Common Solid Cancers Research Articles

Abstract 5259: Application of HT-RNAi-based functional genomics in neuroblastoma

Abstract Neuroblastoma is the most common extra-cranial solid cancer in children. About 70% of patients with neuroblastoma have metastatic disease at the time of diagnosis. Children with favorable disease characteristics and younger than one year of age (stages I and II) have a higher likelihood of disease-free survival. However, older children with advanced disease (stages III and IV) have only a 30% chance of survival even with aggressive therapy. Additionally, amplification of the MYC-N gene has been associated with stage III and IV tumors, thus establishing it as a poor prognostic marker. Current treatment primarily consists of combinations of surgery, radiation, and chemotherapy. Newer regimens also include the topoisomerase I inhibitor topotecan, which has been found to be effective against recurrent disease. In order to identify “Achilles heel” targets that modulate growth of neuroblastoma, we applied a functional genomics approach using High Throughput RNA interference (HT-RNAi). Furthermore, by treatment of cells with low dose topotecan, we hope to identify genes the can improve the response to this current therapy. We first identified optimal siRNA transfection conditions for the four neuroblastoma cell lines; MYC-N amplified, IMR-5 and IMR-32 and MYC-N non-amplified, SK-N-AS and NB-EB. Since these cell lines can be difficult to transfect with siRNA, several cationic lipids were tested at varying lipid:siRNA ratios to obtain the optimal reagent and ratio for each cell line. Next, we determined the optimal low dose (IC10-30) of topotecan for each cell line. Following these optimizations, HT-RNAi assays were conducted on the four neuroblastoma cell lines using a kinase siRNA library targeting 572 kinases and a siRNA library targeting 532 apoptosis associated genes treated with vehicle or low dose topotecan. These HT-RNAi screens identified genes whose silencing decreased neuroblastoma cell growth and genes whose silencing improved topotecan response. We are currently in the process of validating these results. After validation, we hope to develop these molecular targets into innovative therapeutics for children affected with this disease. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5259.

NF-κB, and not MYCN, Regulates MHC Class I and Endoplasmic Reticulum Aminopeptidases in Human Neuroblastoma Cells

Neuroblastoma (NB) is the most common solid extracranial cancer of childhood. Amplification and overexpression of the MYCN oncogene characterize the most aggressive forms and are believed to severely downregulate MHC class I molecules by transcriptional inhibition of the p50 NF-kappaB subunit. In this study, we found that in human NB cell lines, high MYCN expression is not responsible for low MHC class I expression because neither transfection-mediated overexpression nor small interfering RNA suppression of MYCN affects MHC class I and p50 levels. Furthermore, we identified NF-kappaB as the immediate upstream regulator of MHC class I because the p65 NF-kappaB subunit binds MHC class I promoter in chromatin immunoprecipitation experiments, and MHC class I expression is enhanced by p65 transfection and reduced by (a) the chemical NF-kappaB inhibitor sulfasalazine, (b) a dominant-negative IKBalpha gene, and (c) p65 silencing. Moreover, we showed that the endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, which generate MHC class I binding peptides, are regulated by NF-kappaB, contain functional NF-kappaB-binding elements in their promoters, and mimic MHC class I molecules in the expression pattern. Consistent with these findings, nuclear p65 was detected in NB cells that express MHC class I molecules in human NB specimens. Thus, the coordinated downregulation of MHC class I, ERAP1, and ERAP2 in aggressive NB cells is attributable to a low transcriptional availability of NF-kappaB, possibly due to an unknown suppressor other than MYCN.

Behcet’s disease associated with malignancy in Korea: a single center experience

The aim of this study was to determine the clinical characteristics of Behcet's disease (BD) complicated with malignancy in Korea. Of 1,769 patients with BD in our hospital, 32 patients (1.8%, 21 in solid cancer, 11 in hematologic malignancy) developed cancer. In 10 of the 32 subjects (31.3%), malignancy was diagnosed before or concomitantly with BD. Twelve cases (37.5%) occurred within the first 2 years of disease and 9 cases (28.1%) occurred 5 years after the diagnosis of BD. Myelodysplastic syndrome (MDS) was the most common disease (n = 7) followed by thyroid cancer (n = 4), breast cancer, cervix cancer, stomach cancer, rectal cancer, hepatoma, aplastic anemia (n = 3, each), renal cell cancer, endometrial cancer, lymphoma (n = 1, each). There were no significant differences in the clinical characteristic between patients with or without malignancy. Intestinal involvement were more frequent in patients with malignancy than those without, but was not statistically significant (p = 0.083). Our results demonstrate that MDS and thyroid cancer are the most common hematologic disease and solid cancer associated with BD, respectively. Further studies will be required to ascertain the pathogenic link between BD and malignancy and the prevalence of malignancy in BD.

MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3

Neuroblastoma is the most common extra-cranial solid childhood cancer; it arises from neural crest-derived cells of the sympathetic nervous system. The anomalous regulation of embryonic developmental pathways like Delta-Notch and Wnt has been implicated in aberrant cell growth and differentiation in many (childhood) tumours. We have previously found regulation of Delta-Notch pathway genes by the MSX1 neural crest development gene in a neuroblastoma cell line, and significant correlations between these genes in neuroblastic tumours. However, a clear role for the Wnt pathway in neuroblastic tumours has not yet been determined. We now analyze the complete spectrum of genes regulated by inducible expression of MSX1 in the SJNB8 neuroblastoma cell line using Affymetrix expression profiling. We show that MSX1 induces the expression of four different Wnt pathway inhibitor genes: Dickkopf 1-3 (DKK1-3) and secreted frizzled-related protein 1 (SFRP1), and provide evidence that high expression of two of these genes correlates with good prognosis. We were able to demonstrate that both the canonical Wnt3 and the alternative Wnt5A ligands are highly expressed in neuroblastic tumours and cell lines, and specifically activate the DVL3 Wnt co-receptor protein in SJNB8 neuroblastoma cells. These results suggest involvement of MSX1 in Wnt signalling and demonstrate activity of the more upstream Wnt pathway in neuroblastic cells.

The Yin and Yang of vitamin D receptor (VDR) signaling in neoplastic progression: Operational networks and tissue-specific growth control

Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1α,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1α,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1α,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1α,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.

Mutational analysis of JAK1 exon 10 and 13 in common solid cancers

Mutational analysis of JAK1 exon 10 and 13 in common solid cancers

Prenatal Detection of an Extra‐Adrenal Neuroblastoma With Hepatic Metastases

Neuroblastoma is the most common extracranial solid cancer in children and the most frequent cancer in infancy The neoplasm arises from neuroblasts (pluripotent sympathetic cells) found in many locations within the body. More than half of neuroblastomas arise in the abdomen, and two-thirds of these originate in an adrenal gland. However, detection in neonates is distinctly uncommon, and because most of these are situated in the adrenal gland, extra-adrenal lesions in the neonate are rare. Fetal detection is even rarer, and the paucity of reports in the literature attests to this (Table 1). 1-8 We report a case in which sonography and magnetic resonance imaging (MRI) were used in the detection and evaluation of an extra-adrenal metastatic neuroblastoma in a fetus.

Absence of pro-apoptotic CYTOCHROME C gene mutation in common solid cancers and acute leukaemias

Absence of pro-apoptotic CYTOCHROME C gene mutation in common solid cancers and acute leukaemias

High resolution magic angle spinning 1H NMR of childhood brain and nervous system tumours

BackgroundBrain and nervous system tumours are the most common solid cancers in children. Molecular characterisation of these tumours is important for providing novel biomarkers of disease and identifying molecular pathways which may provide putative targets for new therapies. 1H magic angle spinning NMR spectroscopy (1H HR-MAS) is a powerful tool for determining metabolite profiles from small pieces of intact tissue and could potentially provide important molecular information.MethodsForty tissue samples from 29 children with glial and primitive neuro-ectodermal tumours were analysed using HR-MAS (600 MHz Varian gHX nanoprobe). Tumour spectra were fitted to a library of individual metabolite spectra to provide metabolite values. These values were then used in a two tailed t-test and multi-variate analysis employing a principal component analysis and a linear discriminant analysis. Classification accuracy was estimated using a leave-one-out analysis and B632+ bootstrapping.ResultsGlial tumours had significantly (two tailed t-test p < 0.05) higher creatine and glutamine and lower taurine, phosphoethanolamine, phosphorylcholine and choline compared with primitive neuro-ectodermal tumours. Classification accuracy was 90%. Medulloblastomas (n = 9) had significantly (two tailed t-test p < 0.05) higher creatine, glutamine, phosphorylcholine, glycine and scyllo-inositol than neuroblastomas (n = 7), classification accuracy was 94%. Supratentorial primitive neuro-ectodermal tumours had metabolite profiles in keeping with other primitive neuro-ectodermal tumours whilst ependymomas (n = 2) had metabolite profiles intermediate between pilocytic astrocytomas (n = 10) and primitive neuro-ectodermal tumours.ConclusionHR-MAS identified key differences in the metabolite profiles of childhood brain and nervous system improving the molecular characterisation of these tumours. Further investigation of the underlying molecular pathways is required to assess their potential as targets for new agents.

Predictors of Venous Thromboembolism in Patients with Advanced Common Solid Cancers

There is uncertainty about risk heterogeneity for venous thromboembolism (VTE) in older patients with advanced cancer and whether patients can be stratified according to VTE risk. We performed a retrospective cohort study of the linked Medicare-Surveillance, Epidemiology, and End Results cancer registry in older patients with advanced cancer of lung, breast, colon, prostate, or pancreas diagnosed between 1995–1999. We used survival analysis with demographics, comorbidities, and tumor characteristics/treatment as independent variables. Outcome was VTE diagnosed at least one month after cancer diagnosis. VTE rate was highest in the first year (3.4%). Compared to prostate cancer (1.4 VTEs/100 person-years), there was marked variability in VTE risk (hazard ratio (HR) for male-colon cancer 3.73 (95% CI 2.1–6.62), female-colon cancer HR 6.6 (3.83–11.38), up to female-pancreas cancer HR 21.57 (12.21–38.09). Stage IV cancer and chemotherapy resulted in higher risk (HRs 1.75 (1.44–2.12) and 1.31 (1.0–1.57), resp.). Stratifying the cohort by cancer type and stage using recursive partitioning analysis yielded five groups of VTE rates (nonlocalized prostate cancer 1.4 VTEs/100 person-years, to nonlocalized pancreatic cancer 17.4 VTEs/100 patient-years). In a high-risk population with advanced cancer, substantial variability in VTE risk exists, with notable differences according to cancer type and stage.

Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma

Neuroblastoma is the most common pediatric extracranial solid cancer. This tumor is characterized by metaiodobenzylguanidine (MIBG) avidity in 90% of cases, prompting the use of radiolabeled MIBG for targeted radiotherapy in these tumors. The available English language literature was reviewed for original research investigating in vitro, in vivo and clinical applications of radiolabeled MIBG for neuroblastoma. MIBG is actively transported into neuroblastoma cells by the norepinephrine transporter. Preclinical studies demonstrate substantial activity of radiolabeled MIBG in neuroblastoma models, with (131)I-MIBG showing enhanced activity in larger tumors compared to (125)I-MIBG. Clinical studies of (131)I-MIBG in patients with relapsed or refractory neuroblastoma have identified myelosuppression as the main dose-limiting toxicity, necessitating stem cell reinfusion at higher doses. Most studies report a response rate of 30-40% with (131)I-MIBG in this population. More recent studies have focused on the use of (131)I-MIBG in combination with chemotherapy or myeloablative regimens. (131)I-MIBG is an active agent for the treatment of patients with neuroblastoma. Future studies will need to define the optimal role of this targeted radiopharmaceutical in the therapy of this disease.

Lung metastases in neuroblastoma at initial diagnosis: A report from the International Neuroblastoma Risk Group (INRG) project

Neuroblastoma is the most common extracranial pediatric solid cancer. Lung metastasis is rarely detected in children with newly diagnosed neuroblastoma. We aimed to describe the incidence, clinical characteristics, and outcome of patients with lung metastasis at initial diagnosis using a large international database. The subset of patients from the International Neuroblastoma Risk Group database with INSS stage 4 neuroblastoma and known data regarding lung metastasis at diagnosis was selected for analysis. Clinical and biological characteristics were compared between patients with and without lung metastasis. Survival for patients with and without lung metastasis was estimated by Kaplan-Meier methods. Cox proportional hazards methods were used to determine the independent prognostic value of lung metastasis at diagnosis. Of the 2,808 patients with INSS stage 4 neuroblastoma diagnosed between 1990 and 2002, 100 patients (3.6%) were reported to have lung metastasis at diagnosis. Lung metastasis was more common among patients with MYCN amplified tumors, adrenal primary tumors, or elevated lactate dehydrogenase (LDH) levels (P < 0.02 in each case). Five-year overall survival +/- standard error for patients with lung metastasis was 34.5% +/- 6.8% compared to 44.7% +/- 1.3% for patients without lung metastasis (P = 0.0002). However, in multivariable analysis, the presence of lung metastasis was not independently predictive of outcome. Lung metastasis at initial diagnosis of neuroblastoma is associated with MYCN amplification and elevated LDH levels. Although lung metastasis at diagnosis was not independently predictive of outcome in this analysis, it remains a useful prognostic marker of unfavorable outcome.

Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers

The aim of this study was to see whether JAK1, JAK3, and TYK2 genes are altered in human cancers. We analyzed 494 tissues from 186 acute adulthood leukemias, 30 multiple myelomas, and 278 common solid cancers, including 90 breast, 47 gastric, 47 colon, 47 lung, and 47 hepatocellular carcinomas by single-strand conformation polymorphism analysis. Overall, we found six JAK1 mutations (four in acute leukemias, one in a lung carcinoma, and one in a breast carcinoma) and three JAK3 mutations (two in breast carcinomas and one in a gastric carcinoma). Of note, three JAK1 mutations were an identical p.V658F mutation, which is homologous to JAK2 p.V617F mutation. We also found two other JAK1 mutations that occurred at very close sites (p.T782M and p.L783F). We found three of the four leukemias with JAK1 mutations expressed mutated JAK1 at the mRNA level. For JAK3 mutations, one of them was JAK3 p.V715I that is homologous to the JAK1 p.L783F. These recurrent mutations in identical and homologous sites suggest a possibility that alterations of these amino acids might be important for tumor pathogenesis. With respect to the cancer types, T-acute lymphoblastic leukemia (T-ALL) showed the highest incidence of the mutations (3 of 11; 27.3%). Our data indicate that both JAK1 and JAK3 mutations occur in common human cancers and that JAK1 mutation in T-ALL is a frequent event. The data suggest that some of the JAK1 and JAK3 mutations may to be functional and contributes to cancer development, especially to T-ALL development.

A novel triple-regulated oncolytic adenovirus carrying p53 gene exerts potent antitumor efficacy on common human solid cancers

Conditionally replicating adenoviruses (CRAd) can replicate specifically in cancer cells and lyse them. The CRAds were widely used in the preclinical and clinical studies of cancer therapy. We hypothesize that more precisely regulated replication of CRAds may further improve the vector safety profile and enhance its antitumor efficacy. Here, a triple-regulated CRAd carrying p53 gene expression cassette, SG600-p53, was engineered. In SG600-p53, the E1a gene with a deletion of 24 nucleotides within CR2 region is controlled under the human telomerase reverse transcriptase (hTERT) promoter, the E1b gene expression is directed by the hypoxia response element (HRE), whereas the p53 gene is controlled by the cytomegalovirus promoter. The precise triple-regulation endows SG600-p53 with enhanced antitumor potential and improved safety profile. The tumor-selective replication of this virus and its antitumor efficacy were characterized in several tumor cell lines in vitro and in xenograft models of human non-small cell lung cancer in nude mice. With the selective replication and oncolysis, it was found by ELISA assay that SG600-p53 expressed p53 efficiently in cancer cells. In NCI-H1299 tumor xenograft models, SG600-p53 displayed a tumor-selective killing capacity. At a dose of 2 x 10(9) plaque-forming units, SG600-p53 could completely inhibit the tumor growth and more effective than replication-defective Ad-p53. Histopathologic examination revealed that SG600-p53 administration resulted in cancer cell apoptosis. We concluded that the triple-regulated SG600-p53, as a more potent and safer antitumor therapeutic, could provide a new strategy for cancer biotherapy.

Molecular inversion probes (MIPs) identify novel copy number changes in pediatric gliomas

13006 Background: Childhood brain tumors (CBT) are the most common solid pediatric cancer and the leading cause of pediatric cancer mortality. More than half of all CBTs are gliomas. Despite their high prevalence, little is known about the genetic events that contribute to the development and progression of pediatric gliomas (PGs). In this study, we used Molecular Inversion Probes (MIPs) to identify recurrently amplified or deleted genomic loci in advancing stages of pediatric astrocytomas (PAs). Our results help define the molecular characteristics of PAs, which may lead to the development of novel biomarkers and therapeutic agents. Methods: DNA was extracted from 14 flash- frozen PA biopsies (WHO grade II [n=3, mean age 7 yr]; grade III [n=2, mean age 6 yr]; grade IV [n=9, mean age 12 yr]). DNA was also extracted from 5 adult-gliosis biopsies to use as non-neoplastic controls. The MIP assay was run using 37 ng genomic DNA/sample on a customized Affymetrix 24K Cancer Panel representing oncogenes, tumor suppressor, DNA repair, cell growth, and metabolism genes. Copy number (CN) changes were identified by comparing probe signal intensity between brain tumor and controls. Results: We observed the full spectrum of genomic CN aberrations including regions of single copy gain and loss, homozygous deletions, and high-level focal amplifications. Grade-III and -IV tumors showed more CN alterations relative to grade II tumors. CN changes ranged from < 1000 basepairs to entire chromosome arms. Deleted genes included: DRD3 (3q13), GAP43 (3q13), DHFR (5q14), SOX8 (16p13.3), ADAMTS18 (16q23.1), WWOX (16q23.1). Amplified genes included: PTPN7 (1q32), GPR160 (3q26), PGDFRA (4q12), KIT (4q12), TBXAS1 (7q34), PLAG1 (8q12.1), CHCHD7 (8q12.1), MYC (8q24.1), FOXM1 (12p13), CCND2 (12p13), ERC1 (12p13), WNT5B (12p13), MEGF8 (19q13.2), TUBGCP6 (22q13.33). Several amplifications ranged as high as CN of 80. Conclusions: MIPs can identify both known and novel areas of CN events in PGs using minimal DNA. PGs display increasing molecular CN changes with advancing clinical stages. Areas of amplifications and deletions range from microscopic to macroscopic. Further exploration with larger sample sets (including paraffin-embedded specimens) may increase our understanding of the biology and behavior of PGs. No significant financial relationships to disclose.

Mutational analysis of caspase 1, 4, and 5 genes in common human cancers

Mounting evidence indicates that deregulation of apoptosis is involved in the mechanisms of cancer development. Mutations of genes encoding caspases, the executioners of apoptosis, have been detected in human cancers, indicating inactivation of apoptosis by the mutations of caspase is an important mechanism in cancer development. The aim of this study was to see whether genes encoding human caspases 1, 4, and 5 are mutated in human cancers. We analyzed the entire coding region and all splice sites of human caspase 1, 4, and 5 genes for the detection of somatic mutations in 337 human cancers, including 103 colorectal, 54 gastric, 60 breast, 60 hepatocellular, and 60 lung carcinomas by a single-strand conformation polymorphism assay. We detected 2 (0.6%) caspase-1, 2 (0.6%) caspase-4, and 15 (4.4%) caspase-5 mutations in the 343 cancers. The mutations were detected in 11 gastric carcinomas (2 caspase-1 and 9 caspase-5 mutations), 6 colorectal carcinomas (2 caspase-4 and 4 caspase-5 mutations), 1 breast carcinoma (1 caspase-5 mutation), and 1 lung carcinoma (1 caspase-5 mutation). The mutations consisted of 11 mutations in exons and 8 mutations in noncoding sequences. The 11 mutations in the exons consisted of 3 missense, 1 silent, and 7 frameshift mutation(s). Of note, most (6/9) of the caspase-5 mutations in the coding sequences were detected in microsatellite instability (MSI)-positive cancers. These data indicate that somatic mutations of caspase-1 and caspase-4 genes are rare in common solid cancers. In addition, the data indicate that caspase-5 gene is commonly mutated in the MSI-positive cancers, and suggest that inactivation of caspase-5 may play a role in the tumorigenesis of MSI-positive cancers.

Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias

Mounting evidence indicates that alterations of AKT signalling play important roles in cancer development. An earlier study discovered an oncogenic AKT1 gene mutation (AKT1 E17K) in breast, colorectal and ovarian cancers. The aim of this study was to see whether the AKT1 E17K mutation is common in breast, colorectal, lung, gastric and hepatocellular carcinomas and acute leukaemias. We analysed the presence of the AKT1 E17K mutation in 731 cancer tissues by a single-strand conformation polymorphism assay. In addition, we analysed the corresponding sequences of AKT1 E17K in AKT2 and AKT3 genes. Overall, we detected the four AKT1 E17K mutations in the breast cancers (4/93; 4.3%), but none in other cancers. There was no AKT2 or AKT3 mutation in the cancers. This study demonstrated that the AKT1 E17K mutation occurs in breast cancers at a low frequency, and that it is rare in other common cancers, including colorectal, lung, gastric and hepatocellular carcinomas and acute leukaemias. Despite the confirmed oncogenic function of the AKT1 E17K, the rare incidences of the mutation suggest that it may not play a crucial role in the development of the most common types of human cancers.

50: Increased Risk of Cervical Dysplasia in Long Term Survivors of Allogeneic Stem Cell Transplantation – Implications for Screening and HPV Vaccination

Cervical, skin and head-neck cancer are most common secondary solid cancers in long-term survivors after allogeneic stem cell transplantation (allo-SCT). Although these cancers are linked to human papillomavirus (HPV) infection, the relationship between HPV and cancers after allo-SCT is not defined. Furthermore, Pap smear screening after SCT is not practiced routinely. We carried out a cross-sectional study of 92 patients receiving allo-SCT for hematological malignancies, enrolled at a minimum of 3 years post-transplantation between 04/2005–06/2007 in an IRB-approved long-term evaluation protocol. Ninety (98%) patients are alive after a median follow-up of 77 months (range 38–167). Evaluation of the 38 female patients (median age at transplant 33, range 9–60 years) included annual gynecological examination. Thirty five received a fractionated total body irradiation (TBI) (12–13.6 Gy) based myeloablative SCT and 3 received a non-TBI non-myeloablative SCT. Acute graft versus host disease (GVHD) (grade II-IV) occurred in 9 (24%) patients and chronic GVHD in 34 (89%), extensive in 10 (26%). Six (16%) patients received immunosuppressive therapy (IST) for chronic GVHD beyond 3 years from SCT. Thirty-five (92%) adult patients had annual cervical smear examinations, 14 (40%) were abnormal. High grade dysplasia was seen in 8 (23%), low grade lesions in 4 (11%) and 2 patients had atypical cells of uncertain significance. Median time to an abnormal smear was 51 months (17–153) and median age of these 12 patients was 42 years (range 19–62). Extensive chronic GVHD requiring prolonged IST was the only factor associated with an increased risk of cervical dysplasia (p = 0.028). Our data shows that cervical dysplasia (often high grade) is common after allo-SCT. These patients may be at increased risk of developing invasive cervical cancer. Patients requiring prolonged immunosuppression for chronic GVHD treatment may be especially at risk for all forms of HPV-related malignancy. Aggressive screening and preventive strategies with HPV vaccine appear warranted.

Surgery for lung metastases from colorectal cancer: the practice examined

Operations to remove metastases in the lung have become commonplace. In this article, I give a highly critical perspective of a practice that has grown without a secure evidence base, notwithstanding more than 500 articles on the subject. The objectives are mixed and sometimes unclear. The reports are generally in the form of Kaplan–Meier survival analyses but, when challenged on the expected benefit for individuals, clinicians tend to retreat to claims for palliation rather than for ‘cure’. Yet the reports include no symptom checklists, quality-of-life measures or patient-reported outcomes. I see at least four distinguishable contexts, defined by cancer types, which deserve to be considered separately: sarcoma; testicular and germ cell tumors; cancers traditionally seen as having an ‘oligometastatic’ pattern of behavior, such as kidney and thyroid; and the more common solid cancers, such as colorectal and breast cancer. Most surgical series group them together with a tail of one, two or three instances of the less common cancers. The inclusion in these series of all cancer types operated upon adds nothing to knowledge on cancers with low numbers and complicates the analysis for the more common ones. In this article, I will confine the discussion for the main part to colorectal cancer, which is the most common cancer in which pulmonary metastasectomy is practiced.

Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias

NOTCH proteins (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) play crucial roles in embryonic development. Also, mounting evidence indicates that NOTCH contributes to the pathogenesis of hematopoietic and solid malignancies. Recent studies reported a high incidence of gain-of-function mutations of the NOTCH1 gene in T-cell acute lymphoblastic leukemias (ALL). To see whether NOTCH1 mutation occurs in other malignancies, we analyzed NOTCH1 for the detection of somatic mutations in 334 malignancies, including 48 lung, 48 breast, 48 colorectal and 48 gastric carcinomas, and 142 acute leukemias (105 acute myelogenous leukemias, 32 B-ALLs and 4 T-ALLs) by single-strand conformation polymorphism assay. Also, to see whether other NOTCH genes harbor somatic mutations, we analyzed NOTCH2, NOTCH3 and NOTCH4 genes in the same tissue samples. Overall, we detected three NOTCH mutations in the cancers, which consisted of one NOTCH1 mutation in the T-ALLs (25.0%), one NOTCH2 mutation in the breast carcinomas (2.1%), and one NOTCH3 mutation in the colorectal carcinomas (2.0%). There was no NOTCH mutation in other malignancies analyzed. Our data indicate that NOTCH1 is mutated in T-ALL, but not in other common human cancers, and that NOTCH2, NOTCH3 and NOTH4 genes are rarely mutated in common human cancers. Despite the importance of NOTCH activation in many types of human cancers, mutation of NOTCH genes, except for NOTCH1 mutation in T-ALL, may not play an important role in the tumorigenesis of common cancers.