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Objectives/hypothesis: For early-stage oral tongue carcinoma and carcinoma in situ (ESOTCCIS), we evaluated patient-reported quality-of-life (QOL) outcomes following resection with primary closure (R-PC)., Study Design: Retrospective review at an academic cancer center., Methods: Thirty-nine ESOTCCIS patients (Tis, T1, T2) who underwent R-PC without radiation completed the University of Washington Quality of Life Questionnaire Version 4 (UW-QOL) at least 6 months since R-PC (mean = 2.39 years; range = 0.5-6.7 years). We compared UW-QOL scores for pain, swallowing, chewing, speech, and taste to established normative population scores. Multivariable regression analysis evaluated factors associated with QOL impairment., Results: ESOTCCIS patients who underwent R-PC in comparison to the normative population reported significantly worse mean speech (87.7 vs. 98, P < .001) and taste (85.6 vs. 95, P = .002) scores and no significant differences in mean pain (91.7 vs. 86, P = .96), swallowing (100 vs. 98, P = .98), chewing (97.4 vs. 94, P = .98) scores. For speech and taste, 59% (23/39) reported no postoperative change from baseline, whereas 41% (16/39) and 35.9% (14/39) reported mild impairment, respectively. Overall, postoperative QOL was reported as good, very good, or outstanding by 87.2% (34/39). Higher American Society of Anesthesiologists class, cT1 compared to CIS, and ventral tongue involvement were independently associated with worse speech. Age < 60 years was independently associated with worse taste., Conclusions: ESOTCCIS patients who undergo R-PC without radiation can expect long-term swallowing, chewing, and pain to be in the normative range. Although a majority of patients can expect to achieve normative speech and taste outcomes, R-PC carries the risks of mild speech and/or taste impairments., Level of Evidence: 4 Laryngoscope, 131:312-318, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Background and Objectives: This article examines a cervical screening incident from the 1960s and draws lessons for screening policy., Study Design and Setting: Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a 'special series' of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident., Results: In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the 'special series.' A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the 'special series,' who 'in retrospect and by 1987 standards' might have benefited from earlier conisation or hysterectomy., Conclusion: Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Fascin-1 and actinin-4 are involved in key processes of tumor cell adhesion, migration and metastasis. Actinin-4 plays an important role in promotion of cell proliferation, whereas fascin-1 regulates cellular motility. Its over-expression leads to the loss of cell adhesion and metastasis. The aim of our study was to assess fascin-1 and actinin-4 expression in normal pancreatic ducts and in pancreatic intraepithelial neoplasia (PanIN) - precursor lesion of pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: The study involved 70 patients treated surgically due to PDAC, cysts and pancreatitis, who had also been diagnosed with pancreatic intraepithelial neoplasia. Fascin-1 and actinin-4 expressions were evaluated using the immunohistochemistry method., Results: A statistically significant relationship was observed between the expression of fascin-1 and actinin-4 (cytoplasmic) and patients' age (P = 0.01, P = 0.002, respectively). The expression of fascin-1 and actinin-4 was associated with the diagnosis (P <0.001, P = 0.04, respectively). Statistical analysis revealed correlations of fascin-1 and actinin-4 expressions with the presence and grade of PanIN (P < 0.001, P = 0.002, respectively). The expression of these proteins was observed in each degree of PanIN and increased with the pancreatic intraepithelial neoplasia progression., Conclusions: The expression of fascin-1 and actinin-4 is connected with the degree of PanIN advancement and depends on the type of the primary disease. Overexpression of these proteins may be linked to cytological and architectural abnormalities observed in advanced PanIN. Elevated expression of fascin-1 and actinin-4 indicates the role of these proteins in the progression from PanIN to PDAC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Between 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors., Methods: Data of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status., Results: Age at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P < 0.01), hot fluids (P < 0.01), and total fluids intake (P < 0.01), in nonmuscle-invasive bladder cancer patients., Conclusion: Our results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency.

Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing ( Atdc ) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar-ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of β-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events., (© 2019 Wang et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (S t O 2 ) and blood volume (tHb) were studied for associations with patient outcomes., Methods: PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion S t O 2 and tHb was measured., Results: Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but S t O 2 was higher in patients with CR. In tongue/FOM lesions, baseline S t O 2 [mean(SE)] was 54(4)% in patients (n=12) with CR versus 23(8)% in patients (n=6) with local recurrence/persistence (p=0.01). Similarly, for intact disease, baseline S t O 2 was 54(3)% in patients (n=10) with CR versus 28(8)% in patients (n=5) without CR (p=0.03). In patients with intact disease, higher baseline S t O 2 associated with 24-month local control (p=0.02)., Conclusions: Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

To summarize actual knowledge on epidemiology, etiology, pathology, clinical apparence and treatment of ocular surface squamous neoplasias. We summarize up-to-date literature on conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma and present some own cases. Ocular surface squamous neoplasia is the most common malignant ocular surface tumor and the third most common ocular malignancy following malignant melanoma and lymphoma. In spite of its low malignant potential, in advanced stages it may reduce visual acuity significantly or even the eye globe has to be removed. In case of metastasis it may also be life-threatening. As local recurrences of ocular surface squamous neoplasias may occur, knowledge of intra- and postoperative adjuvant treatment options are indispensable and regular control examinations are necessary. Identification and adequate treatment of ocular surface squamous neoplasias are necessary in order to avoid its progression and to prevent recurrences. Orv Hetil. 2017; 158(51): 2011-2022.

Anal squamous cell cancer (SCC) is a relatively uncommon cancer in the United States. Anal SCC has long been associated with human immunodeficiency virus (HIV) positivity and/or men who have sex with men. The incidence of anal SCC has been increasing in both genders regardless of HIV status. Few clinicians are aware that white women, when not controlling for gender and sexual preference together, have the highest incidence of anal SCC. Anal intraepithelial neoplasia (AIN), dysplastic cells of the anal canal due to human papilloma virus infection, is believed to be the precursor to anal SCC. A vaccination has been approved by the Federal Drug Administration (FDA) for the prevention of high-risk human papilloma virus infections in presexually active girls and boys. Currently, there are no consensus guidelines for AIN screening, treatment or follow-up. Although anal SCC is treatable when caught early, treatment is often associated with significant morbidity. The purpose of this paper is to raise awareness of anal SCC and its precursor, AIN, in the non-HIV+ and non-MSM populations, and discuss means by which to decrease the incidence of anal SCC in all populations.

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma arising from apocrine glands. We describe an innovative surgical technique to manage extensive cutaneous malignancies in a notoriously challenging location. The patient is a 78-year-old male who presented with 'jock itch' on his left groin refractory to topical treatment. A shave biopsy of the lesion demonstrated non-invasive EMPD which yielded a urology consult. Rather than the standard wide local excision (WLE), which can lead to positive margins, progression, and recurrence, we used a modified the Mohs technique and staged the procedure, providing excellent oncologic and cosmetic outcomes. The described technique has particular merit with uncertain margin status and when geography of lesions preclude a standard Mohs surgery.

Purpose: Sexual activity (SA) and sexual function (SF) are central outcome measures in women affected by preinvasive (vulvar intraepithelial neoplasia, VIN) and invasive (vulvar cancer, VC) vulvar lesions. Data on sexuality after treatment are scarce., Methods: Validated questionnaires including the female sexual function index (FSFI-d) were provided to 166 women with a history of VIN and VC who attended the colposcopy units of the University Medical Center Hamburg-Eppendorf and Asklepios Medical Clinic Altona for follow-up between March 2011 and June 2012. Additional patients (n = 14) assessed the questionnaires online through the website of the German Vulvar Cancer Support Group (VulvaKarzinom SHG e.V.) during the same time period., Results: Twenty-four patients with VIN and 34 with VC were evaluable. Median age was 51.5 years, with 34 (58.6%) of the patients being postmenopausal. Median time since completion of treatment was 17 months. All women had undergone vulvar surgery (laser/cold knife/combination). Overall, 14 (24.1%) women reported no SA during the last 4 weeks. SF was clearly impaired compared with previously described normal cohorts. SA and SF of active patients did not differ significantly between those with VIN and VC. Analyses contrasting surgical treatment methods yielded no significant associations; likewise, time since diagnosis did not affect SA and SF significantly. Increasing age was negatively associated with most dimensions of the FSFI-d [desire (p = 0.011), arousal (p = 0.004), lubrication (p = 0.003), orgasm (p = 0.013), satisfaction (p = 0.345), pain (p < 0.001)]., Conclusion: Women with VIN and VC after surgical treatment are at high risk to suffer from persistent sexual dysfunction especially at higher age.

Purpose: Sexual dysfunction commonly arises for women following diagnosis and treatment of breast cancer. The aim of this study was to systematically evaluate the acceptability, reliability, and validity of the Female Sexual Functioning Index (FSFI) when used with these women., Methods: Sexually active women previously diagnosed with breast cancer (N = 399) completed an online questionnaire including the FSFI and measures of acceptability (ease of use, relevance), sexual functioning, body image, fatigue, impact of cancer, physical and mental health, and relationship adjustment. Reliability and validity were evaluated using standard scale validation techniques., Results: Participants indicated a high degree of acceptability. Excellent internal consistency (α = 0.83-0.96) and test-retest reliability (r = 0.74-0.86) of the FSFI were evident. According to the confirmatory factor analysis, the best fit was achieved with removal of item 14 (regarding the extent of emotional closeness with the partner) and six subscales (desire, arousal, lubrication, orgasm, satisfaction, pain), without a total score (TLI = 0.96, CFI = 0.97, RMSEA = 0.07). Correlations with measures of sexual functioning and related constructs provided evidence for convergent and divergent validities, respectively. All but one subscale (orgasm) discriminated between women who are, and are not, currently receiving treatment for breast cancer (discriminant validity)., Conclusions: These findings indicate that not only is the FSFI psychometrically sound when used with women with breast cancer, but it is perceived as being easy to use and relevant. It is recommended that the FSFI subscale scores can be used in both clinical and research settings as a screening tool to identify women experiencing sexual dysfunction following breast cancer.

Background: Surgical resection of lentigo maligna (LM) is complicated by noncontiguous, subclinical extension and actinic melanocytic hyperplasia in sun-damaged skin of older individuals., Objective: We sought to determine the long-term effectiveness of imiquimod as primary or adjuvant therapy for LM., Methods: Patients were retrospectively identified from January 1, 2003, to December 31, 2013, with LM, early/evolving LM, and LM melanoma who had used topical imiquimod 5% cream for either primary therapy after diagnostic biopsy, or adjuvant therapy after narrow-margin surgical resection or complete clinical but not histologic resection of LM. Follow-up occurred through December 31, 2014., Results: In all, 63 cases were identified in 61 patients, mean (SD) age 71.1 (12.4) years; 58 were analyzed for local recurrence. Imiquimod was used as primary therapy in 22 of 63 (34.9%) and adjuvant therapy in 41 of 63 (65.1%) for mean duration of 11.7 (range 2-60) weeks. Fifty cases (86.2%) demonstrated clinical clearance at mean (SD) follow-up of 42.1 (27.4) months: 72.7% primary and 94.4% adjuvant at 39.7 (23.9) and 43.1 (28.9) months, respectively., Limitations: Retrospective cohort study and lack of standardized imiquimod application are limitations., Conclusion: Imiquimod cream appears to be a viable option for primary or adjuvant treatment of LM in older patients who are poor surgical candidates., (Published by Elsevier Inc.)

Context: Lobular neoplasia encompasses a spectrum of disease, including atypical lobular hyperplasia and lobular carcinoma in situ. Although classic forms of lobular neoplasia are predominantly heralded as a risk marker, the pleomorphic form of lobular carcinoma in situ is generally regarded as a more aggressive subtype and a possible cancer precursor, and thus is treated in a manner more similar to ductal carcinoma in situ than classic forms of lobular neoplasia., Objective: To focus on the morphologic spectrum of lobular neoplasia as highlighted by 3 cases and current management recommendations. Areas of diagnostic challenge and controversy are addressed., Data Sources: A review of the pertinent published literature and current national guidelines was conducted., Conclusions: Correct classification of classic lobular neoplasia and pleomorphic lobular carcinoma in situ is critical because of differences in clinical management, with current treatment strategies focused on risk reduction for patients with classic lobular neoplasia and eradication of the lesion for those with pleomorphic lobular carcinoma in situ.

Vocal fold pathology changes the appearance and vibratory patterns observed during stroboscopic examination, but a strict correlation between the vibratory pattern and the dysplasia type does not exist. The aims of this study were to determine the role of stroboscopy in vocal fold dysplasia assessment and to determine whether stroboscopy is the deciding factor when performing laryngomicroscopy with biopsy in suspicious lesions. This prospective controlled study involved 112 patients with laryngeal dysplasia treated over a 2-year period at a tertiary medical center. Patient data and clinical, stroboscopy, laryngomicroscopy, and histopathologic reports were reviewed. During the stroboscopy, glottic occlusion, phase symmetry, periodicity, amplitude, mucosal wave, and nonvibratory segments were followed. Laryngomicroscopy with different types of endoscopic cordectomies (types I-III) was performed as a therapeutic measure, with a 12-month follow-up period. Nonvibrating segments were present in 15.1% of the patients with mild dysplasia and in 38.5% of the patients with moderate dysplasia. In 45.5% of the patients with severe dysplasia (carcinoma in situ), nonvibrating segments were absent. The amplitude of vocal fold vibrations in patients with mild dysplasia (P=0.03) was a significant factor indicative of recurrent disease, but none of the stroboscopic signs was significant for the disease progression. Severe dysplasia can be related to both nonvibrating and vibrating vocal fold segments. Stroboscopy cannot be used reliably for classifying laryngeal dysplasia and may indicate the need to perform laryngomicroscopy with biopsy in suspicious vocal fold lesions. The warning factors for recurrence and progression of dysplasia are treatment modality, abnormal amplitude of vibration, and nonvibrating segment., (Copyright © 2014 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Background & Aims: Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice., Methods: We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed., Results: PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1., Conclusions: In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer represents the third cause of cancer. Since its detection in due time is important resolution, appropriate monitoring is mandatory. The present study deals with the relationship between colorectal cancer and renal function, as well as other associated risk factors. Chronic kidney disease (CKD) represents a risk factor of cancer, both in non-dialysed patients and especially in dialysed patients and in patients with renal transplant. It can get aggravated with cancer in general and particularly with colorectal cancer, partly related to the toxins that cannot be appropriately eliminated because of renal functional disturbances. At the same time, immunosuppressive therapy used for treating glomerular or secondary nephropathies represents an important risk factor of cancer. Some patients with colorectal cancer were found to present also impaired renal function, a fact whose significance is still little known. The object of the present paper is an analysis of the case records of a clinic of gastroenterology on the relationship between colorectal cancer and renal functional impairment. We found in the patients with colorectal cancer under study a glomerular filtration rate (GFR calculated with the EPI formula) of < 60 ml/min/1.73m2 in 31/180 patients, respectively 17.22% of the cases, a value that is similar to that in specialised literature. We also analysed associated risk factors that could be related to renal function impairment in these patients: age, gender, anaemia, diabetes mellitus and hypertension. These could represent, together with the colorectal cancer of the investigated patients, risk factors affecting on the one hand renal function, and on the other hand, potentially increasing the risk of cancer. Correction of these risk factors would have beneficial effects on patients. The relationship between renal functional impairment, respectively CKD, and colorectal cancer is to be regarded from the point of view of complex reciprocity: the impairment of the renal function is a factor of risk of colorectal cancer and colorectal cancer can influence renal function of these patients. This report of reciprocity based on important pathogenic mechanisms also interrelates with factors of risk consecutive to both renal function impairment and colorectal cancer.

Aim: To investigate the causes of missed diagnosis of early gastric cancer (EGC) or high-grade intraepithelial neoplasia (HGIN) in Chongqing, China., Methods: The present study summarizes 103 cases of EGC/HGIN detected by esophagogastroduodenoscopy (EGD) and pathological analysis from January 2010 to December 2011. Dimethyl silicone oil was administrated orally 15 min before the EGD procedures. The stomach was cleaned by repeated washing with saline when the gastroscope entered the stomach cavity. Suspected EGC lesions were subject to conventional biopsy sampling and pathological examinations. The correlation between lesion locations, endoscopic morphology of cancerous sites, training level of the examiners, pathological biopsies, and missed diagnosis was analyzed., Results: Twenty-three cases were missed among the 103 cases (22.23%) of EGC/HGIN. The rate of missed EGC in the gastroesophageal junction (8/19, 42.1%) was significantly higher than at other sites (15/84, 17.86%) (χ² = 5.253, P = 0.022). In contrast, the rate of missed EGC in the lower stomach body (2/14, 14.29%) was lower than at other sites (21/89, 23.6%), but there were no significant differences (χ² = 0.289, P = 0.591). The rate of missed EGC in the gastric antrum (5/33, 15.15%) was lower than at other sites (18/70, 25.71%), but there were no significant differences (χ² = 1.443, P = 0.230). Endoscopists from less prestigious hospitals were more prone to not diagnosing EGC than those from more prestigious hospitals (χ² = 4.261, P = 0.039). When the number of biopsies was < 4, the rate of missed diagnosis was higher (20/23, 89.96%) than for when there were > 4 biopsies (3/23, 13.04%) (P < 0.001). In addition, there was no significant difference in the rate of missed diagnosis in patients with 1-3 biopsy specimens (χ² = 0.141, P = 0.932)., Conclusion: Endoscopists should have a clear understanding of the anatomical characteristics of the esophagus/stomach, and endoscopic identification of early lesions increases with the number of biopsies.

Objectives: This study aims to offer an accurate diagnosis for vocal cord nodules, polyps, and intraepithelial neoplasias through videolaryngostroboscopy (VLS) and multi-dimensional voice analysis program (MDVP) and to decide management modalities., Patients and Methods: A total of 397 patients (214 males, 183 females; mean age 46.2 years; range 17 to 71 years) with 218 nodules, 101 polyps and 78 vocal cord intraepithelial neoplasias who were admitted for treatment and follow-up in phoniatry unit of our clinic in the past five years were retrospectively analyzed in terms of VLS findings, the percent of jitter, percent of shimmer, fundamentally frequency, noise-harmonic ratio values, GRBAS [Grade of dysphonia (G), roughness (R), breathiness (B), asthenicity (A) and strain (S)] scores, and voice handicap index (VHI) obtained by MDVP., Results: We obtained better voice parameters with improved GRBAS and SHE scores in patients with vocal cord nodules who underwent voice training and those with polyps who were operated, while these scores worsened following diagnostic phonosurgery in the intraepithelial group., Conclusion: In the initial examination, patients who are prediagnosed vocal cord nodules should have voice therapy as the first-line treatment modality and checked for the response to treatment. If laryngeal cancer is suspected, surgery should be planned according to the biopsy result and biopsy should be performed, if polyp is present.

Human epithelium contains keratin, which is expressed during differentiation. Depending on the target cell type, different types of keratin are expressed, and their alterations seem to represent changes in cell properties. The basal cells of oral epithelium express keratin 5 (K5), K14, K15 and K19, but their alterations in tumors are unclear. To address this issue and to seek possible diagnostic application, we examined the expression of these keratins in oral squamous cell carcinoma (OSCC) and squamous intraepithelial neoplasm (SIN). cDNA microarray analysis of 43 OSCC revealed slight upregulation of KRT14, downregulation of KRT15 and KRT19, and unaltered KRT5 expression. There were great variations in KRT15 and KRT19 expression across each cancer. Well-differentiated OSCC tended to express more KRT15 and less KRT19 compared to moderately- or poorly-differentiated OSCC. KRT15 was positively correlated with differentiation-related keratin, KRT13. These observations were further investigated by immunohistochemical examination. K5 and K14 were ubiquitously expressed in all 50 OSCC and 50 SIN examined. K15 and K19 were generally downregulated, but were considerably retained in about half of the cases and showed diverse expression patterns. K15-positive cancers tended to show a well-differentiated phenotype, and K19-positive cancers tended to show more invasive tumor fronts. Most K19-positive cancers appeared to develop with little associating SIN. K19 was consistently downregulated in SIN, while K15 was downregulated mainly in high grade SIN. In summary, K15 and K19, unlike K5 or K14, are expressed variably in both SIN and OSCC, which reflects the differences in their pathogenesis and biological behaviors, suggesting their prospective applications as markers for subclassifying OSCC and SIN.

Background & Aims: Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras., Methods: We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis., Results: In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of proinflammatory cytokines within the pancreas. Despite the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines, and transcriptional activity of p53 was impaired., Conclusions: Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk., Methods: 124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4-6 mo and chest CT every 6-12 mo, end points were development of carcinoma in situ (CIS) or LC., Results: Among 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6-54 mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p=0.0001), chronic obstructive pulmonary disease (COPD) (p=0.001) or smoking index >52 pack-year (p=0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p=0.146)., Conclusion: Patients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the outcome of CIN 2 diagnosed by colposcopy-directed biopsy in women followed without treatment for 12 months and to verify whether the regression and progression of this lesion are associated with the woman's age at diagnosis and age at first sexual intercourse., Study Design: Women diagnosed with CIN 2 by biopsy and with previous cervical smear showing LSIL were included in this cohort study and followed up for one year with cervical smear and colposcopy every three months. The rates of progression, persistence and regression of the CIN 2 were evaluated. The Kruskal-Wallis test was used to analyze the woman's age at diagnosis, age at first sexual intercourse and interval since the first sexual intercourse according to the CIN 2 outcome, assuming a significance level of 5%., Results: At the end of 12 months of follow-up the CIN 2 regression rate was 74% (31/42), progression rate to CIN 3 was 24% (10/42) and in one case CIN 2 persisted (2%). Among women who had regression, this event was detected in the first six months of follow-up in 26 of the 31 cases. There was no statistically significant association between the evolution of CIN 2 and the woman's age at diagnosis, age at first sexual intercourse and interval since first sexual intercourse. Women whose lesions were restricted to one quadrant were more likely to have CIN 2 regression at three-month follow-up compared with women with a lesion extending to one or more quadrants (OR: 6.50; 95% CI: 1.20-35.23)., Conclusions: The results of this study indicate that the majority of CIN 2 diagnosed by biopsy in women with previous Pap smear showing LSIL will regress in 12 months and therefore an expectant approach could be considered in these cases, not only for young women. Nevertheless these findings are not conclusive, and larger studies are required in order to certify when it is safe to adopt expectant management for CIN 2., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

This study was carried out to determine the underestimation rate of carcinoma upon surgical biopsy after a diagnosis of flat epithelial atypia and atypical ductal hyperplasia and 11-gauge vacuum-assisted breast biopsy. A retrospective review was conducted of 476 vacuum-assisted breast biopsy performed from May 2005 to January 2007 and a total of 70 cases of atypia were identified. Fifty cases (71%) were categorized as pure atypical ductal hyperplasia, 18 (26%) as pure flat epithelial atypia and two (3%) as concomitant flat epithelial atypia and atypical ductal hyperplasia. Each group were compared with the subsequent open surgical specimens. Surgical biopsy was performed in 44 patients with atypical ductal hyperplasia, 15 patients with flat epithelial atypia, and two patients with flat epithelial atypia and atypical ductal hyperplasia. Five cases of atypical ductal hyperplasia were upgraded to ductal carcinoma in situ, three cases of flat epithelial atypia yielded one ductal carcinoma in situ and two cases of invasive ductal carcinoma, and one case of flat epithelial atypia/atypical ductal hyperplasia had invasive ductal carcinoma. The overall rate of malignancy was 16% for atypical ductal hyperplasia (including flat epithelial atypia/atypical ductal hyperplasia patients) and 20% for flat epithelial atypia. The presence of flat epithelial atypia and atypical ductal hyperplasia at biopsy requires careful consideration, and surgical excision should be suggested.

HPV infections have been implicated in the pathogenesis of anal cancers. The mode of infection and subsequent transformation resembles very much the pathogenesis of cervical and other HPV-associated cancers. The molecular dissection of individual steps required to achieve cellular transformation within an HPV-infected cell led to the identification of novel biomarkers that make it possible to identify HPV-transformed cells with substantially higher precision in comparison to conventional methods. Since effective antiretroviral therapy allows for possible long-term survival of HIV-infected individuals who are at very high risk to develop HPV-associated cancers in the anogenital tract, these new developments have become increasingly relevant for practicing dermatologists and proctologists. We here briefly review the basic concepts and some clinical applications of this recent research.

Introduction: Chemokine receptors may regulate the progression and metastasis of invasive malignancies. There are little data, however, regarding their role in premalignant lesions. Our objective was to determine the role of CC chemokine receptor 9 (CCR9) in pancreatic intraepithelial neoplasia (PanIN)., Methods: Human and murine formalin-fixed paraffin-embedded (FFPE) PanIN specimens were assessed for CCR9 expression. The established murine PanIN, invasive pancreatic cancer (5143PDA) and liver metastasis (5143LM) cell lines, and human pancreatic cancer cell line (PANC-1) were obtained to verify CCR9 expression and function., Results: Immunohistochemistry of FFPE specimens demonstrated CCR9 expression in both murine and human PanIN lesions. CCR9 expression in murine and human cell lines was verified by Western blot assay, immunofluorescence, and flow cytometry. CCR9 function was demonstrated by in vitro exposure to CCL25, the selective CCR9 ligand, which resulted in significantly increased cell proliferation in PanIN and pancreatic cancer cell lines., Conclusions: This is the first report of chemokine receptor CCR9 expression in murine and human PanIN tissues. Our results demonstrate enhanced PanIN and pancreatic cancer cell proliferation with activation of CCR9 by its selective ligand CCL25. CCR9 may prove to be a novel therapeutic target for PanIN and its progression to invasive cancer.

Background/aims: To retrospectively evaluate the clinicopathological features, treatment modalities and factors affecting prognosis in patients with both conjunctival intraepithelial and invasive squamous neoplasms., Method: Review and analysis of clinical and pathological records of all cases histologically diagnosed in the Department of Pathology, University College Hospital, Ibadan, Nigeria between January 1990 and December 2004., Results: There were a total of 46 cases in 45 patients (eight intraepithelial carcinomas, 37 invasive squamous cell carcinomas (SCC) and a single case of mucoepidermoid carcinoma in a 71-year-old man). The intraepithelial neoplasms occurred in patients aged between 20 and 90 years. Seven of these patients had actinic changes on histology. For invasive SCC, patients' ages ranged from 18 to 84 years with a mean age of 53 years. Male to female ratio was 1:1. The majority presented with an orbital mass and loss of vision. Twenty-two (60%) of the patients with invasive SCC had enucleation or exenteration as the primary modality of treatment with or without radiotherapy or chemotherapy. Altogether for intraepithelial and invasive squamous neoplasms, the duration of presenting complaints ranged from 1 month to 5 years with an average of 2 years. Human immunodeficiency virus (HIV) infection and smoking were not significantly associated with these cases but a significant number had outdoor occupation. Low socioeconomic status and inability to afford treatment was common among our patients., Conclusion: Patients with invasive SCC in Nigeria present late and have significant delay before having any form of treatment. This contributes to the poor outcome. Human papilloma virus (HPV) and actinic aetiology are possible strong causative agents in Nigerians.

Dermatologic human papillomavirus (HPV) infection in HIV patients manifests as both anogenital and nongenital skin disease. Anogenital HPV-related disease includes benign condyloma acuminata, the most common cutaneous manifestation of genital HPV infection; intermediate malignancy or premalignant conditions including giant condyloma acuminata (also called Buschke-Loewenstein tumor), anal intraepithelial neoplasia, penile intraepithelial neoplasia, and vaginal or vulvar intraepithelial neoplasia; and frankly malignant disease including Bowen's disease and invasive anal, penile, or vulvar carcinoma. Cutaneous HPV-related disease in nongenital skin is also increased in HIV-positive patients, in the form of benign common warts, epidermodysplasia verruciformis-like skin lesions, and nonmelanoma skin cancers. This review and update addresses the above listed dermatologic manifestations of HPV disease in HIV-infected individuals, with an emphasis on new findings and published data from 2006 to 2008.

Background: Minimally invasive approaches to intradural pathology have evolved in part in an effort to reduce approach related destabilization of the spine. No biomechanical data exist however evaluating the effects of traditional and minimally invasive exposures., Methods: A finite element model of the lumbar spine was generated, and a simulated open laminectomy and a modified hemilaminectomy at L4 were performed. Forces were applied to assess changes in flexion, extension, axial rotation, and lateral bending., Findings: Open laminectomy produced much greater changes in extension, flexion, and axial rotation than the modified hemilaminectomy from the intact. Lateral bending was similarly unaffected for both exposures., Interpretation: The results suggest that a minimally invasive hemilaminar exposure preserves the structural integrity of the lumbar spine and minimizes alterations to segmental motion postoperatively.

Testicular cancer (TC) is a rare form of cancer, accounting for 1% of all new cancer cases in Canadian males. TC is the most common malignancy among young men, aged 25-34 yr old. Over previous decades, the incidence of TC has increased in many Western countries. Countries with a sufficiently long period of cancer registration, such as Denmark, document this trend back to the first half of the 20th century. The etiology of TC remains poorly understood. Most of the established risk factors are likely related to in utero events, including some factors that are purported to be surrogate measures for exposure to endogenous estrogens. The correlation of TC with other testicular abnormalities and with pregnancy factors led to the proposal that these conditions are a constellation of sequelae of impairment of testicular development called testis dysgenesis syndrome. There is some limited evidence suggesting that exposure to pharmacological estrogens may contribute to some cases of TC. There is currently no compelling evidence that exposure to environmental estrogenic or other hormonally active substances is contributing to the rise in TC incidence observed in Western nations over the last several decades; however, this question has not been extensively studied. The (1) rarity of this condition in the population, (2) long lag time between the presumed sensitive period during fetal development and clinical appearance of the condition, and (3) lack of a good animal model to study the progression of the disease have greatly hindered the understanding of environmental influences on TC risk.

Background: Several biological markers have been related to prognosis in mammary ductal carcinoma. The aim of the study was to determine biological markers that could predict local recurrence following treatment for all stages of primary operable ductal carcinoma of the breast., Materials and Methods: A consecutive series of patients treated for pure ductal carcinoma in situ (DCIS, n = 110) and invasive ductal carcinoma (IDC, n = 243) was studied. Twenty-three patients with DCIS were excluded because of lack of original paraffin embedded tissue. All patients had been treated between July 1996 and December 2001. Median follow-up was 49.8 mo. From the original paraffin embedded tumors, tissue microarrays (TMAs) were constructed. On these TMAs, immunohistochemistry was performed for estrogen-receptor (ER), progesterone-receptor (PR), Her2/neu, p53, and cyclin D1. Main outcome was the event of LR. All analyses were stratified for diagnosis (DCIS or IDC) and pathological grade., Results: In univariate analyses, Her2/neu overexpression (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.1-8.7, P = 0.032) and p53 overexpression (HR 3.5, 95% CI 1.3-9.3, P = 0.014) were associated with LR in patients treated for both DCIS and IDC. In multivariate analysis, p53 overexpression (HR 3.0, 95% CI 1.1-8.2, P = 0.036 and HR 4.4, 95% CI 1.5-12.9, P = 0.008) and adjuvant radiotherapy (HR 0.2, 95% CI 0.1-0.8, P = 0.026) were independent common predictors of LR in patients who had received treatment for both DCIS and IDC., Conclusions: p53 overexpression is a common predictor of LR following treatment for all stages of primary operable ductal carcinoma of the breast. This marker may help in planning optimal treatment and follow-up.

Conceptual models of epithelial carcinogenesis typically depict a sequence of heritable changes that give rise to a population of cells possessing the hallmarks of invasive cancer. We propose the evolutionary dynamics that give rise to the phenotypic properties of malignant cells must be understood within the context of specific selection forces generated by the microenvironment. This can be accomplished by using an "inverse problem" approach in which we use observed typical phenotypic traits of primary and metastatic cancers to infer the evolutionary dynamics. This has led to the hypothesis that heritable changes in genes controlling cellular proliferation, apoptosis, and senescence, while necessary, are not usually sufficient to produce an invasive cancer. In addition to these evolutionary steps, we propose that the common observation of aerobic glycolysis in human cancers indicates, via the inverse problem analysis, that adaptation to hypoxia and acidosis must be a major component of the carcinogenic sequence. The details of the hypothesis are based on recognition that premalignant populations evolve within ducts and remain separated from their blood supply by a basement membrane. As tumor cells proliferate into the lumen, diffusion-reaction kinetics enforced by this separation result in hypoxia and acidosis in regions of the tumor the most distant from the basement membrane. This produces new evolutionary selection forces that promote constitutive upregulation of glycolysis and resistance to acid-induced toxicity. We hypothesize that these phenotypic adaptations are critical late steps in carcinogenesis conferring proliferative advantages even in normoxic conditions by allowing the population to produce an acidic environment (through aerobic glycolysis) which is toxic to other local cell populations and promotes extracellular matrix degradation, increasing invasiveness.

Background: The epidermal growth factor receptor (EGFR) and Notch signaling pathways have been implicated in self-renewal of normal breast stem cells. We investigated the involvement of these signaling pathways in ductal carcinoma in situ (DCIS) of the breast., Methods: Samples of normal breast tissue (n = 15), pure DCIS tissue of varying grades (n = 35), and DCIS tissue surrounding an invasive cancer (n = 7) were used for nonadherent (i.e., mammosphere) culture. Mammosphere cultures were treated at day 0 with gefitinib (an EGFR inhibitor), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) (a gamma-secretase inhibitor), or Notch 4-neutralizing antibody. Mammosphere-forming efficiency (MFE) was calculated by dividing the number of mammospheres of 60 microm or more formed by the number of single cells seeded and is expressed as a percentage. The Notch 1 intracellular domain (NICD) was detected immunohistochemically in paraffin-embedded DCIS tissue from 50 patients with at least 60 months of follow-up. All statistical tests were two-sided., Results: DCIS had a greater MFE than normal breast tissue (1.5% versus 0.5%, difference = 1%, 95% confidence interval [CI] = 0.62% to 1.25%, P<.001). High-grade DCIS had a greater MFE than low-grade DCIS (1.6% versus 1.09%, difference = 0.51%, 95% CI = 0.07% to 0.94%, P = .01). The MFE of high-grade DCIS treated with gefitinib in the absence of exogenous EGF was lower than that of high-grade DCIS treated with mammosphere medium lacking gefitinib and exogenous EGF (0.56% versus 1.36%, difference 0.8%, 95% CI = 0.33% to 1.4%, P = .004). Increased Notch signaling as detected by NICD staining was associated with recurrence at 5 years (P = .012). DCIS MFE was reduced when Notch signaling was inhibited using either DAPT (0.89% versus 0.51%, difference = 0.38%, 95% CI = 0.2% to 0.6%, P<.001) or a Notch 4-neutralizing antibody (0.97% versus 0.2%, difference = 0.77%, 95% CI = 0.52% to 1.0%, P<.001)., Conclusion: We describe a novel primary culture technique for DCIS. Inhibition of the EGFR or Notch signaling pathways reduced DCIS MFE.

There is a clear association between the development of breast cancer and increasing age, with 80% of cancers occurring in women more than 50 years of age and one-third in women over 70 years. Following the menopause the breast undergoes involution, with the main changes affecting the terminal ductal lobular unit. There is an increase in oestrogen receptor alpha (ERalpha)-positive cells, a decrease in proliferation but, in comparison to premenopausal breasts, a greater number of ERalpha-proliferating cells. The breast cancers that occur in women >/= 75 years are more likely to be ER-positive, with a low growth rate and limited expression of HER-2 and p53. It is proposed that uneven involution of the breast, the persistence of at-risk lesions, the presence of ERalpha-proliferating cells and local oestrogen metabolism in breast adipose tissue are factors in the development of breast cancers with a well-differentiated phenotype., (Copyright (c) 2007 Pathological Society of Great Britain and Ireland.)

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta1 were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta1 expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Objectives: To analyze vocal outcome after endoscopic CO2 laser treatment of early glottic carcinoma by perceptive and objective assessment., Study Design: Retrospective study., Methods: Retrospective analysis of 141 consecutive patients undergoing surgery for previously untreated early glottic carcinoma between October 1993 and July 2003. Five types of laser cordectomies as classified by the European Laryngological Society classification were performed. Comparison of voice results between the different types of cordectomies as well as with a control group was performed., Results: There was no significant difference in the vocal parameters between subepithelial and subligamental cordectomies and controls (P > .05). There was, however, a significant difference between the groups of transmuscular, total, and extended cordectomies and controls (P < .05)., Conclusions: Good oncologic results and vocal outcomes with no difference between controls and subepithelial and subligamental cordectomies support the use of CO2 laser endoscopic surgery as the first line of treatment for early glottic cancer.

Abrogation of the Wnt-signaling pathway is implicated in the carcinogenesis of several malignancies, especially colorectal cancer where up to 90% of cases are thought to have impaired Wnt signaling. It is less frequently involved in conventional ductal pancreatic adenocarcinoma. This pathway has not been explored in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas previously and formed the basis of this study. A tissue microarray of 18 cases of IPMN was stained for proteins involved in the Wnt pathway: adenomatous polyposis coli (APC), pan-beta-catenin, axin 2, glycogen synthase 3alphabeta and 3beta, c-myc, E-cadherin, and cyclin D1. The IPMNs were classified as 8 adenomas, 3 borderline, and 7 cases with carcinoma in situ and/or invasive carcinoma, occurring in 13 females, and the overall age range was 45 to 73 years. Immunohistochemical analysis showed nuclear beta-catenin staining in 7 (39%) of the 18 cases. The cases with nuclear beta-catenin localization included 1 adenoma, 2 borderline IPMN, and 4 carcinomas in situ and/or invasive carcinomas. Seven cases showed absence of APC immunostaining and these included 4 cases with nuclear beta-catenin localization. Fourteen cases displayed marked diffuse up-regulation of c-myc protein, and 12 cases also showed diffuse cyclin D1 protein overexpression. E-cadherin expression was intense and membrane in location (comparable to normal tissue) in 6 of 8 adenomas (no tissue was available in 1 case). Decreased E-cadherin staining was noted in 8 cases where tissue was available for assessment. There was progressive decrease in membrane staining of E-cadherin in 2 of 3 borderline lesions, 1 of 2 carcinomas in situ, and 4 of 5 invasive carcinomas. All other immunostains were either normal in distribution or did not show any correlation with beta-catenin or clinicopathologic parameters. In conclusion, 7 (39%) of 18 cases of IPMN in this study demonstrated abnormal localization of beta-catenin, 4 of which also lacked APC expression. Of 5 carcinomas arising in IPMN, 4 displayed a decrease in E-cadherin expression. There was also a trend for the higher grades of IPMN to show nuclear localization of beta-catenin. These findings suggest that a proportion of cases of IPMN may show abnormalities in the Wnt-signaling pathway with consequent altered expression of downstream related proteins.

Background: The development of non-small cell lung carcinoma proceeds through a series of well-defined pathological steps before the appearance of invasive lung carcinoma. The molecular changes that correspond with pathology changes are not well defined and identification of the molecular events may provide clues on the progression of intraepithelial neoplasia in the lung, as well as suggest potential targets for chemoprevention. The acquisition of anti-apoptotic signals is critical for the survival of cancer cells but the pathways involved are incompletely characterized in developing intra-epithelial neoplasia (IEN)., Methods: We used immunohistochemistry to determine the presence, relative levels, and localization of proteins that mediate anti-apoptotic pathways in developing human bronchial neoplasia., Results: Bronchial epithelial protein levels of the phosphorylated (active) form of AKT kinase and the caspase inhibitor cIAP-2 were increased in more advanced grades of bronchial IEN lesions than in normal bronchial epithelium. Additionally, the percentage of biopsies with nuclear localization of p65/RELA in epithelial cells increased with advancing pathology grade, suggesting that NF-kappaB transcriptional activity was induced more frequently in advanced IEN lesions., Conclusion: Our results indicate that anti-apoptotic pathways are elevated in bronchial IEN lesions prior to the onset of invasive carcinoma and that targeting these pathways therapeutically may offer promise in prevention of non-small cell lung carcinoma.

Testicular germ cell tumours (TGCTs) are the most frequent solid malignant tumour in men 20-40 years of age and the most frequent cause of death from solid tumours in this age group. Up to 50% of the patients suffer from metastatic disease at diagnosis. The majority of metastatic testicular cancer patients, in contrast to most other metastatic solid tumours, can be cured with highly effective cisplatin-based chemotherapy. From a genetic point of view, almost all TGCTs in contrast to solid tumours are characterised by the presence of wild type p53. High p53 expression levels are associated with elevated Mdm2 levels and a loss of p21(Waf1/Cip1) expression suggesting a changed functionality of p53. Expression levels of other proteins involved in the regulation of cell cycle progression indicate a deregulated G1-S phase checkpoint in TGCTs. After cisplatin-induced DNA damage, the increasing levels of p53 lead to the trans-activation of a number of genes but not of p21(Waf1/Cip1), preferentially directing TGCT cells into apoptosis or programmed cell death, both via the mitochondrial and the death receptor apoptosis pathways. The sensitivity of TGCTs to chemotherapeutic drugs may lay in the susceptibility of germ cells to apoptosis. Taken together, this provides TGCT as a tumour type model to investigate and understand the molecular determinants of chemotherapy sensitivity of solid tumours. This review aims to summarise the current knowledge on the biological basis of cisplatin-induced apoptosis and response to chemotherapy in TGCTs.

Objective: To determine the clinical characteristics, outcome following surgical treatment, and natural history of cases of untreated vulvar intraepithelial neoplasia (VIN)., Methods: Four hundred five cases of VIN 2-3 seen between 1962 and 2003 were reviewed., Results: The mean age of women with VIN decreased from 50.0 years before 1980 to 39.0 in subsequent years. After treatment of VIN by excision and/or laser vaporization, half the women required at least one further treatment by the 14th year. It is estimated that 50% of women with positive surgical margins had at least one further treatment within 5 years, but only 15% of women with negative surgical margins required further treatment. Invasive vulvar, perianal, or urethral carcinoma occurred in 17 (3.8%) women (mean age 42 years) after treatment. Nine (2%) cases represented treatment failure, with a median treatment-to-invasion interval of 2.4 years. Eight (1.8%) cases represented new "field" carcinomas, with a median initial treatment-to-invasion interval of 13.5 years. Ten untreated cases, aged 32-76 years (mean age 55 years), progressed to invasion in 1.1-7.3 years (mean 3.9 years). Age, previous pelvic radiotherapy, unifocality, immunosuppression, and association with multicentric neoplasia were not risk factors for the development of invasive vulvar carcinoma in this study. Spontaneous regression of VIN occurred in 47 women (mean age 24.6 years), with a median interval to complete regression of 9.5 months., Conclusion: Surgically treated VIN has a high rate of recurrence. Untreated VIN in women over 30 years has an appreciable invasive potential.

Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFalpha and IL-1beta). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic beta cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study.

Study Objectives: Microscopic residual disease in the bronchial resection margins after surgical resection of lung cancer is rare, and its clinical significance remains unsettled. We studied the natural history of patients with carcinoma in situ (CIS) at their bronchial resection margins to focus on the issue of stump recurrence., Methods: Eleven individuals who had undergone radical surgery for N0M0 lung tumors were found to have CIS at the bronchial resection margins. All of the resection specimens were reviewed with respect to the pattern of CIS extension and reclassified as follows: superficial CIS, involving surface epithelium only (CIS-S), CIS extending into the submucosal gland ducts but not deeper (CIS-D), and CIS extending into submucosal gland acini (CIS-A). Patients were followed using autofluorescence bronchoscopy and high-resolution computer tomography. Clinical parameters and the local extent of CIS at histology review were correlated with outcome., Results: Median follow-up was 35 months (range, 15 to 89). Histology review showed two CIS-S cases, six CIS-D cases, and three CIS-A cases. All of the patients with CIS-A developed stump recurrences in contrast with those with only CIS-S. Three patients with CIS-D have developed metachronous primaries in the contralateral lung, whereas the stump region remained free of tumor., Conclusions: The presence of CIS in the bronchial resection margin after resection of lung cancers is associated with stump recurrences. Although absolute numbers are too small for firm conclusions, our data suggest that those with deep glandular extension of CIS bear the highest risk of early recurrence. However, the development of new primaries away from the stump region and the possible development of distant disease are equally relevant considerations with respect to the choice of additional therapy.

Although human papillomavirus (HPV) DNA is detected in the majority of squamous intraepithelial lesions (SILs) and squamous cell carcinomas (SCCs) of the uterine cervix, the persistence and progression of cervical lesions suggest that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most SILs show quantitative and functional alterations of Langerhans cells (LCs). The aim of this study was to determine whether modulation of E-cadherin-mediated homophilic and heterotypic interactions between keratinocytes and LCs is involved in these abnormalities of LCs in (pre)neoplastic cervical epithelium. Cell membrane expression of E-cadherin and the density of CD1a+ LCs were low in the epithelium of SILs and SCC biopsy specimens, compared with normal exocervical epithelium. Dendritic cells (DCs) and LCs generated in vitro were randomly distributed throughout the full thickness of organotypic cultures of E-cadherin- HPV-transformed cells. In contrast, these cells rapidly adhered to the keratinocyte cell layers when HPV-transformed cells transfected with E-cadherin were used. These data suggest that the E-cadherin-mediated contact between keratinocytes and LCs is potentially important for initiating or maintaining the immune response during chronic HPV infection., (Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

One of the most promising strategies for cancer prevention is chemoprevention by daily used food and beverages. Black tea, the most widely consumed beverage, is a source of compounds with antioxidative, antimicrobial, antimutagenic and anticarcinogenic properties. Lung cancer is the most common cause of cancer deaths in both men and women worldwide. Over one million people around the world are likely to be killed by lung cancer due to increased tobacco smoking and environmental pollutants, especially car exhausts. Therefore chemopreventive intervention using black tea and its active components may be a viable means to reduce lung cancer death. In the present investigation, we used benzo(a)pyrene (BP) to induce lung carcinogenesis in mice for the assessment of potential apoptosis-inducing and proliferation-suppressing effects of theaflavins and epigallocatechin gallate, active components of black tea. Hyperplasia, dysplasia and carcinoma in situ evident in the carcinogen control group on the 8th, 17th and 26th weeks respectively, were effectively reduced after treatment with theaflavins and epigallocatechin gallate. Significant reduction in number of proliferating cells and increased number of apoptotic cells was also found on the 8th, 17th and 26th week of treatment with theaflavins and epigallocatechin gallate in BP-exposed mice. Our observation suggests a promising role for black tea polyphenols in the prevention of lung cancer.

Pancreatic ductal carcinomas are thought to arise from precursor ductal lesions called pancreatic intra-epithelial neoplasias or PanINs. We report the case of a woman suffering from idiopathic chronic pancreatitis associated with PanINs lesions who developed six years later an invasive ductal carcinoma. Immunohistochemistry for p53, HER-2/neu and genetic analysis of K-ras oncogene were performed at different stages of disease and revealed that the PanINs and the carcinoma did not express p53 and HER-2/neu gene products whereas a K-ras mutation was present at the carcinoma stage. The relationship between cancer and chronic pancreatitis and the main difficulties concerning the early diagnostic of pancreatic cancer are discussed.

Squamous cell carcinoma in situ (SCCIS) of the skin is a problem commonly dealt with by dermatologists. The classic presentation, originally described by Bowen, is easily recognized, but presentation on some anatomical surfaces may be associated with less than typical features. Major aetiological factors for this disease are UV light, human papillomavirus infection and immunosuppression. The natural course of SCCIS is usually prolonged, with treatment being appropriate, but not urgent. The choice of therapy requires consideration of the location of the lesion, and a desire for a high cure rate without causing loss of form, function or cosmesis. The immunomodulatory agent imiquimod has offered a significant advance for the topical treatment of SCCIS. Our improved understanding of the underlying biology of SCCIS permits us to make rational choices of treatment. In the future we may be able to determine which of these lesions may progress to invasive disease, and help us select the most effective therapy.

Objective: Clinical and experimental data have suggested that surgical removal of primary tumours promotes the growth of metastatic lesions. We assessed the effect of surgery on proliferation of breast carcinomas, in particular those overexpressing HER2 oncoprotein., Methods: Proliferation of breast carcinoma cells was assessed by MIB-1 immunohistochemistry in sections of primary breast carcinomas and in residual tumour found in re-excision specimens, and in in-vitro cell lines by colorimetric assay. Epidermal growth factor (EGF)-like growth factors were measured by displacement of radiolabelled EGF from its receptor. Cellular damage was measured in terms of creatine phosphokinase level. Downmodulation of HER2 was investigated by cytoplasmic expression of anti-HER2 antibody and by inhibition with anti-HER2 antibody trastuzumab., Findings: Residual breast carcinomas that had been surgically removed within 48 days after first surgery showed a significant increase in proliferation if they were HER2-positive. Wound drainage fluid and postsurgical serum samples from patients stimulated in-vitro growth of HER2-overexpressing breast carcinoma cells. Removal of HER2 from the cell membrane led to a striking reduction of the induced proliferation. The amount of EGF-like growth factors in post-surgical serum samples, as well as the extent of drainage-fluid-induced proliferation, directly correlated with the amount of surgical damage assessed by creatine phosphokinase levels (r=0.77, p=0.002 and r=0.69, p=0.009, respectively). Treatment of HER2-positive tumour cells with trastuzumab before adding the growth stimulus abolished drainage-fluid-induced proliferation., Interpretation: HER2 overexpression by breast carcinoma cells has a role in postsurgery stimulation of growth of breast carcinoma cells.

Introduction: Most cases of anal carcinoma seem to develop from high grade anal intraepithelial neoplasia (AIN) caused by persistent anal warts. Similar pre-invasive epithelial genital lesions (e.g. those of the cervix and vulva) have been shown to be associated with increased angiogenesis. In this study we examined biopsies of anal lesions ranging from warts to invasive anal carcinoma, with the aim of assessing the degree of angiogenesis in pre-invasive anal lesions., Method: Samples from 70 patients (51 male) who had undergone excision biopsy or resection of anal wart lesions (20), low grade AIN (12), high grade AIN (27) and anal squamous cell carcinoma (SCC) (11) were studied. Samples (6) from normal HIV-anal skin were used as controls. The samples were stained for von Willebrand factor, a specific marker of endothelial cells. Angiogenesis was measured by microvessel density (MVD) analysis, quantifying the microvessels in the stroma adjacent to the epithelial lesion., Results: There was a statistically significant (P < 0.001) progressive increase in MVD between low grade AIN, high grade AIN and anal SCC. The difference in MVD between normal skin, warts and low grade AIN was not statistically significant., Conclusion: There are progressive abnormal patterns of angiogenesis in highly dysplastic lesions, similar to those found in cervical and vulvar pathology. These findings may have biological, prognostic and therapeutic implications.