Mutagenic Therapies Research Articles

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

Adaptive dynamics of unstable cancer populations: The canonical equation.

In most instances of tumour development, genetic instability plays a role in allowing cancer cell populations to respond to selection barriers, such as physical constraints or immune responses, and rapidly adapt to an always changing environment. Modelling instability is a nontrivial task, since by definition evolving instability leads to changes in the underlying landscape. In this article, we explore mathematically a simple version of unstable tumour progression using the formalism of adaptive dynamics (AD) where selection and mutation are explicitly coupled. Using a set of basic fitness landscapes, the so‐called canonical equation for the evolution of genetic instability on a minimal scenario associated with a population of unstable cells is derived. We obtain explicit expressions for the evolution of mutation probabilities, and the implications of the model on further experimental studies and potential mutagenic therapies are discussed.

Risk for congenital anomalies in offspring of childhood, adolescent and young adult cancer survivors.

Offspring of cancer survivors (CS) may be at risk for congenital anomalies due to the mutagenic therapies received by their parents. Our population-based cohort study aimed to investigate the risk for congenital anomalies in offspring of CS compared to offspring of their siblings. Using the Finnish Cancer Registry, Central Population Register, and Hospital Discharge Register, we identified hospital contacts due to congenital anomalies in 6,862 offspring of CS (early-onset cancer between 1953 and 2004) and 35,690 offspring of siblings. Associations between congenital anomalies and cancer were evaluated using generalized linear regression modelling. The ratio of congenital anomalies in offspring of CS (3.2%) was slightly, but non-significantly, elevated compared to that in offspring of siblings (2.7%) [prevalence ratio (PR) 1.07, 95% confidence interval (CI) 0.91-1.25]. When offspring of childhood and adolescent survivors (0-19 years at cancer diagnosis) were compared to siblings' offspring, the risk for congenital anomalies was non-significantly increased (PR 1.17, 95% CI 0.92-1.49). No such increase existed for offspring of young adult survivors (20-34 years at cancer diagnosis) (PR 1.01, 95% CI 0.83-1.23). The risks for congenital anomalies were elevated among offspring of CS diagnosed with cancer in the earlier decades (1955-1964: PR 2.77, 95% C I 1.26-6.11; and 1965-1974: PR 1.55, 95% C I 0.94-2.56). In our study, we did not detect an overall elevated risk for congenital anomalies in offspring of survivors diagnosed in young adulthood. An association between cancer exposure of the parent and congenital anomalies in the offspring appeared only for those CS who were diagnosed in the earlier decades.

Dynamics and bifurcations in a simple quasispecies model of tumorigenesis

Cancer is a complex disease and thus is complicated to model. However, simple models that describe the main processes involved in tumoral dynamics, e.g., competition and mutation, can give us clues about cancer behavior, at least qualitatively, also allowing us to make predictions. Here, we analyze a simplified quasispecies mathematical model given by differential equations describing the time behavior of tumor cell populations with different levels of genomic instability. We find the equilibrium points, also characterizing their stability and bifurcations focusing on replication and mutation rates. We identify a transcritical bifurcation at increasing mutation rates of the tumor cells. Such a bifurcation involves a scenario with dominance of healthy cells and impairment of tumor populations. Finally, we characterize the transient times for this scenario, showing that a slight increase beyond the critical mutation rate may be enough to have a fast response towards the desired state (i.e., low tumor populations) by applying directed mutagenic therapies.

Drug Development for Chronic Cancers: Time to Think Differently?

As the treatments for epithelial cancers have inched forward, the chronic management of patients with high performance status has become a common problem in the practice of oncology. This conundrum is clearly illustrated by the excellent, yet negative, randomized trial by Colombo et al that accompanies this editorial. This large, well-designed clinical trial tested another modestly active agent, patupilone, in comparison with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer. Sadly, this study did not meet its prespecified superiority end point, namely an overall survival improvement compared with the use of PLD. What drug development lessons can be learned from yet another trial that fails to meet its designed superiority outcome? There are several potential points for consideration by solid tumor oncologists and gynecologic oncologists as we design strategies to incrementally improve the lives of patients with cancer until we find the rare breakthroughs that will irrefutably extend patient survival. First, we need to acknowledge that the barriers for achieving major advances are formidable. Previously treated solid tumors have been selected in a devilishly Darwinian crucible of genetic instability, heterogeneity, and mutagenic primary therapy. Drug-resistant cancers tend to be broadly refractory to additional agents, regardless of mechanism. Platinum-resistant tumor response rates to topotecan, PLD, and trabectedin are all half of what would be expected in the untreated or platinum-sensitive patient groups. Without a predictive biomarker to enrich for patients who are likely to benefit, many nonresponders will be present in both arms of a randomized trial in platinum-resistant ovarian cancer, making it difficult to detect small but potentially important signs of clinical benefit. This low response rate and the brief duration of improvement combine to dictate very large and costly sample sizes. Yet even adequately sized superiority trials like that of Colombo et al are likely to fail. Table 1 details the recent phase III randomized trials in platinum-refractory ovarian cancer. From these trials, performed over more than a decade, it is apparent that classic chemotherapy development has hit a glass ceiling in platinum-resistant ovarian cancer. One must conclude that inferiority is a real possibility in these trials (because the approved drugs have reproducible, modest effects), therapeutic equivalence is an optimistic outcome, and superiority to current treatment is a distant, unlikely achievement. New superiority trials with classic chemotherapy must be regarded like third Hollywood marriages: a “triumph of hope over experience.” Second, our models for predicting success are unreliable. The phase II experience that led to this phase III trial is not yet published but is described as a single-arm, nonrandomized study. These modestly sized, nonrandomized trials are treacherous guides and have increasingly been criticized for their lack of predictive power. The reliability of single-arm, phase II trials is undermined by undefined patient selection factors and the wide variability that is caused by the

Direct analysis by small-pool PCR of MS205 minisatellite mutation rates in sperm after mutagenic therapies

We have used small-pool PCR to analyse mutation in samples of sperm taken from men after mutagenic therapy. Small-pool PCR uses direct analysis of germline DNA at a highly unstable tandem-repeated “minisatellite” locus to measure rates of length-change mutation in individual sperm samples. The advantages of this approach are that the normal mutation rate is extremely high (about 0.4% per gamete at the locus analysed here), so that relatively small increases in mutation rate can be detectable in individual samples. It is known from work on sperm from untreated individuals that different alleles at this locus have different mutation rates. For this reason, we have analysed the germline mutation rates in sperm samples from two men, in each case comparing a post-treatment sample with a pre-treatment sample from the same individual. We find no evidence for altered mutation in the post-treatment sample, suggesting that the repopulation of the germ-cell compartment after treatment may be subject to stringent mechanisms for the detection and elimination of germ-cell damage.

Genetic Disease in Offspring of Long-Term Survivors of Childhood and Adolescent Cancer

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Characterization of Acute Leukemia with t(4;12)

Acute leukemia with t(4;12)(q11–13;p12–13) is rare but has unique characteristics. The incidence of t(4;12) in acute leukemias was about 0.6% in our laboratory. Twelve patients with acute leukemia with t(4;12) have been reported until now. They included eight acute myeloid (AML: M0 2, M1 3, M2 1, M4 1, and M7 1), three acute lymphoblastic (ALL: L1) and one acute unclassified leukemia (AUL). There were some differences between adults and children with t(4;12). The eight adult patients included seven with AML and one with AUL, two of whom had a history of exposure to mutagenic agents and/or genotoxic therapy. Three patients had the CD7+HLA-DR+CD13+CD34+c-kit+ phenotype, suggesting that the leukemic cells were of stem cell origin. Four children expressed the B lymphoid phenotype (HLA-DR+CD10+CD19+) although one had myeloperoxidase positivity. It was difficult for adult patients to achieve complete remission with the usual therapy regimen, whereas children with t(4; 12) seemed to be easier to treat. Rearrangement of the TEL gene located on the short arm of chromosome 12 (12p13), was investigated in two adult patients. FISH analysis using the YAC probe that covers the TEL gene region, revealed split signals in these patients, suggesting a break inside or near the TEL gene. The t(4;12) abnormality is associated with unique characteristics of acute leukemia namely stem cell or secondary AML in adults, and B lymphoid leukemia in children.

Brain tumor as a second malignant neoplasm following neuroblastoma stage IV S

A rare brain tumor (spongioblastoma polare) occurring 7 years after treatment of neuroblastoma stage IV S is reported. The literature concerning the occurrence of a second cancer in children exposed to mutagenic therapy for their initial tumor is reviewed, and genetic and environmental factors are discussed. Diminishing aggressiveness of the treatment in childhood cancer with good prognosis should be considered. Continuous follow-up of children cured of cancer is warranted.

Drug-resistant lymphocytes in man as indicators of somatic cell mutation.

Direct in vivo tests of somatic mutation in man may provide realism in assessing the genetic risks of potential environmental mutagens. The autoradiographic determination of purine analogue (8-azaguanine; 6-thioguanine) resistant (AGr; TGr) peripheral blood lymphocytes (PBLs) arising in vivo in man is proposed as a candidate test. PBLs bearing the naturally occurring Lesch-Nyhan (LN) mutation are prototype mutant cells. LN PBLs are AGr and TGr, whereas normal PBLs are AG and TG sensitive. When judged by the inhibition of phytohemagglutinin (PHA) stimulated 3H-thymidine incorporation in vitro, analogue-resistant LN PBLs may be distinguished from analogue-sensitive normal PBLs by several methods. Early studies quantitating PHA stimulation by scintillation spectrometry detected down to 1% of LN PBLs in artificial mixtures with normal PBLs. Although LN heterozygous females could be identified on the basis of lymphocyte mosaicism, scintillation spectrometry was too insensitive to detect rare "LN-like" PBLs in non-LN individuals. Autoradiography, however, detected rare TGr PBLs in normal non-LN individuals. Their frequencies did not increase with age. With this method, TGr PBL frequencies in LN heterozygous females were found to range from 1 x 10(-3) to 5 x 10(-2), whereas blood samples from LN males showed from 23% to 100% TGr cells. Rare LN PBLs could be detected in artificial mixtures with normal cells. Studies in human patients undergoing various potential mutagenic therapies assessed the effects of these therapies on the TGr PBL variant frequencies (Vf) of non-LN individuals. Group TGr PBL Vf values were higher in treated patient groups than in controls. However, some untreated patient groups (cancer and psoriasis) also had elevated values, suggesting that disease itself may affect TGr PBL frequencies. Nonetheless, one patient group (vitiligo) showed elevated Vf values in treated (8-methoxypsoralen and long-range UV light = PUVA) but not in untreated patients, suggesting that treatment was responsible for the TGr PBL elevations. Longitudinal studies over time in cancer patients receiving X-irradiation therapy demonstrated that such exposures also are associated with TGr PBL frequency rises and suggested that longitudinal studies may be necessary to relate TGr PBL Vf elevations to specific environmental influences. Variant TGr PBLs were found at frequencies comparable to those in man in the peripheral blood of rats. They increased in a single study following treatment of the animals with a clinical alkylating agent. Characterization of the TGr PBLs suggests that some of these cells are mutants. Presumably the mutant cells arise in vivo by somatic cell mutation.

Simultaneous Occurrence of Non-Hodgkin’s Lymphoma and Spontaneous Acute Granulocytic Leukemia

The diagnosis of non-Hodgkin's lymphoma with spontaneous acute granulocytic leukemia was confirmed by examination of the patient's bone marrow and peripheral blood specimens at the light and electron microscopic level, and by autopsy findings. Only one previous case of simultaneous non-Hodgkin's lymphoma and acute myelomonocytic leukemia with no prior history of chemotherapy, radiotherapy, or both, has been reported. Although the present patient was given no mutagenic therapy, his chronic exposure to an unknown insecticide may have played a leukemogenic role.