You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Cyclin D1 and Cancer Development in Laryngeal Premalignancy Patients
Abstract 1:
In a previous trial , we found that combined 13-cis-retinoic acid , IFN-α , and α-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 ( CD1 ) G/A870 single nucleotide polymorphism correlated with cancer risk . We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1 , both genotype and protein expression , in association with cancer risk in this setting . Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily , α-IFN twice weekly , and α-tocopherol daily for 1 year ; 14 nonprogressing patients then were r and omized to maintenance fenretinide or placebo for 2 years . During induction , two patients had pathologic complete responses , six had partial responses ( 30 % overall response rate ) , and five developed laryngeal cancer . There were no significant differences between maintenance fenretinide and placebo in response or cancer rates . Ten patients developed cancer overall . Twenty-four patients were evaluated for the CD1 G/A870 genotype , and 23 for pretreatment and posttreatment CD1 protein expression . Consistent with our earlier report , shorter cancer-free survival was associated with the CD1 AA/AG genotype ( P = 0.05 ) . Extending our earlier work , high CD1 expression was associated with worse cancer-free survival overall ( P = 0.04 ) and within each CD1 genotype group . These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription


Title 2:
Prognostic value of CD44 variant 6 in laryngeal epidermoid carcinomas.
Abstract 2:
BACKGROUND CD44 variant exon 6 ( v6 ) belongs to a family of transmembrane glycoproteins involved in cell adhesion . OBJECTIVES To determine the prognostic role of CD44v6 in laryngeal cancer and to examine its relation with other clinicopathologic prognostic factors . DESIGN A retrospective cohort study was design ed with 93 laryngeal cancer cases . They were selected r and omly from patients treated with laryngectomy between January 1 , 1983 , and December 31 , 1993 . SETTING Faculty of Medicine , Hacettepe University , Ankara , Turkey . PATIENTS The ages of the patients ranged from 31 to 73 years . Eighty-eight patients were men and 5 were women . Three had stage I , 33 had stage II , 27 had stage III , and 30 had stage IV disease at the time of surgery . INTERVENTION Histological sections of tumors and metastatic lymph nodes were reevaluated for several histopathological factors . Sections were stained using anti-CD44v6 monoclonal antibody by immunohistochemical methods . RESULTS CD44v6 expression was seen only in the lower one third of the normal squamous epithelium but in all layers of dysplasia and in situ carcinoma . Besides a general evaluation of tumor staining , immunostaining was evaluated separately for cell groups located in the center of neoplastic isl and s ( nonbasal cells ) , at the periphery of the neoplastic isl and s ( basal cells ) , and at the infiltration zones ( marginal cells ) . Decreased disease-free survival was noted when there was extensive staining in the general evaluation and in cases with extensive staining in marginal and nonbasal cells ( P = .03 ) . Using Cox regression analysis , the greatest dimension of the largest metastatic lymph node and extensive expression of CD44v6 in nonbasal tumor cells were independent prognostic factors . CONCLUSION Our results suggest that CD44v6 expression is an important prognostic factor in laryngeal cancer


Title 3:
Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer.
Abstract 3:
BACKGROUND Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract ( UADT ) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy ( 13-cis-retinoic acid , alpha-interferon , and alpha-tocopherol ) . Both alleles of the adenine (A)/guanine ( G ) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts , but the A allele preferentially encodes a protein with an extended half-life . We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein , post-treatment modulation of cyclin D1 protein levels , histologic response to treatment , and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy . METHODS UADT tissue biopsy sample s were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions . Tissues were examined for cyclin D1 genotype ( by DNA single-str and conformation polymorphism analysis ) , for cyclin D1 protein expression ( by immunohistochemistry ) , and for cyclin D1 gene copy number ( by fluorescence in situ hybridization ) . Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated . All statistical tests were two-sided . RESULTS The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer ( 16 of 18 AA/AG subjects versus four of nine GG subjects ; P = .02 ) , decreased histologic response to biochemopreventive treatment  ( six of 21 AA/AG subjects versus four of 10 GG subjects ; P = .70 ) , decreased favorable modulation of cyclin D1 expression by the treatment ( seven of 18 AA/AG subjects versus eight of nine GG subjects ; P = .02 ) , and shorter progression-free survival ( P = .05 ) . CONCLUSIONS The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1 , a decreased likelihood of response to biochemopreventive  intervention , and an increased rate of progression to cancer development , findings that require validation in a larger cohort


Title 4:
p53 immunostaining and image cytometry DNA analysis in precancerous and cancerous squamous epithelial lesions of the larynx.
Abstract 4:
BACKGROUND Squamous epithelial cancer can develop from progressive epithelial changes connoted dysplasias . Histopathologic evaluation/grading of these lesions is difficult and gives poor information concerning the risk for progression to cancer . Squamous cell carcinoma of the head and neck ( SCCHN ) frequently show p53 alteration and DNA-ploidy aberration . Could these markers be used as indicators for malignancy risk in the larynx ? METHODS Immunohistochemical staining ( IHC ) , with the CM-1 antibody against p53 , and image cytometry ( ICM ) DNA analysis were performed in 60 lesions from 12 patients -- and 21 controls -- who were initially seen with laryngeal lesions prior to cancer in situ ( cis ) or invasive cancer diagnosis at the same site . RESULTS All but one of the invasive cancers , and 77 % of the lesions which preceded cancer or cancer in situ , showed positive p53 immunostaining , as compared with only 10 % of the controls . All but one of the invasive cancer lesions , and 77 % of the precancerous lesions , showed aberrant DNA-ploidy results , whereas all controls were diploid . When DNA and p53 analysis were combined , only one of the lesions preceding cis or invasive cancer was negative . CONCLUSIONS Both p53 immunoreactivity and DNA-ploidy aberration appear to be early events in the multistep process of squamous epithelial carcinogenesis . Immunohistochemical staining p53 analysis and ICM DNA analysis does increase the diagnostic sensitivity for cancerous and true precancerous lesions in the larynx


Title 5:
Biologic correlates of a biochemoprevention trial in advanced upper aerodigestive tract premalignant lesions.
Abstract 5:
OBJECTIVE To identify tissue biomarkers that might be used to assess an individual 's cancer risk and response to chemoprevention , we studied in dysplastic lesions of the larynx and the p.o . cavity , a series of biomarkers extensively used in previous chemoprevention trials , including chromosome polysomy ( CP ) , proliferative status , p53 expression and gene mutations , and loss of heterozygosity at 9p , 3p , and 17p . METHOD Biopsies from 32 participants in a prospect i ve chemoprevention trial using 13-cis-retinoic acid , IFN-alpha , and alpha-tocopherol for 12 months ( 20 with vocal cord and 12 with p.o . cavity lesions ) were analyzed for p53 and Ki-67 expression by immunohistochemistry , loss of heterozygosity by PCR amplification , p53 mutations by PCR-based direct sequencing , and CP by in situ hybridization . RESULTS High CP ( > or = 4 % cells with more than three chromosome copies per nucleus ) was more common in p.o . ( 8 of 10 ) than laryngeal lesions ( 4 of 16 ; P = 0.01 ) , and so was a combination of CP > or = 4 % and parabasal layer p53 labeling index > or = 0.2 ( P = 0.02 ) . Low CP was a significant predictor of complete histological response ( 8 of 14 cases with low versus 1 of 12 cases with high CP ; P = 0.01 ) . A trend for histological progression or cancer development was observed in cases with high CP and parabasal layer p53 labeling index . CONCLUSION Low CP , more frequently observed in laryngeal lesions , appears to be a predictor of response to chemoprevention and could be used as a screening tool to identify suitable c and i date s for such approaches . Further investigation of biological parameters of response and cancer risk is warranted


Title 6:
Distinctive clinicopathological associations of amplification of the cortactin gene at 11q13 in head and neck squamous cell carcinomas.
Abstract 6:
Amplification of the 11q13 region is a prevalent genetic alteration in head and neck squamous cell carcinoma ( HNSCC ) . We investigated the clinical significance of  cortactin ( CTTN ) and cyclin D1 ( CCND1 ) amplification in both malignant transformation and tumour progression . CTTN and CCND1 amplification was analysed by differential and real-time PCR in a prospect i ve series of laryngeal/pharyngeal carcinomas and archival premalignant tissues .  CTTN mRNA and protein expression were respectively determined by real-time RT-PCR and immunohistochemistry , and correlated with gene status . Molecular alterations were associated with clinicopathological parameters and disease outcome . CTTN and CCND1 amplifications were respectively found in 75 ( 37 % ) and 90 ( 45 % ) tumours . Both correlated with advanced disease ; however , only CTTN amplification was associated with recurrence and reduced disease-specific survival ( p = 0.0022 ) . Strikingly , CTTN amplification differentially influenced survival depending on tumour site ( p = 0.0001 larynx versus p = 0.68 pharynx ) and was an independent predictor of reduced survival in the larynx ( p = 0.04 ) . CCND1 amplification was detected in early tumourigenesis and increased with the severity of dysplasia . Importantly , CTTN amplification was only found in high- grade dysplasias that progressed to invasive carcinoma . CTTN gene status strongly correlated with mRNA and protein expression . Furthermore , CTTN overexpression correlated significantly with reduced disease-specific survival ( p = 0.018 ) . Taken together , these data indicate that CTTN may serve as a valuable biomarker to identify patients with laryngeal tumours at high risk of recurrence and poor outcome
Currently there is no good evidence for the use of biomarkers in predicting the future behavior of laryngeal dysplastic lesions .