Is dose escalation achievable for esophageal carcinoma?

Aim

To investigate the feasibility of dose escalation using rapid arc (RA) and Helical Tomotherapy (HT) for patients with upper, middle and distal esophageal carcinomas, even for large tumor volumes.

Background

In esophageal cancer, for patients with exclusive radio-chemotherapy, local disease control remains poor. Planning study with dose escalation was done for two sophisticated modulated radiotherapy techniques: Rapid arc against Tomotherapy.

Materials and methods

Six patients treated with a RA simultaneous integrated boost (SIB) of 60 Gy were re-planned for RA and HT techniques with a SIB dose escalated to 70 Gy. Dose volume histogram statistics, conformity indices and homogeneity indices were analyzed. For a given set of normal tissue constraints, the capability of each treatment modality to increase the GTV dose to 70 Gy was investigated.

Results

Either HT or VMAT may be used to escalate the dose delivered in esophageal tumors while maintaining the spinal cord, lung and heart doses within tolerance. Adequate target coverage was achieved by both techniques. Typically, HT achieved better lung sparing and PTV coverage than did RA.

Conclusions

Dose escalation for esophageal cancer becomes clinically feasible with the use of RA and HT. This promising result could be explored in a carefully controlled clinical study which considered normal tissue complications and tumor control as endpoints.     

DNA-PKcs: A promising therapeutic target in human hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is a frequent and deadly disease worldwide. The absence of effective therapies when the tumor is surgically unresectable leads to an extremely poor outcome of HCC patients. Thus, it is mandatory to elucidate the molecular pathogenesis of HCC in order to develop novel therapeutic strategies against this pernicious tumor. Mounting evidence indicates that suppression of the DNA damage response machinery might be deleterious for the survival and growth of the tumor cells. In particular, DNA dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the non-homologous end-joining (NHEJ) repair process, seems to represent a valuable target for innovative anti-neoplastic therapies in cancer. DNA-PKcs levels are strongly upregulated and associated with a poor clinical outcome in various tumor types, including HCC. Importantly, DNA-PKcs not only protects tumor cells from harmful DNA insults coming either from the microenvironment or chemotherapeutic drug treatments, but also possesses additional properties, independent from its DNA repair activity, that provide growth advantages to cancer cells. These properties (metabolic and gene reprogramming, invasiveness and metastasis, resistance to apoptosis, etc.) have started to be elucidated. In the present review, we summarize the physiologic and oncogenic roles of DNA-PKcs, with a special emphasis on liver cancer. In particular, this work focuses on the molecular mechanism whereby DNA-PKcs exerts its pro-tumorigenic activity in cancer cells. In addition, the upstream regulator of DNA-PKcs activation as well as its downstream effectors thus far identified are illustrated. Furthermore, the potential therapeutic strategies aimed at inhibiting DNA-PKcs activity in HCC are discussed.     

Cytohistologic correlation of cirrhosis and hepatocellular carcinoma. Pitfall in diagnosis?

OBJECTIVE: To compare the diagnostic criteria for cirrhosis and hepatocellular carcinoma (HCC) noted on liver fine needle aspirates (FNAs) and their corresponding liver needle core biopsies (NCBs). STUDY DESIGN: We reviewed FNA slides from 15 cases of cirrhosis and 6 cases of HCC and their corresponding NCBs. We compared a variety of specific nonarchitectural criteria, including small cell dysplasia (SCD) and large cell dysplasia (LCD), for distinguishing cirrhosis from HCC. RESULTS: FNA smears diagnostically correlated with NCBs. The cytologic criterion with the greatest correlation in predicting HCC on FNA was SCD. This was not noted in all the core biopsies, probably due to sampling error. LCD was seen more frequently in cirrhosis than HCC on both cytology and histology and therefore was not a criterion useful in establishing a diagnosis of malignancy. The remaining cytologic criteria had good correlations but did not aid in diagnosing HCC. CONCLUSION: FNA has good cytohistologic correlation with NCB for both cirrhosis and HCC. There is an association of SCD with HCC; however, LCD is not a reliable "precancerous" change as it is commonly seen in cirrhosis and HCC. Therefore, the presence of SCD on FNA should be reported and is an indication for close clinical follow-up to exclude HCC.     

Phenotype alteration in colon carcinoma cells: Effect of in vivo passage?

Summary A panel of rat colon adenocarcinoma cell lines (the Per series) were used to investigate the phenotype and karyotype changes induced by in vivo passage in the subcutis of athymic nude mice. One poorly and one well-differentiated tumor cell line were serially passaged through the athymic nude mouse and then back to the syngeneic rat host. Each of the primary and xenograft cell lines expressed fetal crypt cell (“CaCo”) antigens. The well differentiated primary and xenograft lines (Per305, Per305N1, and Per305N2a) were different in each of their growth factor reponsiveness in vitro [i.e. epidermal growth factor (EGF), bombesin, vasoactive intestinal peptide], their EGF receptor expression, their secretion of transforming growth factor-α, and their exhibition of anchorage independent (A-I) growth capabilities. The poorly differentiated primary and xenograft cell lines were also different but were all capable of A-I growth; their responsiveness to exogenous growth factor stimulation decreased with progressive in vivo passage, as did their basal unstimulated proliferation rate. Cytogenetic alterations detected were those associated with clinical specimens from various stages of malignancy, i. e. aneuploidy, structural aberrations, and marker chromosomes. Genetic and mitogenic individuality of each line demonstrated the diversity of the growth control mechanisms in neoplasms at different stages of progression. Financial support was provided from the Richard Walter Gibbon Fund of the Faculty of Medicine, the University of Western Australia; and from the Sir Charles Gairdner Hospital Research Foundation.     

Do younger women with non-metastatic and non-inflammatory breast carcinoma have poor prognosis?

Background  

Controversy abounds over whether breast cancer in younger women is more aggressive than those in older. The aim of the study was to assess the influence of age on long-term survival of women with breast carcinoma.     

Is helodermin produced by medullary thyroid carcinoma cells and normal C-cells? Immunocytochemical evidence

Helodermin is a VIP/secretin-like 35-amino acid peptide originally isolated from the venom of the lizard Gila monster. Recently, helodermin-immunoreactive material was demonstrated in mammalian salivary glands, brain and gut. In the present study 8 human medullary thyroid carcinomas as well as 4 normal thyroid glands were examined immunocytochemically for the presence of helodermin using an antiserum raised against helodermin-(5-35) that does not cross-react with VIP or secretin. Cells displaying helodermin-like immunoreactivity were found in all tumours examined except one. On the whole the helodermin-immunoreactive cells had the same distribution as those storing calcitonin, suggesting coexistence of the two peptides in most of the tumour cells. Also normal human C-cells displayed helodermin immunoreactivity. The results suggest that a peptide chemically related to helodermin is a constituent of human medullary thyroid carcinoma cells as well as of normal C-cells.     

Gallium-67 scintigraphy and non-small-cell bronchogenic carcinoma: a quantitative in-vivo predictive assay?

Gallium-67 scintigraphy has been of limited use in detecting lung cancers and micrometastases. To study its potential for determining the aggressiveness of a cancer, we reviewed the charts of 44 patients with non-small-cell bronchogenic carcinoma who had not been receiving treatment when 67Ga scintigraphy was performed. The mean length of survival for the 18 patients with low or little uptake of the tracer, corrected for tumour size, was 19.7 months, and for the 26 with high uptake 9.4 months (p less than 0.01). Such in-vivo predictive assays may be a rational goal for tumour scintigraphy.     

Verrucous carcinoma of the head and neck – not a human papillomavirus-related tumour?

Association between verrucous carcinoma (VC) of the head and neck and human papillomaviruses (HPV) is highly controversial. Previous prevalence studies focused mostly on α‐PV, while little is known about other PV genera. Our aim was to investigate the prevalence of a broad spectrum of HPV in VC of the head and neck using sensitive and specific molecular assays. Formalin‐fixed, paraffin‐embedded samples of 30 VC and 30 location‐matched normal tissue samples were analysed, by using six different polymerase chain reaction‐based methods targeting DNA of at least 87 HPV types from α‐PV, β‐PV, γ‐PV and μ‐PV genera, and immunohistochemistry against p16 protein. α‐PV, γ‐PV and μ‐PV were not detected. β‐PV DNA was detected in 5/30 VC (16.7%) and in 18/30 normal tissue samples (60.0%): HPV‐19, ‐24 and ‐36 were identified in VC, and HPV‐5, ‐9, ‐12, ‐23, ‐24, ‐38, ‐47, ‐49 and ‐96 in normal tissue, whereas HPV type was not determined in 2/5 cases of VC and in 6/18 normal tissue samples. p16 expression was detected in a subset of samples and was higher in VC than in normal tissue. However, the reaction was predominantly cytoplasmic and only occasionally nuclear, and the extent of staining did not exceed 75%. Our results indicate that α‐PV, γ‐PV and μ‐PV are not associated with aetiopathogenesis of VC of the head and neck. β‐PV DNA in a subset of VC and normal tissue might reflect incidental colonization, but its potential biological significance needs further investigation.