A little to a lot or a lot to a little: is NTCP always minimized in multiport therapy?

Purpose: We address the question of whether or not, for the same average (or integral) dose, a smaller uniform dose to an entire normal tissue structure always results in a lower normal tissue complication probability (NTCP) than does a proportionally larger dose to a partial volume of the same structure.Methods and Materials: A recent compilation of NTCP data and two theoretical formulations of the dependence of NTCP on dose and partial volume irradiated—the Lyman probit equation and the binomial model—are used to examine this question. Both models fit equally well available NTCP data.Results: Empirical data indicate that for lung, kidney, and possibly liver (but not for esophagus, brain, or heart), given a fixed tumor dose and fixed integral dose, NTCP can be minimized by irradiating a partial volume fraction rather than the entire normal organ. The binomial model supports this interpretation, whereas the probit model predicts that for all organs uniform irradiation of the whole organ always results in the lowest possible NTCP.Conclusions: In contrast to what is commonly believed, this study suggests that for at least two normal tissues, namely lung and kidney, there may be situations where “a lot to a little” (i.e., fewer treatment ports) will result in higher tumor control probability and better treatment plan than “a little to a lot” (i.e., multifield treatment). This finding, which is independent of the binomial or probit models used here, depends only on the accuracy of the empirical NTCP data. It is also interesting to note that: a) lung and kidney are commonly classified as parallel tissues, while the others have more of a serial architecture; and b) the choice of the NTCP model can have a profound impact on treatment planning decisions.     

Adding Mendelian randomization to a meta-analysis—a burgeoning opportunity

Current literature is teeming with tens of thousands of meta-analyses, but only a small fraction made seminal contributions to enriching our understanding of the mechanisms of carcinogenesis, possibly due to chance, bias, confounding, or reverse causality. The incorporation of Mendelian randomization (MR) with a meta-analysis has revolutionized traditional practice and is emerging as a viable technique to strengthen causal unconfounded inferences from observational data. We therefore highlight the importance of integrated MR meta-analysis in cancer epidemiology and provide an overview of three existing instrumental selection strategies in medical literature.     

How to develop a successful cancer drug – molecules to medicines or targets to treatments?

Cancer chemotherapy remains the only treatment modality with curative activity against multiple forms of metastatic malignancy. Over the past decade, cytotoxic and anti-endocrine drugs have been supplemented by targeted therapies that seek to exploit the molecular lesions that underlie the carcinogenic process or maintain the cancer phenotype. Success with, for example, Imatinib and Trastuzumab has suggested that identification and validation of the drug target is the starting point for the optimal route to the development of active drugs. However, in reality, our understanding of the biology of cancer is still too rudimentary to allow drug developers to rely on the simplistic linear pathway of target identification and validation, lead identification and optimisation, followed by Phase I, II and III trials. As pre-clinical and clinical drug developers investigate the second wave of targeted agents, it is worthwhile reflecting on experience gained during the initial development of cytotoxic drugs. For example, the clinical activity of alkylating agents and antimetabolites was demonstrated before the targets for these drugs were defined in any detail. Recent experience with signal transduction modifiers has again shown that agents initially developed to exploit one target may actually hit other targets, and that interaction with these other targets may be responsible for the clinical activity of the compound. Using lung cancer, the world's single biggest cancer problem, as an example the development of recently evaluated drugs, both cytotoxic and targeted, is reviewed. On the basis of this Review, it is concluded that drug developers should design pre-clinical studies and early clinical trials in a manner that allows both the pharmacology of the drug as well as the biology of the target to inform the development process.     

Resistance to trastuzumab: a necessary evil or a temporary challenge?

The aim of this review article is to examine the potential mechanisms of resistance to trastuzumab. In the clinical setting, when trastuzumab is given as a single agent for first-line treatment of HER2-overexpressing metastatic breast cancer, it is associated with a 40% objective response rate. In the remaining cases, no tumor regression is observed, although HER2 protein is overexpressed and/or the corresponding gene is amplified. Hence, some other factors besides HER2 must play a role in determining the level of sensitivity to trastuzumab. The identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Moreover, thorough understanding of the HER2 pathway is essential to the identification of new predictive markers of response to trastuzumab that will help to better define the patients who are most likely to benefit from this drug.     

Is a dense mammographic parenchymal pattern a contraindication to hormonal replacement therapy?

The aim of the study was to find out whether the effect of hormonal replacement therapy (HRT) is modified by the mammographic parenchymal patterns on the risk of breast cancer. Subjects were 4163 Finnish women aged 40-47 years at entry who were invited to breast cancer screening every second year from 1982 to 1990. Mammographic parenchymal patterns (Wolfe's classification) were recorded at each screening round. The information, on use of HRT, was recorded from 1984. The follow-up ended in 1993 and up until that time 68 new breast cancers were diagnosed. A Poisson regression model was used in the analysis of the data. Use of HRT was not related to the risk of breast cancer (RR = 0.7, 95% CI 0.4-1.4), whereas mammographic parenchymal pattern was statistically significantly associated with risk of breast cancer. The age-adjusted relative risk of breast cancer among women with P2 versus N1 pattern was 2.5 (95%CI 1.3-4.8) and with DY versus N1 pattern 4.9 (95%CI 1.6-15.1). Women using HRT and with DY pattern were at substantially increased risk of breast cancer (RR = 11.6, 95%CI 2.5-53.6) compared with women not using HRT and with N1 pattern. There was an increased risk of breast cancer among women with DY mammographic parenchymal pattern who used HRT, which was consistent with a synergistic joint effect.     

Would you like to purchase a rodent with dermatophytes?

The zoophilic dermatophyte Trichophyton benhamiae has received attention due to increasing infections in human in recent years. Trichophyton benhamiae has been found on asymptomatic rodents from pet shops in several countries posing a potential risk for transmission to humans. The aim of this study was to determine the prevalence of positive dermatophyte cultures from rodents in Danish pet shops in order to clarify the magnitude of potential sources of zoophilic infections and to prevent further spread. Specimen sampling was performed in 17 Danish pet shops using the brush technique (MacKenzie technique). After incubation, cultures were sent to ITS DNA sequencing for molecular species identification. Pet shop employees were asked to fulfil a five‐question survey regarding purchase and procedures of diseased animals. A total of 98 animals were sampled (N = 32 rabbits, N = 32 guinea pigs and N = 34 hamsters). Trichophyton benhamiae was found in 14/98 samples (14%); 12/32 guinea pigs (38%) were positive with T benhamiae, 2/34 (6%) hamsters and 0/32 rabbits (0%). We found that hamsters and particularly guinea pigs from Danish pet shops are common asymptomatic carriers of the dermatophyte T benhamiae. Although a larger study is warranted to test this postulate, and it raises the question if infection control measures should be implemented in pet shops.