Small Number Of Tumors Research Articles

Differential expression of biomarkers in gastrointestinal versus pulmonary carcinoid tumors.

e13571 Background: Carcinoid tumors are endocrine neoplasms that commonly arise in the GI and pulmonary system. About 12,000 cases of carcinoid tumor are diagnosed a year with a 5-year survival rate of 67.2% .The majority of the cases present with advance disease with limited treatment options,therefore evaluation of predictive markers for chemotherapeutic agents is highly desirable. We studied the biomarker expression in carcinoid tumors and evaluated any differences based on site of origin. Methods: By computer search we retrospectively identified all cases submitted to Caris Life Sciences with the diagnosis of “carcinoid”. The cases were classified by primary site into three groups: Pulmonary, GI tract (including esophagus, stomach, small bowel, colon, rectum, appendix and pancreas) and miscellaneous. Biomarker expression performed by IHC and scored semi quantitatively by a pathologist for SPARC mono, SPARC poly, Her2, TOPO2, TOPO1, PGP, MRP1, PTEN, TS, ERCC1, RRM1,MGMT, C-KIT, ER, PR and AR and SSTR2 and SSTR5 analysis by DNA Microarray were compared between the groups. Results: 146 carcinoid tumors were interrogated for biomarkers, 33 pulmonary, 97 GI and 16 miscellaneous (mediastinum, thymus, cervix, breast and unknown primary site). Due to small number of tumors in the miscellaneous category, analysis was restricted to pulmonary and GI carcinoid tumors only. Based on our analysis the pulmonary carcinoids differentially express Topo2, PGP, MGMT, CKIT and PR, while the GI carcinoids differentially express Topo1, RRM1 and ER and SSTR2 and SSTR5. There is equivalent expression of SPARC, MRP1, PTEN, TS, ERCC1 at both sites . All pulmonary and GI carcinoid tumors were negative for Her2. Conclusions: Based on this study it appears that there are differences in biomarker expression in GI and Pulmonary Carcinoid tumors. Treatment with irinotecan, gemcitabine, anti-estrogens and Octreotide may be more relevant in GI carcinoids based on molecular markers present while targets associated with response to anthracyclines, temozolomide, imatinib may be more commonly expressed in pulmonary carcinoid tumors. Further studies are needed to understand the underlying biology and molecular drivers in this group of tumors.

Editorial Comment

The holy grail in PCa is to differentiate the relatively small number of tumors that will ultimately cause patient death from the large number of tumors that are unlikely to result in metastatic disease or eventual patient death. A key success factor would be a simple, inexpensive, readily available laboratory test, such as %FT. Albisinni et al provide intriguing findings in this regard. They reported that among 812 Italian men who underwent PCa biopsy, the %FT was increased in Gleason score 7 and greater tumors and neither testosterone nor free testosterone was associated with PCa development. In particular, men in the greatest %FT tertile had a significant twofold increased risk of high-grade PCa (95% CI 1.23-3.37). Although the findings are based on a single-site evaluation, the blood tests and biopsy and pathology protocols were all standardized, although only 1 sample was used to classify the hormonal concentrations. Greater Percent-free Testosterone Is Associated With High-grade Prostate Cancer in Men Undergoing Prostate BiopsyUrologyVol. 80Issue 1PreviewTo analyze the serum androgen concentrations in men who underwent an initial prostate biopsy, focusing on the percent-free testosterone (%FT) as a predictor of low- and high-grade prostate cancer (PCa). Most studies have suggested that the absolute serum testosterone and free testosterone levels are not related to PCa risk. However, to date, the concurrent effect of free and total testosterone levels has not been evaluated. In particular, the association of the %FT (free testosterone/total testosterone) with PCa risk has not been explored. Full-Text PDF

Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras

K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele.

Dermatoscopic vascular patterns in cutaneous Merkel cell carcinoma

Merkel cell carcinoma (MCC) is one of the most aggressive primary cutaneous malignancies. The clinical diagnosis of MCC is often delayed. Although the rarity of this skin cancer partially explains the low clinical suspicion by physicians, the absence of characteristic clinical features contributes to the delay in diagnosis. Dermatoscopy has proven a useful diagnostic tool in other cutaneous malignancies; however, the dermatoscopic features of cutaneous MCC are unknown. We performed dermatoscopy on 10 primary cutaneous MCC to describe the dermatoscopic features and correlate these findings with the histopathologic parameters. Consecutive patients with cutaneous MCC were identified and their tumors were evaluated under dermatoscopy. An 8-point MCC histopathology profile was recorded for each primary tumor in an attempt to correlate individual parameters with dermatoscopic features. All 10 tumors showed an irregular vascular pattern under dermatoscopy and demonstrated milky-red areas/globules and numerous linear irregular vessels. No correlation was noted between dermatoscopic and histopathologic features. The patients were from a single institution and tumors evaluated by a single dermatoscopic reviewer. Because of the rarity of this tumor, a small number of tumors were evaluated (10). MCC exhibits a variety of dermatoscopic vascular patterns, most commonly milky-red areas/globules, polymorphous vessels, and linear-irregular vessels. Although we found no specific dermatoscopic pattern for MCC in our series, the polymorphous vascular pattern was atypical and suggestive of a malignant process. Further studies should be done to investigate the potential correlation between dermatoscopic features and histopathologic parameters.

Sequential expression of putative stem cell markers in gastric carcinogenesis

Background:Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers.Methods:We investigated expression of PSC markers CD44, Musashi-1 and CD133 in relation to gastric carcinogenesis and prognosis and chemoresponse. Immunohistochemistry staining was performed in gastric cancer (GC) clinical specimens representing different steps of the Correa pathway. Gastric cancer samples taken before and after neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DCX) were also evaluated for PSC marker expression.Results:We showed that the expression of three PSC markers was significantly elevated in GC relative to normal gastric mucosa (P<0.001 for each marker). Precancerous lesions, including intestinal metaplasia and dysplasia, demonstrated increased expression of CD44 and Musashi-1. CD133 was predominantly expressed along the border between intramucosal carcinoma and connective tissue at later stages. High CD44 and CD133 expression showed prognostic value for worse patient survival (P=0.014 and P=0.019, respectively). A small number of tumours with high expression of CD44 and CD133 showed pathological response to DCX-based neoadjuvant chemotherapy.Conclusion:CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive GC, whereas CD133 expression is restricted mainly to neoplastic tissues.

Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response

BackgroundGenome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors.ResultsWe describe an unsupervised method to extract robust, consistent metagenes from multiple analogous data sets. We applied this method to expression profiles from five "double negative breast cancer" (DNBC) (not expressing ESR1 or HER2) cohorts and derived four metagenes. We assessed these metagenes in four similar but independent cohorts and found strong associations between three of the metagenes and agent-specific response to neoadjuvant therapy. Furthermore, we applied the method to ovarian and early stage lung cancer, two tumor types that lack reliable predictors of outcome, and found that the metagenes yield predictors of survival for both.ConclusionsThese results suggest that the use of multiple data sets to derive potential biomarkers can filter out data set-specific noise and can increase the efficiency in identifying clinically accurate biomarkers.

Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study

BackgroundThe randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC). Patients and methodsThe biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented. ResultsOf 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed. ConclusionsThese results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Non-pancreatic cancer tumors in the pancreatic region.

Most of tumors found in the pancreas are adenocarcinoma of the pancreas. A small number of tumors in the pancreas, such as islet cell tumors or neuroendocrine tumors, papillary cystic neoplasms, lymphoma, acinar cell tumors, metastatic tumors to the pancreas often, have a far better prognosis, and the majority of these tumors are non-malignant or benign. The author reviewed the recent literatures, and summarized where the tumor comes originally in the pancreas, what is the type of the tumor, and how to treat the tumor.

Reply to Bonnefoix and Callanan: Significance of Akt/Wnt pathway in radiation resistance of TICs

Whereas we appreciate the statistical concerns expressed about the use of the single-hit Poisson (SHPM) model to evaluate the data shown in tables 1–3 of ref. 1) and summarized in Fig. 1 here, it is unfortunate that these authors (2) did not bother to read or evaluate the previous studies upon which the identification of the LinnegCD29high/CD24high cells as tumor initiating cells (TICs) in the p53 model were based (3), nor did they take into consideration accompanying molecular and biochemical analyses shown in figs. 1–4 and the supplementary data (1). Furthermore, they did not evaluate the conclusions of our study in the context of other recent publications cited concerning targeting the Akt/Wnt pathway in cancer stem cells in both breast cancer (4) and gliomas (5). In the previous study by Zhang et al. (3), a much larger dataset involving 10 tumors and 426 limiting dilution transplantations showed very similar relative effect sizes to data in ref. 1 and was, perhaps due to the larger sample size, consistent with SHPM. As clearly discussed in ref. 1, the data shown in table 1 represent a much smaller number of tumors and transplants and are included to illustrate how the calculation of absolute TIC frequency can be influenced by cell isolation methods and FACS sorting methodology. However, the fold difference between the Linneg and TIC populations is still ≈65-fold. The biochemical and molecular analyses shown in figs. 1–4 of ref. 1 also clearly illustrate that the statistically significant decrease in PTEN expression in TICs is accompanied by an increased activity of the Akt and Wnt pathways. The use of a Wnt pathway reporter shows a highly significant overlap with TICs identified by FACS sorting using the cell surface markers. Furthermore, treatment with perifosine inhibits the selective activation of the Akt and Wnt pathways in the TIC population, whether assayed by FACS using the cell surface markers or the Wnt pathway reporter. Again a smaller number of tumors are used in the more labor-intensive and costly limiting dilution analyses of the Wnt(TOP-GFP) and perifosine-treated samples, giving low power to test that slopes are nonzero, although failure to reject does not mean the slope is zero. Bonnefoix and Callanan rightly point out that the data in the perifosine experiment are so sparse that the models may not converge. Despite this, the differences between the cell types are so large that Fisher's exact tests at individual doses are significant (Fig. 1). Most importantly, the results of our studies identify significant differences in the response to DNA damage in the TIC population as compared with the other tumor bulk subpopulations and show this difference was abrogated by perifosine treatment both in mammosphere cultures and following in vivo treatment. Thus, although we think it is valuable to emphasize the need for the application of appropriate statistical tests to specific datasets, especially because the SHPM is most often used for the evaluation of TIC frequency, Bonnefoix and Callanan (2) are remiss in dismissing the conclusions of our studies without having properly evaluated the supporting literature or accompanying data.

Aberrations of ERBB2 and TOP2A genes in breast cancer

Copy number changes in TOP2A have frequently been linked to ERBB2 ( HER2) amplified breast cancers. To study this relationship, copy number changes of ERBB2 and TOP2A were investigated by fluorescence in situ hybridization (FISH) in two cell lines; one characterized by having amplification of both genes and the other by having amplification of ERBB2 and deletion of TOP2A. The characteristics are compared to findings on paired ERBB2 and TOP2A data from 649 patients with invasive breast cancer from a previously published biomarker study. The physical localization of FISH signals in metaphase spreads from cell lines showed that simultaneous amplification is not a simple co-amplification of a whole amplicon containing both genes. Most gene signals are translocated to abnormal marker chromosomes. ERBB2 genes but not TOP2A genes are present in tandem amplicons, leading to a higher ERBB2 ratio. This observation was confirmed by patient FISH data: among 276 (43% of all patients) abnormal tumors, 67% had different ERBB2 and TOP2A status. ERBB2 amplification with normal TOP2A status was found in 36% of the abnormal tumors (15% of all patients). Simultaneous amplification of both genes was found in 28% of the abnormal tumors (12% of all patients) while TOP2A deletion and ERBB2 amplification was observed in 16% of the abnormal cases (8% of all patients). A small number of tumors had TOP2A amplification (4%) or deletion (6%) without simultaneous changes of the ERBB2 gene. ERBB2 deletion was also observed (5%) but only in tumors with simultaneous TOP2A deletion. The average gene/reference ratio was significantly different: 5.0 for TOP2A but 7.2 for ERBB2 in the amplified tumors ( P < 0.01). Amplification of the two genes may be caused by different mechanisms, leading to higher level of amplification for ERBB2 compared to TOP2A. In the majority of breast cancer patients, simultaneous aberration of ERBB2 and TOP2A is not explained by simple co-amplification.

The Apoptotic Paradox in Retinoblastoma

The purpose of this study was to investigate the clinicopathological features and the expression of proteins involved in cell proliferation and the different pathways of apoptosis in retinoblastoma. Nineteen retinoblastoma patients were included, and mitotic index (MI) and apoptotic index (AI) were assessed. The expression of MIB-1, p53, caspase-3, Bcl-2, and Fas protein was assessed by immunohistochemistry. Mann-Whitney U test and Fisher's exact test were used for statistical comparison. High MI (mean 16.84, range 0-66) and high MIB-1 expression (mean 57.89, range 0-90) were found. The MI was significantly related to MIB-1 expression (P= 0.01). The tumors showed a high apoptotic index (mean 40.26, range 1-110), and the AI was associated with the mitotic index (P= 0.02). The caspase-3 expression was positively related to the AI (P= 0.03), although a small number of tumors with no significant or very low caspase-3 staining showed a high number of apoptotic cells, suggestive of a caspase-3-independent apoptosis pathway. Bcl-2 expression was not significantly related to AI (P= 0.07). No striking relationship was found in expression patterns of p53, Bcl-2, caspase-3, and Fas. In conclusion, we found that (1) cell proliferation and apoptosis are linked in retinoblastoma; (2) activation of effector caspase-3 induces apoptosis in retinoblastoma, but Bcl-2 overexpression does not prevent apoptosis in many tumors; (3) there is a p53-independent pathway in approximately one-quarter of cases; (4) the findings suggesting a caspase-3-independent pathway might lead to apoptosis in retinoblastoma; and, finally, we found no consistent pattern of expression of apoptotic and antiapoptotic molecules, suggesting that in retinoblastoma there is no preference for any single pathway of apoptosis. Confirmation of the results in a large set of tumors would be useful.

Radiosurgery for metastatic brain tumors

Stereotactic radiosurgery (SRS) precisely delivers high-dose radiation to a small target (usually less than 3-4 cm in diameter), in a single session with steep dose-fall, employing various radiation methods. SRS provides good tumor control for small brain metastases from various primary cancers, with minimal untoward effects on surrounding normal brain. This excellent tumor control prevents neurological death and maintains good activity of daily life. Although surgery with whole-brain radiation therapy (WBRT) remains an important option for patients with a solitary brain metastasis, SRS with or without WBRT should be considered in patients with a limited number of small tumors and a good prognosis. Many reports, as well as both retrospective and prospective reviews, have shown WBRT before or after SRS to improve local control and reduce new distant lesion emergence. However, upfront WBRT does not improve survival. There are two major delivery techniques, Gamma Knife (GK; Elekta AB, Stockholm, Sweden) SRS and linear accelerator (LINIAC)-based SRS. They are based on quite different concepts, and have different techniques and clinical applications. These differences complicate the discussion of the limitations of and indications for SRS and the necessity for prophylactic WBRT. This review discusses numerous aspects of SRS, its value as compared with other treatment modalities, the necessity for prophylactic WBRT with SRS, the limitations of and indications for SRS, and the difference between GK and LINIAC SRS, based on the literature and our experience, and proposes a new strategy for the treatment of brain metastases in view of the available clinical data and experience.

The Standard of Perfection: Thoughts about the Laying Hen Model of Ovarian Cancer

In a way not possible in humans, cancer prevention scientists have used animal models to study the role of genes, molecular pathways and networks, and environmental factors that relate to carcinogenesis. These studies are also designed to qualify the animal model as an eventual source of preclinical

Distribution of Microsatellite Instability in Danish Ovarian Tumor Patients and the Prognostic Value in Ovarian Cancer Patients

The repeated frequency of microsatellite instability (MSI) in ovarian cancer (OC) ranges from 0% to 50%. Most MSI studies including OC patients have involved relatively small number of tumors, a wide range of different MSI markers, different patient characteristics, and varying criteria for defining tumors as MSI positive. Thus, no conclusive evidence about MSI occurrence in OC has been provided and the large variation has made interpretation of these previous studies difficult. The majority of MSI studies have been performed on OC cases with few borderline ovarian tumor (BOT) cases included. Few BOT studies showed no evidence of MSI, but in one study the frequency of MSI was 27.7% with all tumors of serous type, suggesting that MSI may play a role in the development of serous BOT. The aim of our study was to determine the frequency of MSI using a panel of 16 dinucleotide markers: TP53, D17S250, CACNLB1, D18S58, D19S49, DXS538, DXS454, D5S117, D5S107, D6S284, D6S305, D9S171, D9S15, D11S554, D11S29, and D13S272 in tissue from patients with OC or BOT and to correlate the presence of MSI at these markers with the clinical information, such as FIGO stage, histological type, age, and survival in OC. The overall frequencies of MSI were within 2-10%. We observed MSI at different loci and with different extent (2.3-9.8%) in the different histopathological types. In both BOT and OC cases, we observed that all high MSI (MSI-H) were of serous type. No significant difference in disease specific survival was found between stage III/IV OC patients who presented MSI compared to patients being microsatellite stable (MSS) (p = 0.72). In conclusion, we found no association to any of the clinical parameters evaluated, although a tendency of a higher frequency of MSI was observed among serous OC.

Histopathologic grading of adult medulloblastomas

Histopathologic evaluation of the degree and extent of anaplasia is a useful prognostic parameter in pediatric medulloblastomas. Whether the same applies to adult medulloblastomas is not known. The study included 74 adult patients with histologically confirmed medulloblastomas and retrospectively reassessed 67 cases with available slides for the presence of nodularity, collagen deposition (desmoplasia without nodules), and degree and extent of anaplasia. Patients included 43 men and 31 women with the following age distribution: 18-40 years (84%); 41-50 years (9%); and 51-70 years (7%). At last follow-up, 56 patients were alive with a mean follow-up of 6.3 years (range, 0.1-20.8 years). A variety of treatments were employed during the study period, including postoperative radiation (85%) and chemotherapy (27%). Precise treatment modalities were unknown in 12% of patients. Anaplasia was absent (34%), mild (34%), moderate (27%), or severe (5%). Severe anaplasia was diffuse in 2 cases and focal in 1, although in the latter cases severe anaplasia was diffusely present at the time of disease recurrence. Male sex was associated with decreased 10-year recurrence-free survival (40% vs 66%; P = .021) and overall survival (38% vs 68%; P = .005). Severe anaplasia at first resection was found to be an independent predictor of decreased recurrence-free survival (P = .005) and overall survival (P = .015). The incidence of severe anaplasia in adult medulloblastomas is lower than in the pediatric population. Male sex and the presence of severe anaplasia at the time of first resection are predictors of decreased recurrence-free and overall survival. However, the significance of severe anaplasia should be regarded with caution based on the small number of tumors with this feature in the current study.

The Role of Surveillance in the Management of Small Renal Masses

Incidentally detected, small renal masses (SRMs) have been increasing significantly in recent years due to the widespread use of improved cross-sectional imaging. A significant number of incidental SRMs are diagnosed in elderly patients who are more likely to undergo imaging for other medical issues. The natural history of SRMs has not been historically well understood because most masses are surgically removed soon after diagnosis.Several reports of surveillance of SRMs have been published in the last few years. When followed conservatively with serial imaging, SRMs have variable growth rates with an average of 0.28 cm/year, according to a recent meta-analysis. Larger series with longer follow-up are needed, but a significant number of small tumors seem to have an indolent behavior with a slow growth rate and a limited tendency to progress. The standard of care for enhancing SRMs is surgery. Up to one-third of surgically removed, <4-cm tumors are histologically benign. The outcomes of current surgical treatment of histologically confirmed, <4-cm, renal cell carcinomas are excellent, but this has not led to a decrease in mortality. Based on these considerations and on the available data on the natural history of SRMs, it seems reasonable to consider that we may be overtreating these lesions. This is especially true for elderly or unfit patients who have a decreased life expectancy. In these selected patients and in patients who refuse active treatment, it seems reasonable to propose an initial period of active surveillance for incidental SRMs, with delayed intervention for those tumors that will exhibit fast growth during follow-up. Percutaneous needle biopsies of renal tumors can be safely performed with the use of modern techniques and have the potential to characterize SRMs at histologically diagnosis, thereby allowing a better selection of the conservative or active treatment that is best suited for each individual patient.

Distal Bile Duct Carcinoma: Prognostic Factors After Curative Surgery. A Series of 112 Cases

The identification of independent prognostic indicators in distal bile duct carcinomas (DBDCs) has been limited by the small number of tumors and a lack of molecular prognostic markers. Markers assessed in combination may perform better than those considered individually. We conducted this study to identify prognostic predictors of patients with DBDC with special focus on combination of expression of p53 protein and clinicopathological predictors. Between December 1996 and 2002, 112 consecutive patients undergoing pancreaticoduodenectomy in the Eastern Hepatobiliary Surgery Hospital for distal bile duct carcinomas were identified in a prospectively collected database. The survival of patients was comparable with respect to patient characteristics, clinicopathological factors and degree of p53 protein expression followed by a univariate and multivariate analysis. Actual 1, 3, and 5-year survival rates were 85.7, 50.9, and 25.0%, respectively. By Cox proportional hazards survival analysis, the most powerful predictors of survival rate were p53 expression [relative risk (RR) 5.2, 95% CI 4.8-5.6], pancreatic invasion (RR 5.6, 95% CI 4.3-6.9), lymph nodes metastasis (RR 3.9, 95% CI 3.3-4.5), and operative time (RR 1.8, 95% CI 1.5-2.1). Overexpression of p53 in DBDC is strongly associated with significantly reduced survival, independently of clinicopathological prognostic factors. The resection margin status provides little independent prognostic information. Longer operative time may have unfavorable effect on prognosis of patients with DBDC.

Reply to Jaskowski et al

Jaskowski et al1 have confirmed our previous paper2 reporting an association between BAT26 stability and germline MSH2 deletion. Among seven highly unstable tumours with MSH2 deletion spanning exon 5 they found normal BAT26 sequences in 4. Although their analysis was based on a small number of tumours, they observed this phenomenon in 57% of cases, a percentage very close to the 68% we obtained in the analysis of 19 tumour DNAs.2 It is reasonable to suppose that the molecular mechanism leading to somatic loss of BAT26 sequences, as we described previously,2 is responsible for the observed BAT26 stability in both subsets of MSH2 deleted tumours.

Characterization of CD133 + hepatocellular carcinoma cells as cancer stem/progenitor cells

The CD133 antigen, identified as a hematopoietic stem cell marker, appears in various human embryonic epithelia including the neural tube, gut, and kidney. We herein investigated whether CD133 + cells isolated from human hepatocellular carcinoma cell lines possess cancer stem/progenitor cell-like properties. Among the three cell lines studied, the CD133 antigen was found to be expressed only on the surface of Huh-7 cells. CD133 + cells from Huh-7 performed a higher in vitro proliferative potential and lower mRNA expressions of mature hepatocyte markers, glutamine synthetase and cytochrome P450 3A4, than CD133 − population of Huh-7 cells. When either CD133 + or CD133 − cells were subcutaneously injected into SCID mice, CD133 + cells formed tumors, whereas CD133 − cells induced either a very small number of tumors or none at all. Taken together, the identification of CD133 + cells could thus be a potentially powerful tool to investigate the tumorigenic process in the hepatoma system and to also develop effective therapies targeted against hepatocellular carcinoma.

Basal cell carcinoma on the trunk is associated with excessive sun exposure

Basal cell carcinoma (BCC) is the most common of all cancers. Ultraviolet radiation is the major etiologic agent in the pathogenesis of BCC, but there is not a straightforward relationship between cumulative exposure and risk. A high proportion of lesions arise on the trunk, which is generally much less exposed to the sun than the head, the major site affected. We tested the hypothesis that the phenotypic determinants and patterns of sun exposure that give rise to BCC on the head and trunk vary in a way that explains the anomalous site distribution. The study was set in the context of the Nambour Skin Cancer Study, a community-based follow-up study among 1621 participants with virtually complete ascertainment of BCCs between 1992 and 2004. We compared phenotypic and sun exposure characteristics of participants who developed a first BCC of the head or trunk with those of participants who had no diagnosis of BCC. BCCs of the trunk were more likely to occur in men; they also occurred at a younger age than BCCs of the head. There was a positive association between sun sensitivity and BCC of the head that was absent for BCC of the trunk. A high number of solar keratoses conferred a greater than 3-fold risk for BCCs of both the head and the trunk. BCCs of the trunk had a particularly strong association with the number of reported sunburns and solar lentigines on the trunk, whereas many lentigines conferred a greater than 3-fold risk of truncal BCC compared with a 50% increased risk of BCC of the head. The relatively small numbers of tumors may have limited our ability to detect statistically significant differences. BCCs of the trunk are the result of overexposure of the sensitive basal cells of the epidermis to ultraviolet radiation. This may result from acute intense exposures sufficient to cause sunburn among people whose ability to tan makes the skin of their face generally less susceptible to the carcinogenic effects of ultraviolet radiation.