Late Complications in Long-Term Childhood Cancer Survivors: What the Oral Health Professional Needs to Know.

With diagnostic and therapeutic advances, over 80% of children diagnosed with cancer become long-term survivors. As the number of childhood cancer survivors (CCS) continues to increase, dental practitioners become more likely to have CCS among their patients. CCS may develop late complications from damage caused by their cancer treatment to endocrine, cardiovascular, musculoskeletal, and other organ systems. These complications may surface decades after the completion of treatment. Adverse outcomes of childhood cancer treatment frequently involve oral and craniofacial structures including the dentition. Tooth development, salivary gland function, craniofacial growth, and temporomandibular joint function may be disturbed, increasing oral health risks in these individuals. Moreover, CCS are at risk of developing subsequent malignancies, which may manifest in or near the oral cavity. It is important that dental practitioners are aware of the childhood cancer history of their patients and have knowledge of potential late complications. Therefore, this narrative review aims to inform dental practitioners of late oral complications of cancer treatment modalities commonly used in pediatric oncology. Furthermore, selected common non-oral late sequelae of cancer therapy that could have an impact on oral health and on delivering dental care will be discussed.

Tooth Formation as Experimental Model to Study Chemotherapy on Tissue Development: Effect of a Specific Dose of Temozolomide/Veliparib.

BACKGROUND: Chemotherapy treatment of cancer in children can influence formation of normal tissues, leading to irreversible changes in their structure and function. Tooth formation is susceptible to several types of chemotherapy that induce irreversible changes in the structure of enamel, dentin and dental root morphology. These changes can make the teeth more prone to fracture or to caries when they have erupted. Recent studies report successful treatment of brain tumors with the alkylating drug temozolomide (TMZ) in combination with veliparib (VLP) in a glioblastoma in vivo mouse model. Whether these drugs also affect tooth formation is unknown. AIM: In this study the effect of TMZ/VLP on incisor formation was investigated in tissue sections of jaws from mice and compared with mice not treated with these drugs. MATERIALS AND METHOD: The following aspects were studied using immunohistochemistry of specific protein markers including: (1) proliferation (by protein expression of proliferation marker Ki67) (2) a protein involved in paracellular ion transport (expression of tight junction (TJ) protein claudin-1) and (3) in transcellular passage of ions across the dental epithelium (expression of Na+, K+ 2Cl- cotransporter/NKCC1). RESULTS: Chemotherapy with TMZ/VLP strongly reduced immunostaining for claudin-1 in distal parts of maturation ameloblasts. No gross changes were found in the treated mice, either in cell proliferation in the dental epithelium at the cervical loop or in the immunostaining pattern for NKCC1 in (non-ameloblastic) dental epithelium. The salivary glands in the treated mice contained strongly reduced immunostaining for NKCC1 in the basolateral membranes of acinar cells. DISCUSSION/CONCLUSIONS: Based on the reduction of claudin-1 immunostaining in ameloblasts, TMZ/VLP may potentially influence forming enamel by changes in the structure of TJs structures in maturation ameloblasts, structures that are crucial for the selective passage of ions through the intercellular space between neighboring ameloblasts. The strongly reduced basolateral NKCC1 staining seen in fully-grown salivary glands of TMZ/VLP-treated mice suggests that TMZ/VLF could also influence ion transport in adult saliva by the salivary gland epithelium. This may cause treated children to be more susceptible to caries.

The Importance of Connexin 43 in Enamel Development and Mineralization.

During enamel development, formation of hydroxyapatite crystals and regulation of pH in the enamel matrix require massive transport of ions. Both ameloblasts and adjacent dental epithelial cells in the stellate reticulum co-express several transmembrane cotransporters/ion-exchangers for transport of ions across plasma membranes. Gap junctions (GJs) enable intercellular exchanges of ions between neighboring cells. This suggests that the ameloblasts and other cell layers of the enamel organ, form a functional unit. During the bell stage of tooth formation, the non-ameloblast dental epithelium highly expresses the Na-K-Cl cotransporter (Nkcc1). Nkcc1-null mice are associated with enamel hypomineralization and increased expression of GJ protein connexin 43 (Cx43), suggesting that reduced ion transport in the Nkcc1-null mouse is in part compensated by increased intercellular ion transport through GJs. To understand the role of GJs in ion transport and its effect on pH regulation, we examined in a mouse strain in which Cx43 was ablated selectively in DMP1 expressing cells (Cx43flox/flox mice crossed with DMP1-8kb-Cre mice), including ameloblasts. Micro-CT analysis showed that the mineral density at late maturation stage incisal enamel of the Cx43-null mice was 10% less than in controls, whereas that in dentin was unchanged. Maturation stage ameloblasts of mice lacking the pH regulating sodium/bicarbonate transporter NBCe1 (Nbce1-null), or chloride channel Cftr (Cftr-null) were found to have increased Cx43-immunostaining. These results support the possibility that GJs in the ameloblast-papillary complex at the maturation stage contribute to ion transport by enabling passage of ions directly from cells of the papillary layer into ameloblast layer. Increasing the number of GJs may partly compensate the reduction of ion-cotransporters and ion exchangers in dental epithelium.

The effect of a single injection of irinotecan on the development of enamel in the Wistar rats.

Cancer is the second most frequent cause of death in children. Because the prognosis for childhood malignancies has improved, attention has now focused on long-term consequences of cancer treatment. The immediate effects of chemotherapy on soft tissues have been well described; however, there is less information about long-term effects of chemotherapy on the development of dental tissues. To test the association between the effect of chemotherapy on enamel development, we examined two groups of rats: one that had received an intraperitoneal dose of 200 mg/kg of irinotecan, whereas the other (control) group had received vehicle only. Rats were killed at 6, 48 and 96 hr post-injection; the mandibles dissected out, fixed for histological evaluation and scanned for mineralization defects by Micro-CT. Our results showed structural changes in the ameloblast layer along with a significant reduction in mineralization and thickness of enamel at 96 hr after chemotherapy. These data demonstrate that irinotecan induces structural changes in forming enamel that become apparent after anticancer chemotherapy treatment.

Oral Mucositis Induced By Anticancer Therapies.

Oral mucositis induced by conventional cytotoxic cancer therapies is a common and significant clinical problem in oncology. Mucositis symptoms, which include severe pain, may lead to dose reductions and unplanned interruptions of chemotherapy and/or radiotherapy, and often affect patients' quality of life. In addition, ulcerative mucositis represents a risk factor for local or systemic infectious complications that may be life-threatening in immunosuppressed patients. The development of biologically based targeted cancer therapies, which aim to block the growth, spread, and survival of tumors by interfering with specific molecular targets, may have reduced mucosal injury, but did not eliminate it. This article will review the epidemiology, pathobiology, and management of oral mucositis associated with conventional cytotoxic therapies for malignant diseases and will briefly summarize emerging information on oral mucosal injury associated with targeted therapies. Considerations for future research aimed at the development of more efficient and effective supportive care approaches will be presented, with emphasis on the contribution of dental researchers and clinicians in these efforts.

Novel hemostatic patch achieves sutureless epicardial wound closure during complex cardiac surgery, a case report.

Treatment of damaged cardiac tissue in patients with high bleeding tendency can be very challenging, damaged myocardial tissue has a high rupture risk when being sutured subsequently on-going bleeding is a major risk factor for poor clinical outcome. We present a case demonstrating the feasibility in using a novel haemostatic collagen sponge for the management of a myocardial wound. This report is the first description in cardiac surgery where Hemopatch sponges are used to successfully seal a left ventricle wound. Our patient was diagnosed with endocarditis, had a low pre-operative haemoglobin count and underwent cardiac surgery for multiple valve repairs. The procedure was performed on cardiopulmonary bypass, which meant our patient had to be heparinized. Despite these major risk factors for bleeding Hemopatch managed to contain bleeding and seal the wound, no sutures were needed.

Cognitive performance and convulsion risk after experimentally-induced febrile-seizures in rat.

Many reports indicated that small percentage of children with febrile seizures develop epilepsy and cognitive disorders later in adulthood. In addition, the neuronal network of the hippocampus was reported to be deranged in adult animals after being exposed to hyperthermia-induced seizures in their neonatal life. The aims of this study were to investigate (1) latency and probability of seizures, (2) spatial learning and memory, in adult rats after neonatal hyperthermia-induced febrile seizures (FS). Prolonged FS were elicited in 10-day old, male Sprague Dawleys (n=11/group) by exposure to heated air (48-52 °C) for 30 min; control rats were exposed to 30 °C air. After 1.5 months the animal's cognitive performance was assessed by 5 day trial in the Morris water maze. In another experiment the latency and probability of seizures were measured in response to pentylenetetrazole (PTZ) injections (increased doses ranged from 7 to 140 mg/kg; i.p.). In water maze, both groups showed improvements in escape latency and distance swam to reach the platform; effects were significantly greater in control versus hyperthermia-treated animals on days 3 and 4. Latency and probability of PTZ-induced seizures were shorter and higher respectively, in hyperthermia-treated animals compared to controls. We concluded that FS in neonatal rats leads to enhanced susceptibility for seizures, as well as cognitive deficits in adults.

Single-chain VEGF/Cy5.5 targeting vegf receptors to indicate atherosclerotic plaque instability.

PURPOSE: Unstable plaques may cause clinical events. Plaque destabilization results from the synergy between intraplaque angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) are considered to be involved in these processes. We investigated the efficacy of the anti-VEGFR mimic single-chain VEGF (scVEGF) to map intra-plaque VEGFR expression and atherosclerotic plaque instability using near-infrared fluorescence (NIRF). PROCEDURES: Human carotid plaques were retrieved from 15 symptomatic and five asymptomatic patients. NIRF plaque imaging was performed pre-/post-incubation with scVEGF/Cy5.5. Biopsies taken from regions with high (hot spot) and low (cold spot) NIRF signals were examined for VEGF-A, VEGFR-1 and VEGFR-2 mRNA expression levels using real-time RT-PCR analysis. Immunohistochemistry for CD31 (endothelium), CD68 (macrophages) and αSMA (smooth muscle cells) was performed to evaluate plaque composition. RESULTS: NIRF imaging of 20 plaques revealed a heterogeneous distribution of scVEGF/Cy5.5 binding. After incubation NIRF activity increased from 3.9×10(-5) ± 5.2×10(-6) to 3.0×10(-4) ± 2.2×10(-5) and 5.8×10(-5) ± 1.9×10(-5) to 3.1×10(-4) ± 1.9×10(-5) photons/s/cm(2)/sr/illumination intensity on the intraluminal and extraluminal side, respectively (both p < 0.001). Real-time RT-PCR analysis showed a ~1.2- and ~16.4-fold increased mRNA expression of VEGFR-1 and VEGFR-2, respectively, in hot spots (vs. cold spots). Immunohistochemistry exhibited higher intraplaque capillary density in hot spots (vs. cold spots) (17.2 ± 3.7 vs. 5.4 ± 2.2 capillary/mm(2); p = 0.037). Hot spots contained significantly reduced numbers of α-SMA-positive cells (vs. cold spots) (2.2 ± 0.7 % vs. 6.9 ± 1.5 %; p = 0.038). Finally, a ~2-fold increase of CD68(+) infiltrating macrophages within hot spots (vs. cold spots) was observed (not significant, p = 0.17). Significant higher capillary density in hot spots (vs. cold spots) was observed in plaques from symptomatic patients but not in plaques from asymptomatic patients. CONCLUSION: Our data support that scVEGF/Cy5.5 is a suitable indicator for plaque instability and a promising diagnostic tool for risk assessment in cardiovascular diseases.

Galectins in atherosclerotic disease.

Although cells constantly adapt to external humoral cues, like cytokines and hormones, in practice, most cellular behavior is under locally guided control, via cell-cell interactions. The most prominent members of this group of molecules involved in this intercellular signaling are the galectins, a family of carbohydrate-binding proteins, which by binding specific receptors induce signaling. It has become clear that galectins are important in the pathogenesis of cardiovascular disease, in particular atherosclerosis, stroke, myocardial infarction, and heart failure. Modulation of galectin signaling holds great promise for the treatment of cardiovascular disease as evident from preclinical studies.