The role of imaging in adaptive radiotherapy for head and neck cancer

Radiotherapy (RT), alone or combined with surgery and/or chemotherapy is given to almost all head and neck cancer (HNC). The goal of RT is to increase as much as possible the dose in the tumor to cure the patient, while limiting the dose in the organs at risk, mainly the parotids gland to limit the xerostomia. HNC RT appears particularly challenging due to the complexity of the shape of the anatomical structures, which also changes during the 7 weeks of treatment. Advances in imaging-modalities, -processing and -integration at the different RT steps have been crucial to develop a new image and dose-guided adaptive RT (ART) strategy. Moreover, the integration of functional imaging such as FDG-PET (performed before and during the treatment) leads to an even more highly targeted and dose-escalated ART. This article is an overview of the place and role of imaging at the different steps of HNCART, from a medical point of view.     

Thyroid cancer causing obstruction of the great veins in the neck

Tumor related pancreatic surgery has progressed significantly during recent years. Pancreatoduodenectomy (PD) with lymphadenectomy, including vascular resection, still presents the optimal surgical procedure for carcinomas in the head of pancreas. For patients with small or low-grade malignant neoplasms, as well as small pancreatic metastases located in the mid-portion of pancreas, central pancreatectomy (CP) is emerging as a safe and effective option with a low risk of developing de-novo exocrine and/or endocrine insufficiency. Total pancreatectomy (TP) is not as risky as it was years ago and can nowadays safely be performed, but its indication is limited to locally extended tumors that cannot be removed by PD or distal pancreatectomy (DP) with tumor free surgical margins. Consequently, TP has not been adopted as a routine procedure by most surgeons. On the other hand, an aggressive attitude is required in case of advanced distal pancreatic tumors, provided that safe and experienced surgery is available. Due to the development of modern instruments, laparoscopic operations became more and more successful, even in malignant pancreatic diseases. This review summarizes the recent literature on the abovementioned topics.     

Functional imaging in radiation therapy planning for head and neck cancer

Functional imaging and its application to radiotherapy (RT) is a rapidly expanding field with new modalities and techniques constantly developing and evolving. As technologies improve, it will be important to pay attention to their implementation. This review describes the main achievements in the field of head and neck cancer (HNC) with particular remarks on the unsolved problems.     

Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic

Thyroid hormone (l-thyroxine, T(4), or 3,5,3'-triiodo-l-thyronine, T(3)) treatment of human papillary and follicular thyroid cancer cell lines resulted in enhanced cell proliferation, measured by proliferating cell nuclear antigen (PCNA). Thyroid hormone also induced activation of the Ras/MAPK (ERK1/2) signal transduction pathway. ERK1/2 activation and cell proliferation caused by thyroid hormone were blocked by an iodothyronine analogue, tetraiodothyroacetic acid (tetrac), that inhibits binding of iodothyronines to the cell surface receptor for thyroid hormone on integrin alphaVbeta3. A MAPK cascade inhibitor at MEK, PD 98059, also blocked hormone-induced cell proliferation. We then assessed the possibility that thyroid hormone is anti-apoptotic. We first established that resveratrol (10 microM), a pro-apoptotic agent in other cancer cells, induced p53-dependent apoptosis and c-fos, c-jun and p21 gene expression in both papillary and follicular thyroid cancer cells. Induction of apoptosis by the stilbene required Ser-15 phosphorylation of p53. Resveratrol-induced gene expression and apoptosis were inhibited more than 50% by physiological concentrations of T(4). T(4) activated MAPK in the absence of resveratrol, caused minimal Ser-15 phosphorylation of p53 and did not affect c-fos, c-jun and p21 mRNA abundance. Thus, plasma membrane-initiated activation of the MAPK cascade by thyroid hormone promotes papillary and follicular thyroid cancer cell proliferation in vitro.     

Thyroid cancer risk 40+ years after irradiation for an enlarged thymus: an update of the Hempelmann cohort

Although ionizing radiation is a known carcinogen, the long-term risk from relatively higher-dose diagnostic procedures during childhood is less well known. We evaluated this risk indirectly by assessing thyroid cancer incidence in a cohort treated with "lower-dose" chest radiotherapy more than 55 years ago. Between 2004 and 2008, we re-surveyed a population-based cohort of subjects treated with radiation for an enlarged thymus during infancy between 1926 and 1957 and their unexposed siblings. Thyroid cancer occurred in 50 irradiated subjects (mean thyroid dose, 1.29 Gy) and in 13 nonirradiated siblings during 334,347 person-years of follow-up. After adjusting for attained age, Jewish religion, sex and history of goiter, the rate ratio for thyroid cancer was 5.6 (95% CI: 3.1-10.8). The adjusted excess relative risk per gray was 3.2 (95% CI: 1.5-6.6). The adjusted excess absolute risk per gray was 2.2 cases (95% CI: 1.4-3.2) per 10,000 person-years. Cumulative thyroid cancer incidence remains elevated in this cohort after a median 57.5 years of follow-up and is dose-dependent. Although the incidence appeared to decrease after 40 years, increased risk remains a lifelong concern in those exposed to lower doses of medical radiation during early childhood.     

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation: II. The role of connexin 32

The objective of this study was to determine whether connexin 32-type gap junctions contribute to the "contact effect" in follicular thyrocytes and whether the response is influenced by radiation quality. Our previous studies demonstrated that early-passage follicular cultures of Fischer rat thyroid cells express functional connexin 32 gap junctions, with later-passage cultures expressing a truncated nonfunctional form of the protein. This model allowed us to assess the role of connexin 32 in radiation responsiveness without relying solely on chemical manipulation of gap junctions. The survival curves generated after gamma irradiation revealed that early-passage follicular cultures had significantly lower values of alpha (0.04 Gy(-1)) than later-passage cultures (0.11 Gy(-1)) (P < 0.0001, n = 12). As an additional way to determine whether connexin 32 was contributing to the difference in survival, cultures were treated with heptanol, resulting in higher alpha values, with early-passage cultures (0.10 Gy(-1)) nearly equivalent to untreated late-passage cultures (0.11 Gy(-1)) (P > 0.1, n = 9). This strongly suggests that the presence of functional connexin 32-type gap junctions was contributing to radiation resistance in gamma-irradiated thyroid follicles. Survival curves from proton-irradiated cultures had alpha values that were not significantly different whether cells expressed functional connexin 32 (0.10 Gy(-1)), did not express connexin 32 (0.09 Gy(-1)), or were down-regulated (early-passage plus heptanol, 0.09 Gy(-1); late-passage plus heptanol, 0.12 Gy(-1)) (P > 0.1, n = 19). Thus, for proton irradiation, the presence of connexin 32-type gap junctional channels did not influence their radiosensitivity. Collectively, the data support the following conclusions. (1) The lower alpha values from the gamma-ray survival curves of the early-passage cultures suggest greater repair efficiency and/or enhanced resistance to radiation-induced damage, coincident with the expression of connexin 32-type gap junctions. (2) The increased sensitivity of FRTL-5 cells to proton irradiation was independent of their ability to communicate through connexin 32 gap junctions. (3) The fact that the beta components of the survival curves from both gamma rays and proton beams were similar (average 0.022 +/- 0.008 Gy(-2), P > 0.1, n = 39) suggests that at higher doses the loss of viability occurs at a relatively constant rate and is independent of radiation quality and the presence of functional gap junctions.     

Antioxidant role of N-acetyl cysteine isomers following high dose irradiation

High dose, acute radiation exposure, as in radiation accidents, induces three clinical syndromes that reflect consequences of oxidative protein, lipid, and DNA damage to tissues such as intestine, lung, and liver. In the present study, we irradiated C57BL/6 mice with 18 Gy whole-body radiation (XRT) and evaluated N-acetyl cysteine (NAC) isomers LNAC and DNAC as potential radioprotectors under conditions that would model the gastrointestinal syndrome. We focused on tissues thought not immediately involved in the gastrointestinal syndrome. Both LNAC and DNAC protected the lung and red blood cells (RBC) from glutathione (GSH) depletion following radiation exposure. However, only LNAC also supplemented the spleen GSH levels following XRT. Protection from increased malondialdehyde (MDA) levels (lung) and increased 8-hydroxy-deoxyguanosine (8-oxo-dG) presence (liver) following XRT was observed with treatment by either isomer of NAC. These results imply that either NAC isomer can act as a radioprotectant against many aspects of oxidative damage; chirality is only important for certain aspects. This pattern would be consistent with direct action of NAC in many radioprotection and repair processes, with a delimited role for NAC in GSH synthesis in some aspects of the problem.     

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine)

In the Zhytomyr region, about 52 000 measurements of the ¹³¹I activity in thyroids were performed. On the basis of these measurements, individual doses have been assessed for the people monitored and age-dependent average doses have been estimated for those settlements with more than 11 direct measurements. In order to estimate the pattern of thyroid exposure in the Zhytomyr region, these doses have been interpolated or extrapolated to population groups who were not monitored during May–June 1986. For this purpose, a model has been developed based on a correlation between thyroid dose estimates with the ¹³⁷Cs deposition and the co-ordinates of the settlements relative to Chernobyl. Collective doses of people who were born in the years 1968 to 1986 were calculated. The radiation-induced thyroid cancer incidence in the period 1991 to 1995 was assessed by subtracting the spontaneous incidence from the observed incidence. The result is considerably lower than that observed in longer periods after external exposures. Possible reasons for this difference are discussed. Received: 17 January 1997 / Accepted in revised form: 2 October 1997     

Hypopituitarism following pituitary irradiation for acromegaly

Endocrine evaluation is reported in 8 acromegalic patients who received 5,500 rad to the pituitary from a linear accelerator. There was a mean decrease in hGH levels of 72%. Plasma testosterone levels were low in 1 of the 6 male patients prior to pituitary irradiation and were below normal in all male patients on the final evaluation (3.1 +/- 0.2 SD years postirradiation). Deficiency of TSH secretion developed in 2 patients following irradiation. This rather high incidence of postirradiation partial hypopituitarism was not anticipated, and is thought to be related to radiation necrosis of the normal pituitary tissue which surrounds the adenoma.     

Booster irradiation to the spleen following total body irradiation. A new immunosuppressive approach for allogeneic bone marrow transplantation

Graft rejection presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, after conditioning exactly as for leukemia patients, it was shown that over 99% of the residual host clonable T cells are concentrated in the spleen on day 5 after completion of cytoreduction. We have now corroborated these findings in a mouse model. After 9-Gy total body irradiation (TBI), the total number of Thy-1.2+ cells in the spleen reaches a peak between days 3 and 4 after TBI. The T cell population is composed of both L3T4 (helper) and Lyt-2 (suppressor) T cells, the former being the major subpopulation. Specific booster irradiation to the spleen (5 Gy twice) on days 2 and 4 after TBI greatly enhances production of donor-type chimera after transplantation of T cell-depleted allogeneic bone marrow. Similar enhancement can be achieved by splenectomy on day 3 or 4 after TBI but not if splenectomy is performed 1 day before TBI or 1 day after TBI, strengthening the hypothesis that, after lethal TBI in mice, the remaining host T cells migrate from the periphery to the spleen. These results suggest that a delayed booster irradiation to the spleen may be beneficial as an additional immunosuppressive agent in the conditioning of leukemia patients, in order to reduce the incidence of bone marrow allograft rejection.     

Adhesion molecules in cancer of the head and neck: role of dysadherin

Dysadherin is a recently discovered cancer-related cell membrane glycoprotein that has an important role in tumor progression and metastasis. We are focusing on the role of dysadherin in E-cadherin downregulation, the different expression patterns of the molecule in cancer of the head and neck and its potential role as a molecular target for future applications in diagnosis, prognosis, and management of the disease.