Unfavorable Clinical Course Research Articles

Traumatic hand amputations, the analysis of medical aid on different levels of rural healthcare

Aim. The analysis of diagnostic and management measures offered for patients with traumatic hand amputations at different levels of rural healthcare. Methods. The medical charts of 115 patients [including 98 (85.2%) in-patients] aged 14 to 67 years with complete and incomplete traumatic hand amputation treated since 1985 to 2010 were analysed. Results. 81 (70.4%) of patients were of working age, 18 (15.7%) - adolescents (up to 18 years of age). 65 (56.5%) of patients were blue-collar workers, 6 (5.2%) - white-collar workers, 19 (16.5%) - students, 12 (10.4%) - unemployed, 13 (11.3%) - retired. Occupational injuries were registered in 25 (21.7%) of patients, including 24 (36.9%) blue-collar workers and 1 (16.7%) white-collar worker. Traumatic hand amputations due to incised wounds were registered in 1 (0.9%) case, due to bites - 1 (0.9%) case, due to chopped wound - in 26 (22.6%) cases, due to lacerated wounds - in 35 (30.4%) cases, due to high-energy trauma - in 45 (39.1%) cases. No trauma mechanism was registered in patient’s medical charts for 7 (6.1%) cases. Traumatic hand amputations at wrist level were registered in 2 (1.7%) cases, at finger level - in 113 (98.7%) cases. The primary care was provided in regional paramedic stations and regional hospitals to 71 (61.7%) patients. High-energy traumas had the most unfavorable clinical course and were associated with worst prognosis. The chosen reconstructive surgery type depended on the mechanism of trauma, wound shape and size and the condition of surrounding tissues. The local reconstructive surgery was the most frequent choice. Complications were observed in 11.2% of cases (in 27.1% of high-energy trauma cases). Patients became constantly disabled in 4.3% of cases. Most of the medical errors were made at primary care level, including unjustified rejection of wound debridement and improper finger stump debridement. Conclusion. To optimize the medical aid for patients with traumatic hand amputations a continuous theoretical training of medical staff, providing emergency care, in quarterly seminars, is needed. Patients with traumatic hand amputations should be admitted directly to the hospital emergency room, bypassing the outpatient services.

OP050: Expression of fascin in squamous cell carcinoma of the oral cavity: Clinicopathological, prognostic significance and cell line study

Head and neck squamous cell carcinoma (HNSCC) is one of the most common head and neck cancers. The prognosis of HNSCC is usually poor because of extensive local invasion at initial diagnosis. Fascin, an actin-bundling protein, has been reported responsible for cell motility and overexpression of Fascin contributes to an unfavorable clinical course in several malignancies. Nevertheless, the roles of Fascin protein playing in aggressiveness of HNSCC and their potential mechanisms need to be elucidated. Tca8113(cell lines of OSCC) via the vector-based small interfering RNA (siRNA) to suppress the expression of the Fascin gene were used. Subsequent analyses and observation regarding the expression of Fascin protein and cyto-morphological alterations were detected by Western blot and Boyden chamber invasion assay, cell migration assay and adhesion assay were also applied to investigate the functional changes of Tca8113. Paraffin sections using tissue microarrays of 84 patients with OSCC were investigated immunohistochemically, to determine the level of expression of Fascin labelling index in tumor specimens. The role of Fascin in OSCC was evaluated by correlation with clinical-pathological parameters. There were statistically significant differences ( P < 0.05) of Fascin expression before and after silencing. Down-regulation of Fascin protein directly resulted in suppression of migration, invasion and increase of adhesion in cell line ( P < 0.05). Overexpression of Fascin was significantly associated with regional lymph node metastases ( P = 0.044),advanced T stage (T1 vs T2-4, P = 0.046) advanced tumor stage (I/II vs III/IV, P = 0.049), histologic grade (well vs moderately/poorly, P = 0.018). In 54 patients with tongue carcinoma, overexpression of Fascin was significantly associated with muscle invasion ( P = 0.002). Our results suggest that expression of Fascin protein may play an essential role in regulation of progression of OSCC. Overexpression of Fascin contributes to a more aggressive clinical course and suggests that Fascin has the potential of being a new molecular target for therapeutic intervention.

Abstract 263: Identification of subgroup of triple negative breast cancer by cancer stem cell markers.

Abstract [Background] Anti-cancer agents are essential for treating triple negative breast cancer (TNBC). The cases resistant to them showed unfavorable clinical courses and thus may require novel agents. It is crucial to predict the efficacy of existing agents in TNBC. Recently, cancer stem cell (CSC) theory has drawn an attention in relation to TNBC and chemoresistance. Aldehyde dehydrogenase 1 (ALDH1) is a biomarker of breast cancer stem cell. [Aims] In order to subdivide TNBC and finally find subgroup resistant to existing anti-cancer agents and better markers for stem cell phenotype. [Methods] 1)The expression of ALDH1 was examined immunohistochemically in each subtype of 447 breast cancer patients. 2)The expression of ALDH1 and its association with Ki-67,P53, CK5/6 or EGFR were examined in TNBC. 3)Correlation between ALDH1 and pathological response by neoadjuvant chemotherapy was examined. 4)ALDH1 positive and negative cells were collected by microdissection from 5 ALDH1 positive breast cancer cases. The expression profile was assessed by Affymetrix cDNA microarray. The difference of profile between ALDH-1 positive and negative cells was assessed. [Results] 1)The expression rate of ALDH1 was 4.5% in Luminal type, 11.1% in Luminal-HER2 type, 23.8% in HER2-enriched type and 33.6% in triple negative type. ALDH1 was expressed highly in TNBC. 2)In 79 TNBC with neoadjuvant chemotherapy, 29 cases(36.7%) was positive for ALDH1.The averages of NG, Ki67 and p53 were 2.7, 37.8% and 37.7% respectively in ALDH1 positive TNBC. 80% of them were positive for CK5/6 or EGFR. There was no significant correlation between ALDH1 and these pathological markers. 3) Poorly responsiveness to NAC (0-1b) was found in 17 cases (21.5%). Only ALDH1 was associated with chemoresistance to NAC (P=0.033), suggesting ALDH1 positive TNBC were resistant to anticancer agents. 4)63 and 41 genes were up- and down-regulated respectively in ALDH1 positive cells. These potential related genes are now under investigation. [Conclusions] ALDH1 could be a marker for chemoresistance in TNBC. As ALDH1 identifies some specific subpopulation of breast cancer, further studies will provide important information on subdividing TNBC and individualizing treatment of this intractable subtype. Citation Format: Kumiko Kida, Takashi Ishikawa, Akimitsu Yamada, Kazuhiro Shimada, Kazutaka Narui, Sadatoshi Sugae, Daisuke Shimizu, Mikiko Tanabe, Takeshi Sasaki, Yasushi Ichikawa, Itaru Endo. Identification of subgroup of triple negative breast cancer by cancer stem cell markers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 263. doi:10.1158/1538-7445.AM2013-263

Detection ofABL1kinase mutations in Philadelphia-positive patients exhibiting an inadequate molecular response using restriction fragment mass polymorphism and its clinical significance: a single-center experience in Korea

ABL1 kinase mutations represent a major mechanism of imatinib resistance in Philadelphia-positive (Ph+) patients. There is a paucity of data on ABL1 kinase mutations in Ph+ patients in Korea. We used restriction fragment mass polymorphism (RFMP) analysis to detect ABL1 kinase mutations in blood or bone marrow specimens from 80 Ph+ patients. Fifty-seven patients met the criteria for inadequate molecular response (IMR). ABL1 kinase mutations were found in 2.6% of patients with chronic-phase chronic myelogenous leukemia (CML), 25.0% of accelerated-phase CML, 66.7% of blast-phase CML, and in 58.3% with Ph+ acute lymphoblastic leukemia. Twelve mutations were identified: 7 T315I, 2 E255V, 1 E255K, 1 F359V, and 1 Y253H. The majority of mutation-positive patients showed an unfavorable clinical course and often had an extra Ph or additional chromosomal abnormalities. Mutations were detected in two patients who had very low or absent BCR-ABL1 normalized ratios. Mutation analysis should be performed in Ph+ patients exhibiting an IMR to imatinib. RFMP analysis is helpful for revising therapeutic strategies because it can sensitively detect clinically relevant ABL1 kinase mutations with high frequencies.

The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL

AbstractAbstract ▪3892▪This icon denotes a clinically relevant abstract Background:13q deletions (del(13q)) are the most frequent abnormalities in CLL and, if present as a sole abnormality, associated with favorable outcome. Since the size of the deletion varies considerably, class I (del(13q) not including the RB1 locus) and class II (del(13q) including the RB1 locus) deletions were defined. Previous data suggested that class II deletions were associated with genomic complexity and an unfavorable clinical course. However, confirmation in a large patient cohort was lacking. Aim:Cytogenetic and molecular genetic characterization of patients with class I and class II deletions and evaluation of the impact on outcome. Patients and Methods:263 cases with newly diagnosed CLL and del(13q) were analyzed by FISH using probes for RB1, D13S25, D13S319 (13q14), ATM (11q22), TP53 (17p13), SEC63 (6q21) and 12 cen. Data from chromosome banding analyses (CBA) (n=263), IGHV mutation status (n=230) and TP53 mutation status (n=206) were also available. Results:145/263 patients (55.1%) showed a class I and 118 cases (44.9%) a class II deletion. In 79/263 patients (30%) a homozygous del(13q) was observed. No significant difference in frequency of homozygous deletions was observed between cases with class I vs class II deletions (48/145 (33.1%) vs 31/118 (26.3%)). Abnormalities in addition to del(13q):Based on FISH data 66 cases (25.1%) showed abnormalities in addition to del(13q) (del(6q): 5, del(11q): 28, +12: 27, del(17p): 11). The frequency of additional abnormalities did not differ between patients with class I vs class II deletions (25.5% vs 24.6%). Considering also CBA 101 patients (38.4%) showed additional abnormalities. A complex karyotype defined as 3 or more abnormalities in addition to del(13q) was observed in 34 cases (12.9%) and was more frequent in cases with class II deletion (17.8% vs 9.0%, p=0.042). The mean number of abnormalities per case was significantly higher in patients with class II deletions (1.25 vs 0.7, p=0.002). Patients with homozygous del(13q) less frequently showed additional chromosome abnormalities compared to patients with heterozygous del(13q) (22.8% vs 45.1%, p=0.001).IGHV mutation status: In the total cohort, 156/230 patients (67.8%) showed a mutated and 74 (32.2%) an unmutated IGHV status. No difference with respect to the IGHV mutation status was observed between class I vs class II cases. However, an unmutated IGHV status was more frequent in cases with additional abnormalities detected by FISH or CBA compared to those without (52.6% vs 25.4%, p<0.0001 and 48.3% vs 22.4%, p<0.0001). A mutated IGHV status was more frequent in patients with homozygous as compared to heterozygous del(13q) (81.2% vs 62.1%, p=0.005).TP53 mutation status:TP53 mutations were observed in 15/206 cases (7.3%). The TP53 mutation frequency did not differ between class I vs class II patients (6.9% vs 7.8%). However, TP53 mutations were more frequent in cases with additional abnormalities detected by FISH or CBA as compared to those without (18.8% vs 3.8%, p=0.002 and 13.2% vs 3.8%, p=0.023), in cases with complex karyotype (19.2% vs 5.6%, p=0.027), and in cases with TP53 deletions detected by FISH as compared to those without (70.0% vs 4.1%, p<0.0001). Overall survival and time to treatment:OS at 3 yrs in the total cohort was 94% (median time of follow-up of 3.0 yrs). Only Binet stage B/C was significantly associated with shorter OS (p=0.014; relative risk (RR): 6.56). A trend for shorter OS was observed for additional TP53 mutations and/or deletions, while no difference in OS was observed between class I vs class II and homozygous vs heterozygous deletions. The following parameters were associated with longer TTT: no additional abnormalities present in CBA or FISH (p=0.009; RR: 0.55; p=0.010; RR: 0.54), and a mutated IGHV status (p<0.0001; RR: 0.381). A complex karyotype (p=0.040; RR: 1.80) and ATM deletions (p=0.013; RR: 2.04) were associated with shorter TTT. Conclusions:1. Neither the size nor homozygosity of del(13q) showed impact on OS or TTT. However, a mutated IGHV status and the absence of additional abnormalities were associated with longer TTT. Patients with an additional del(11q) or a complex karyotype showed shorter TTT. 2. A complex karyotype was significantly associated with class II deletions. 3. CLL with del(13q) can be further subdivided by the RB1 deletion status, additional chromosome abnormalities based on CBA and IGHV mutation status. Disclosures:Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

CORRELATION BETWEEN CLINICAL MANIFESTATIONS OF OSTEOARTHRITIS AND FLUCTUATING BLOOD LEVELS OF INTERLEUKIN 6

Objective — to evaluate associations between fluctuating interleukin 6 (IL6) levels and clinical manifestations of osteoarthritis (OA). Material and methods. Totally 81 patients aged 47—73 y.o. with OA diagnosis, meeting ACR criteria, were evaluated. Anthropometric measurements, duration of the disease, degree of functional disability, IL6 levels and joints radiographs were assessed in all patients. Correlation between different IL6 secretion levels and the severity of OA clinical course and of pain syndrome was also analyzed. Results and discussion. Elevated IL6 levels were associated with more pronounced radiographic structural damage, greater degree of functional disability, presence of synovitis and more severe pain syndrome. Therefore, elevated IL6 levels are associated with unfavorable clinical course of OA.

O1-032 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Pulmonary Fibrosis (PF) and Advanced Non-Small-Cell Lung Cancer (NSCLC)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil, and oteracil potassium. Although most of the anti-cancer agents have pulmonary toxicity, post marketing surveillance reported that S-1 has lower pulmonary toxicity incidence. We have conducted a feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0–2 and chemo-naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80 mg/m2/day) on day 1 to 14 for four to six cycles. End points were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 patients (19 males/2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3 patients, 2: 3 patients, 3: 3 patients, 4: 10 patients, 5; 1 patient, 6: 1 patients. Partial responses were observed in 7 patients (RR; 33%). The median progression-free survival duration was 4.0 months, and the median overall survival duration in 10.4 months. During the treatment, two patients experienced moderate deterioration of pulmonary fibrosis, one experienced infectious pneumonia—all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

Case of high‐risk epithelioid hemangioendothelioma of the neck

Epithelioid hemangioendotheliomas (EHEs) of the head and neck region are uncommon malignant neoplasms that exhibit various biologic behaviors characteristic of both low- and high-grade malignancy. A subgroup of EHEs identified as "high-risk" EHEs because of their size and mitotic activity is associated with an unfavorable clinical course and poor prognosis. We describe the treatment of the first and, in terms of size, largest case of high-risk EHE arising from the neck. Despite wide excision, recurrence occurred 9 months after surgery, as had been expected. However, the tumor was found to express both vascular endothelial growth factor (VEGF) and VEGF receptor 2, indicating the potential of anti-VEGF therapy in the treatment of such cases. The finding that a high-risk EHE arising from the head and neck region is characterized by expression of VEGF and its receptor provides further support for the development of targeted molecular therapies.

1334 - A Prospective, Feasibility Study of S-1 and Carboplatin for Patients with Advanced Non Small Cell Lung Cancer (NSCLC) Concomitant with Pulmonary Fibrosis (PF)

ABSTRACT Background PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent has pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo-naive patients were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials. Disclosure All authors have declared no conflicts of interest.

Loss of SLC45A3 protein (prostein) expression in prostate cancer is associated with SLC45A3‐ERG gene rearrangement and an unfavorable clinical course

The majority of prostate cancer harbors recurrent gene fusions involving ETS transcription factors, most commonly ERG. The second most common 5' fusion partner after TMPRSS2 is SLC45A3. The aim of our study was to quantify the protein expression of ERG, TMPRSS2 and SLC45A3 in prostate cancer to assess for diagnostic or prognostic utility. Six hundred and forty consecutive prostate cancer cases in tissue microarray format were immunohistochemically analyzed for ERG, TMPRSS2 and SLC45A3 protein. Resultant protein expression data was correlated to the respective gene rearrangement status and clinico-pathological parameters including PSA follow up times. ERG showed no expression in benign prostate glands. In cancer tissue, ERG protein expression showed a high rate of concordance with an underlying ERG rearrangement (91.5%). SLC45A3 showed a weaker expression in cancer as compared to benign tissue, which was pronounced in cases with SLC45A3-ERG fusion. Importantly, SLC45A3 down regulation was significantly associated with shorter PSA-free survival times. In contrast, TMPRSS2 was neither differentially expressed nor did it show a correlation between protein expression and rearrangement status. This study provides first evidence that the expression of SLC45A3 protein is down regulated through SLC45A3-ERG fusion in prostate cancer. Moreover, these cases may represent a distinct molecular subclass of ERG rearranged prostate cancer with distinct clinical features. This study also confirms that ERG protein expression is predominantly found in prostate carcinomas with ERG gene rearrangement and does not occur in benign glands.

Influence of Prereferral Surgery in Soft Tissue Sarcoma: 10 Years’ Experience in a Single Institution

Soft tissue sarcomas are a group of rare mesenchymal neoplasms comprising 0.8% of all malignant tumors. Workup should include medical history, physical examination, magnetic resonance imaging, biopsy, and thoracoabdominal computed tomography scan, in that order. Centralized multimodality treatment in a cross-disciplinary setting is mandatory. Treatment not according to current clinical practice guidelines is a common problem before referral to a specialized institution. The purpose of this 10-year, single-institution review was to investigate the influence of curative surgery on outcome, with a special emphasis on surgery before referral. A cohort of 266 patients who underwent curative surgery for soft tissue sarcoma between 1998 and 2008 was analyzed. One hundred thirty-one (49%) patients underwent surgery contrary to current clinical guidelines before referral, most (73%) at primary care units. One hundred thirteen (86%) of these patients underwent surgery without previous biopsy with a higher rate of intralesional margins (P<.001), a smaller mean diameter of primary lesion (P<.001), a higher rate of subcutaneous situs (P<.001), a lower mean American Joint Committee on Cancer score (P=.008), a higher rate of additional plastic surgery after re-resection (eg, flap surgery) (P<.001), and a longer period before referral (P<.001). No influence on survival, local recurrence, or metastasis existed. Prereferral surgery necessitating re-resection has no influence on survival but leads to an unfavorable clinical course. More effort should be made to improve awareness and referral modalities for general practitioners and physicians at community hospitals.

Hepatitis B e antigen‐suppressing mutations enhance the replication efficiency of adefovir‐resistant hepatitis B virus strains

Hepatitis B e antigen (HBeAg) negative hepatitis B virus (HBV) infections caused by precore (PC) or basal core promoter (BCP) mutations are associated with disease progression and complications. PC or BCP mutations may enhance the replication capacity of distinct drug-resistance-associated polymerase mutations, but their effect on adefovir-resistant HBV mutants is unclear. Importantly, BCP mutations were an independent risk factor for virological breakthrough in lamivudine-resistant patients treated with adefovir. We aimed at addressing the functional consequences of PC and BCP mutations on the replication and drug susceptibility of adefovir-resistant HBV mutants. Therefore, HBV constructs with wild type (WT) or adefovir-resistant rtN236T, rtA181V and rtA181T mutations, with or without concomitant PC or BCP mutations, were analysed in vitro using molecular assays. The adefovir-resistant polymerase mutations rtN236T, rtA181V and rtA181T showed a drastically reduced viral replication compared with WT. Interestingly, additional PC or BCP mutations enhanced the reduced replication efficacy of adefovir-resistant constructs and restored HBV replication to WT level. HBV rtA181T mutants displayed abolished hepatitis B surface antigen (HBsAg) secretion, owing to a sW172* stop codon in the overlapping envelope gene. All rtN236T- or rtA181V/T-containing constructs, regardless of concomitant PC or BCP mutations, were resistant to adefovir, but remained susceptible to telbivudine, entecavir and tenofovir. In conclusion, adefovir drug resistance mutations reduced viral replication, which can be significantly increased by additional HBeAg-suppressing PC or BCP mutations. Because increased HBV replication in HBeAg-negative patients has been associated with an unfavourable clinical course, close monitoring appears indispensable during adefovir treatment in HBeAg-negative patients.

The Prognostic Significance of Lower Uterine Segment Involvement in Endometrioid Endometrial Adenocarcinoma

Endometrial carcinoma is the most common gynecologic malignancy in the United States. Prognostic factors include tumor stage, FIGO grade, lymphovascular invasion (LVI), and nodal metastasis. Lower uterine segment involvement (LUSi) has not been considered an independent prognostic factor; however, it may be predictive of an unfavorable clinical course. We gathered histologic data regarding prognostic indicators from patients with endometrioid …

The effect on patients with pulmonary fibrosis (PF) and advanced non small cell lung cancer (NSCLC): A prospective, feasibility study of S-1 and carboplatin.

e19583 Background: PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent have pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods: Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results: From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions: This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

Prognostic significance of del 17p, ZAP-70 and CD38 as independent indicators for B-CLL: correlation to response to treatment and disease outcome

Prognostic markers as CD38 and ZAP-70 and specific chromosomal abnormalities as del 17p have now been developed to refine the risk of progressive disease in chronic lymphocytic leukemia (CLL). This study analyzed 40 recently diagnosed, untreated B-CLL patients for CD38 and ZAP-70 expression by flow cytometry and for del 17p by conventional cytogenetics (CCG) and by fluorescence in situ hybridization (FISH) technique to evaluate their effect on the clinical course of CLL and as risk factors for disease progression in addition to their impact on response to treatment and disease outcome. Twenty healthy age- and sex-matched subjects were included as a control. The results revealed that CD38 and ZAP-70 expression were detected in 42.5% and 47.5% of cases, respectively. They were associated with an unfavorable clinical course. Higher levels were significantly associated with increased risk of unfavorable response to treatment (P=0.003), with poor clinical outcome (P=0.0001). Del 17p was detected in 35% of cases by FISH technique and in 7.5% by CCG. The deletion was significantly associated with progressive clinical course; poor response to treatment (P=0.007) but not with disease outcome (P=0.103).Combined analysis of ZAP-70 and CD38 yielded concordantly negative results in 50% of patients and concordantly positive results in 40% of patients, while 10% were discordant. CD38+/ZAP-70+ patients were significantly associated with progressive disease (P<0.05) and with del 17p than CD38−/ZAP-70- patients (P=0.008).Time to disease progression (TDP) was 6months among CD38+/ZAP-70+ patients as compared to 16months in CD38−/ZAP-70− patients. In patients with discordant results, the TDP was 9months. Over-representation of the three parameters (CD38, ZAP-70 and del 17p) was detected in 22.5% of cases, and pointed towards even shorter TDP (4.5months), more aggressive disease; more resistance to chemotherapy and poor outcome thus providing a precise tool for identifying high-risk patients.In conclusion, the combined expression of CD38 and ZAP-70 together with del 17p in CLL is a precise diagnostic tool for identifying high-risk patients and convey rapid progression; they are accurate predictors of clinical outcome thus could be used to indicate when more novel chemotherapeutic approaches are needed and provided help in guiding individual patient treatment.

Clinical, serological and genetic predictors of inflammatory bowel disease course

Patients with extensive or complicated Crohn's disease (CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines. In patients with localized and uncomplicated CD at diagnosis, early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact. In this context, there is a need for predictors of benign or unfavourable subsequent clinical course, in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions. At diagnosis, an age below 40 years, the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course. The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts. Consequently, the use of these predictors can be integrated into the elements that influence individual decisions. In the CD postoperative context, keeping smoking and history of prior resection are the strongest predictors of disease symptomatic recurrence. However, these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice. In ulcerative colitis (UC), extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease, and also with long-term colectomy and colorectal inflammation-associated colorectal cancer. In patients with extensive UC at diagnosis, a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered. At the moment, no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.

A Gastrointestinal Stromal Tumor of the Stomach Demonstrating a Stepwise Progression from Low- to High-Grade Malignancy

We report a case of a gastrointestinal stromal tumor (GIST) of the stomach that demonstrated a stepwise progression from low- to high-grade malignancy. The patient had been followed for a small gastric submucosal tumor that had turned malignant after 8 years of indolence, manifested by tarry stools. The tumor was enucleated, and gastric GIST was diagnosed. The most significant histological finding was that the tumor comprised two clearly demarcated areas, one with less aggressive characteristics and the other with highly aggressive characteristics. The patient exhibited multiple liver metastases 24 months after surgery. Imatinib mesylate was not administered throughout the clinical course because it was not available for clinical use at that time. The patient followed an unfavorable clinical course and died of liver dysfunction 55 months after surgery. Autopsy was performed. By comparing the immunohistochemical profiles of primary and metastatic tumors, it was established that only the tumor cells with highly aggressive characteristics had metastasized.

The Impact of Cyclooxygenase-2 and Vascular Endothelial Growth Factor C Immunoexpression on the Prognosis of Penile Carcinoma

We assessed the influence of cyclooxygenase-2 and vascular endothelium growth factor-C immunoexpression on groin metastasis and cancer survival, and their association with histological variables in patients with penile carcinoma. We evaluated the histological and cyclooxygenase-2/vascular endothelium growth factor-C immunohistochemical profiles of patients with penile carcinoma treated at a single institution between 2001 and 2008. Univariate and multivariate analysis was done to determine the impact of histological and immunohistochemical markers on the risk of inguinal metastasis and on cancer survival. Survival analysis of relevant variables was also done. Of the 127 patients enrolled 76 and 30 had positive cyclooxygenase-2 and vascular endothelium growth factor-C immunoexpression, respectively. Univariate analysis identified an association between vascular endothelium growth factor-C immunoexpression and groin metastasis, and certain histological variables. Logistic regression showed that high tumor grade, Jackson stage and vascular endothelium growth factor-C immunoexpression were independent predictors of inguinal metastasis. Cancer survival was only influenced by advanced Jackson stage and groin metastasis. Findings suggest that vascular endothelium growth factor-C expression may help identify patients with an unfavorable clinical course of penile carcinoma. Cyclooxygenase-2 did not alter the risk of groin metastasis or cancer death. Inguinal disease and advanced Jackson stage were independent prognostic factors for worse cancer survival.

ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression

The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.

Expression of Claudins and Their Prognostic Significance in Noninvasive Urothelial Neoplasms of the Human Urinary Bladder

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.