptor, progesterone receptor and Ki-67 expression. Mutant p53 protein was detected using a mutant specific ELISA. Immunoreactivity of p53 significantly correlated with the presence of mutant p53 protein detected by ELISA (r = 0.654, p = 0.00001). An inverse correlation was observed between bcl-2 expression and the extent of apoptosis (r = -0.33369, p = 0.01912). The extent of apoptosis directly correlated with p53 protein accumulation (r = 0.485, p = 0.00041), Ki-67 immunoreactivity (r = 0.435, p = 0.001), histopathological grade (r = 0.492, p = 0.0003), tumor size (r = 0.326, p = 0.023) and lymph node status (r = 0.287, p = 0.047). A direct correlation was also observed between p53 expression and Ki-67 immunoreactivity (r = 0.623, p = 0.0002). There was no statistically significant association between estrogen and progesterone receptor status and apoptosis. In addition, the TNM stage of the disease correlated with immunoreactivity of p53 (r = 0.572, p = 0.00012) and Ki-67 (r = 0.3744, p = 0.00818). Bcl-2, by inhibiting apoptosis, may cause a shift in tissue kinetics towards the preservation of genetically aberrant cells, thereby facilitating tumor progression. These results imply that rapidly proliferating tumors appear to have a high "cell turnover state" in which there may be an increased chance of apoptosis amongst the proliferating cells. The ability of apoptosis to also occur in the presence of mutant p53 protein suggests the existence of at least two p53-dependent apoptotic pathways, one requiring activation of specific target genes and the other independent of it.

Background and Objectives Breast cancer continues to frustrate oncologists worldwide. In India, it is the second most common neoplasm among women and is increasing in incidence. Several molecular markers have been associated with a poor prognosis in patients with breast cancer, and the presence of these markers is often thought to provide information on the biological behavior of the malignant breast tumor. Much attention has recently been focused on the tumor suppressor gene p53. Mutation or alteration in this gene leads to the loss of negative growth regulation and hence to rapid cell proliferation. The present study was designed to evaluate the connection between expression of the p53 protein and its relation to the tissue proliferative compartment as measured by expression of the proliferating cell nuclear antigen (PCNA). Methods Expression of p53 and PCNA were detected by immunocytochemistry in paraffin-embedded sections of infiltrating duct carcinoma and control breast tissue (normal tissue and adenoma). Results A significant correlation was observed between expression of p53 and PCNA. A significant correlation was also observed between expression of p53 and grade of tumor and stage of disease. Conclusions Our results support the hypothesis that accumulation of p53 is associated with a high tumor proliferation rate an association that might be expected in view of the role of wild p53 as a negative regulator of cell proliferation. J. Surg. Oncol. 1997;65:159–163 © 1997 Wiley-Liss, Inc.

Tissue homeostasis and the maintenance of cell populations depend on a delicate balance between the rates of cell proliferation and cell death. Programmed cell death or apoptosis is believed to play a major role in physiological processes which, when defective, could contribute to the pathogenesis and progression of tumors. A role for altered programmed cell death in cancer stems from the description of alterations on tumor-associated genes involved in the regulation of apoptosis such as p53 and bcl-2. The p53 gene promotes apoptosis in cells with genetic damage, while bcl-2 is an antiapoptotic gene. It is therefore possible that the balance between p53 and bcl-2 may have significant implications for the pathobiology of breast cancer. This study was therefore undertaken to evaluate the expression of these two proteins with opposite functions and their relation to the total growth fraction of the tumor as measured by PCNA immunoreactivity. A significant correlation was observed between expression of p53 and PCNA. In contrast, bcl-2 expression did not correlate with the expression of p53. There was also no correlation observed between expression of bcl-2 and PCNA. A significant correlation was observed between expression of p53 and the grade of the tumor and stage of the disease. Our results thus support the hypothesis that accumulation of p53 is associated with a high tumor proliferation rate, an association that might be expected in view of the role of wild-type p53 as a negative regulator of cell proliferation. Another important observation was the lack of relationship between bcl-2 expression and PCNA immunoreactivity, supporting the hypothesis that bcl-2 is not a major regulator of proliferation.

Low survival rate of individuals with oral cancer emphasize the significance of early detection and treatment. Optical spectroscopic techniques are under various stages of development for diagnosis of epithelial neoplasm. This study evaluates the potential of a multivariate statistical algorithm to classify oral mucosa from autofluorescence spectral features recorded in vivo.Autofluorescence spectra were recorded in a clinical trial from 15 healthy volunteers and 34 patients with diode laser excitation (404 nm) and pre-processed by normalization, mean-scaling and its combination. Linear discriminant analysis (LDA) based on leave-one-out (LOO) method of cross validation was performed on spectral data for tissue characterization. The sensitivity and specificity were determined for different lesion pairs from the scatter plot of discriminant function scores.Autofluorescence spectra of healthy volunteers consists of a broad emission at 500 nm that is characteristic of endogenous fluorophores, whereas in malignant lesions three additional peaks are observed at 635, 685, and 705 nm due to the accumulation of porphyrins in oral lesions. It was observed that classification design based on discriminant function scores obtained by LDA-LOO method was able to differentiate pre-malignant dysplasia from squamous cell carcinoma (SCC), benign hyperplasia from dysplasia and hyperplasia from normal with overall sensitivities of 86%, 78%, and 92%, and specificities of 90%, 100%, and 100%, respectively.The application of LDA-LOO method on the autofluorescence spectra recorded during a clinical trial in patients was found suitable to discriminate oral mucosal alterations during tissue transformation towards malignancy with improved diagnostic accuracies.

Background Laser-induced autofluorescence (LIAF) and diffuse reflectance (DR) were collectively used in this clinical study to improve early oral cancer diagnosis and tissue grading. Methods LIAF and DR emission from oral mucosa were recorded on a fiber-optic spectrometer by illumination with a 404-nm diode laser and tungsten halogen lamp in 36 healthy volunteers and 40 lesions of 20 patients. Results Absorption dips in LIAF spectra at 545 and 575 nm resulting from changes in oxygenated hemoglobin were corrected using DR spectra of the same site. These corrected spectra were curve-fitted using Gaussian spectral functions to determine constituent emission peaks and their relative contribution. The Gaussian peak intensity and area ratios F500/F635 and F500/F685 were found to be useful indicators of tissue transformation. The diagnostic capability of various ratios in differentiating healthy, hyperplastic, dysplastic, and squamous cell carcinomas (SCCs) were examined using discrimination scatterplots. Conclusions The LIAF/DR technique, in conjunction with curve-fitting, differentiates different grades of dysplasia and SCC in this clinical trial and proves its potential for early detection of oral cavity cancer and tissue grading. © 2009 Wiley Periodicals, Inc. Head Neck, 2010

Diffuse reflectance (DR) spectroscopy is a simple, low-cost, and noninvasive modality with potential for distinguishing oral precancer. Recently, in an ex vivo study, the DR spectral ratio (R545/R575) of oxygenated hemoglobin bands at 545 and 575 nm was used for grading malignancy. This work presents the results of clinical trials conducted in 29 patients to detect oral precancer using this ratio. We use site-specific normal spectra from a group of 36 healthy volunteers for comparison with those of patients. Toward this, in vivo DR spectra from 14 anatomical sites of the oral cavity of healthy volunteers are recorded on a miniature fiber optic spectrometer with white light excitation. The R545/R575 ratio is lowest for healthy tissues and appears to increase with the grade of malignancy. As compared to scatter plots that use the mean DR ratio from all anatomical sites, those using site-specific data show improved sensitivity and specificity for early diagnosis and grading of oral cancer. In the case of buccal mucosa, using scatter plots of R545/R575 ratio, we obtain a sensitivity of 100% and specificity of 86% for discriminating precancer (dysplasia) from hyperplasia, and a sensitivity of 97% and specificity of 86% for discriminating hyperplasia from normal.

Primary adenoid cystic carcinoma occurring in the orbital apex is rare. We present the clinical features of a patient who initially presented with the clinical and radiologic features of an orbital pseudotumor. He developed features of orbital apex syndrome and repeat imaging showed a tumor of the orbital apex with intracranial invasion. He underwent radical skull base surgery and pathologic examination revealed adenoid cystic carcinoma in the orbital apex with a normal lacrimal apparatus. He received post operative radiation and the outcome in the light of a review of available literature is being discussed.

The glutathione S-transferases (GSTs) are a superfamily of genes whose products are phase II enzymes, catalyzing the conjugation of reactive intermediates to soluble glutathione. Some of the GSTs are polymorphic and may play a role in lung cancer susceptibility. We investigated whether genetic polymorphisms of GSTM1, GSTP1 and GSTT1 genes modulated lung cancer risk and affect survival among lung cancer patients. We determined the GST genotypes in 422 study subjects, using polymerase chain reaction (PCR) and reverse PCR and restriction fragment length polymorphism (RFLP). Logistic Regression analysis was carried out to find the association of various polymorphisms and GSTs and lung cancer. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for deaths. GSTT1 -/- genotype conferred a higher odds ratio of 2.9 (P = 0.001) compared to the GSTT1+/+. So also, the GSTP1 GG genotype too had higher risk compared to the GSTP1 AA genotype (OR = 2.3, P = 0.033). When the combined GST M1, GSTT1 and GSTP1 genotypes were examined, patients with the combinations GSTM1 null and GSTT1 null had a significant OR of 3.6. So also the combinations GSTT1-/- GSTP1 AA (P = 0.005) and GSTT1-/- GSTP1 AG/GG (P = 0.001) came out to be significant. There were some significant interactions between GST genotypes with tobacco smoking and also for clinicopathological factors. Regarding survival analysis, no association of GSTM1 or GSTP1 genes with survival was noted. The GSTT1 -/- genotype along with stage was significantly associated with overall survival and found to be an independent prognostic factors for shorter lung cancer survival.

BACKGROUND Laser-induced autofluorescence (LIAF) is an emerging noninvasive technique in the biomedical field, especially for cancer detection. The goal of the study was to develop a spectral ratio reference standard (SRRS) to discriminate different grades of oral cancer. METHODS LIAF emission spectra from oral mucosa were recorded in the 420–720 nm spectral range on a miniature fiberoptic spectrometer from 14 anatomical sites of 35 healthy volunteers and 91 sites of 44 patients, with excitation at 404 nm from a diode laser. RESULTS Histopathologic analysis of biopsy samples showed that oral mucosa of adjoining malignant sites in patients are not usually normal, but showed various degrees of epithelial dysplasia and hyperplasia. Therefore, instead of using LIAF data from apparently normal lesions of patients as control, spectral data values of the oral mucosa of healthy volunteers were used as control. The autofluorescence emission at 500 nm is characteristic of oral mucosa, whereas in malignant lesions a new peak is seen at 685 nm in addition to the previously reported peaks at 635 and 705 nm. Three spectral ratio reference standard (SRRS) scatterplots were created to differentiate the normal mucosa from hyperplasia, hyperplasia from dysplasia, and dysplasia from squamous cell carcinoma (SCC) using the mean fluorescence intensity ratios (F500/F635, F500/705 and F500/F685) measured from 40 sites in 20 patients and 11 sites in 35 healthy volunteers. During blind tests at 21 sites in 17 patients all 3 SRRS plots showed 100% sensitivity and specificity to discriminate hyperplasia from dysplastic and normal tissues, whereas only the F500/F685 SRRS showed the same sensitivity and specificity to differentiate dysplasia from SCC. CONCLUSIONS An SRRS criteria based on scatterplots of autofluorescence spectral intensity ratios is described to discriminate oral mucosal variations and screen early stages of tissue progression toward malignancy. Cancer 2008. © 2008 American Cancer Society.

In response to many forms of cellular stress, including DNA damage, the p53 protein functions to induce growth arrest, DNA repair, or apoptosis. Common allele variants in the TP53 gene modulate pathways of lung carcinogenesis and susceptibility to or prognosis of lung cancer. The prognostic role of the polymorphism was assessed in 422 subjects using PCR-RFLP. Logistic regression analysis showed a dominant presentation of Pro/Pro homozygotes in lung carcinoma population than in control population (OR = 2.1, P = 0.003). We further investigated the association of p53 codon 72 polymorphism with prognosis in 170 lung cancer patients. Kaplan-Meier survival analyses showed a significant difference in survival between p53 variant genotypes and overall survival (P = 0.02). Cox regression analysis showed p53 Arg72Pro heterozygous genotype was overall an independent prognostic factor (Risk ratio of death, 2.2; P = 0.02), suggesting Pro72Pro genotype to be a potential risk factor favoring the development of lung carcinoma and that Arg72Pro genotype is independently associated with a poorer prognosis of lung cancer.

The role of fluorine-18 fluorodeoxyglucose. (18F-FDG) positron emission tomography. (PET)/computed tomography. (CT) in the initial staging of various malignancies is now well established. However, nonspecificity of FDG occasionally results in tracer uptake in benign lung lesions. The authors describe a complicated case of carcinoma stomach with multiple nodules and a cavitary lesion in lungs where 18F-FDG PET CT done for initial staging revealed FDG avid mass in stomach, FDG avid multiple mediastinal lymph nodes and multiple intensely FDG avid bilateral lung lesions. The FDG avid lung lesions turned out to be due to silicosis as confirmed by histopathology.

Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.

Argyrophilic nucleolar organizer regions (AgNORs) appear to be of diagnostic and prognostic significance in different types of human tumour. The present study examined the AgNOR counts in normal, premalignant and malignant oral mucosa to evaluate their potential as a biological marker for tumour progression and a prognostic predictor for treatment outcome in oral carcinomas. The Spearmann's rank correlation analysis between AgNOR counts and various stages of tumour progression in oral mucosa exhibited a highly significant positive coefficient (r(s) = 0.7969; por = 0.001), thus indicating the role of AgNORs in the early diagnosis of potentially malignant oral leukoplakia. When analyzing the prognostic significance of AgNOR in oral carcinomas, mean count2.8 concurred with poor prognosis in both univariate and multivariate analysis. Along with AgNOR counts, the T-status of disease was also found to be an independent predictor for treatment outcome in multivariate analysis. Thus T3 and T4 tumours, with mean AgNOR counts more than 2.8, are aggressive and may exhibit resistance to current treatment protocols.

Breast cancer is the single largest cancer and causes the high rate of cancer mortality among women. A positive family history of breast cancer is recognized as one of the major risk factors for this disease. The present study evaluates bleomycin (BLM)-induced chromosome sensitivity analysis in breast cancer families which provides indirectly a measure of the DNA repair defect of each person. BLM sensitivity assay on cultured lymphocytes of 36 familial breast cancer patients, their 85 first or second degree female relatives, 36 sporadic breast cancer patients and 40 age- and sex-matched controls (without any family history of cancer) were carried out to measure interindividual variation in their DNA repair capacity through mutagen-induced chromosome sensitivity analysis. Fifty percent of familial breast cancer patients and seven unaffected relatives showed hypersensitivity. Compared to hyposensitive relatives these seven subjects may be considered as high risk individuals.

7540 Background: Talactoferrin alfa (TLF), an immunomodulatory protein with a novel anti-cancer mechanism of action, was active preclinically and in non-small cell lung cancer (NSCLC) patients in Phase 1b studies. Randomized Phase 2 studies in NSCLC were conducted with TLF as a single agent and combined with chemotherapy. The 110-patient combination therapy study, which was previously presented (ASCO 2006, #7095), met its primary endpoint with an improved BOR over chemotherapy alone. We now present results from the placebo- controlled single agent study. Methods: 100 Stage IIIB/IV NSCLC patients who had progressed after first or second line therapy were enrolled at 10 leading Indian cancer centers, and randomized to receive best supportive care plus either oral TLF (1.5 g bid) or placebo. TLF/placebo was administered until disease progression, for up to three 14-week cycles (12 weeks on, 2 weeks off), in a centrally monitored trial. The primary endpoint was overall survival (OS) with 80% power to detect an improvement in median OS with an a=0.05. Results: All patients had previously received a 1st line platinum based regimen; 26 also received 2nd line therapy. The TLF and placebo arms enrolled 47 and 53 patients, respectively. Baseline characteristics were similar in both groups, including proportion of patients receiving 1 or 2 prior regimens. All patients were included in the Intent To Treat (ITT) analysis. The trial met its primary endpoint with a 55% increase (2.1 month; p [Table: see text] [Table: see text]

7095 Background: Talactoferrin alfa (TLF) is an oral immunomodulatory protein with a novel mechanism. TLF showed preclinical anti-cancer activity alone and in combination with chemotherapy. In Phase I/II trials, TLF was safe with apparent single-agent anti-cancer activity in non-small cell lung cancer (NSCLC). Methods: 110 chemo-naive patients with advanced or metastatic NSCLC were randomized (1:1) in a multi-center trial to carboplatin/paclitaxel (C/P) therapy plus either TLF or placebo. Starting the day after C/P (C:AUC 5 mg/mL/min; P:175 mg/m2) in chemo-cycles 1, 3 and 5, oral TLF (1.5 g BID) or placebo was administered in 35-day cycles for up to three cycles or until progression. Primary endpoint was Confirmed Response Rate (RR; PR+CR) by CT using RECIST. Secondary endpoints included Progression Free Survival (PFS) and Overall Survival (OS). Results: Baseline patient and disease characteristics were comparable in both groups. All 110 patients were included in the Intent To Treat (ITT) population. 100 patients with at least one CT scan after starting treatment were prospectively defined as the Evaluable population. Adding oral TLF to C/P enhanced efficacy on all endpoints examined including RR, PFS and OS. Confirmed RR in the 100 evaluable patients significantly increased from 29% to 47% (P = 0.05). Confirmed RR in the 110 ITT patients improved from 27% to 42% (P = 0.08). Median PFS in both evaluable and ITT patients improved by 2.8 months (67%). Median OS improved by 31% and 18% in evaluable and ITT patients, respectively. A landmark analysis comparing survival in patients with and without a PR showed a significant difference (P < 0.01), suggesting a strong association between RR and survival. TLF appeared to be very safe and well tolerated with no drug-related SAEs. Fewer AEs were observed in the TLF arm than in the placebo arm, 346 and 432 AEs, respectively (P = 0.0023). The number of Grade 3/4 AEs was also lower in the TLF arm, 60 versus 91 (P = 0.0144). Conclusions: Adding oral TLF to standard C/P chemotherapy in NSCLC was safe and increased efficacy in a randomized, multi-center, double-blind, placebo-controlled trial, with apparent improvements in RR, PFS and OS. Results with TLF compare favorably to other anti-cancer agents. Oral TLF will be further evaluated in a Phase III trial. [Table: see text]

Introduction: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. Methods: Patients ( n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29–47%; p = 0.05) and 15% (27–42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. Conclusion: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.