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Chemotherapy-induced nausea and vomiting (CINV) is one of the most common treatment side-effects, and remains a significant concern, in children undergoing chemotherapy. Although adult patients receive chemotherapy regimens combined with appropriate standardized antiemetic treatment, children can receive markedly varying antiemetic treatments. A narrative review of CINV was performed regarding CINV definition, scoring system, prevention and treatment, specifically focussing on studies conducted with paediatric oncology patients. The review highlighted a lack of rigorously developed CINV scoring systems and standardized CINV pharmacological treatment for paediatric oncology patients. Different scoring systems were found to identify potential risk factors for CINV associated with the use of several different antiemetic drugs, however, few studies have been performed in children undergoing chemotherapy. Thus, CINV remains a distressing and partially controlled side-effect in the paediatric patient population. To reduce emesis and improve quality of life in paediatric oncology patients, standardized antiemetic treatment may be preferred, using a unique CINV scoring system that accounts for the emetogenic level of the chemotherapy regimen adopted and the children's clinical characteristics.

The clinical use of antineoplastic drugs can be limited by different drug-induced toxicities. Of these, renal dysfunction may be one of the most troublesome in that it can be cumulative and in general is only partially reversible with the discontinuation of the treatment. Renal toxicity may be manifested as a reduction of the glomerular filtration rate, electrolyte imbalances, or acute renal failure. Careful assessment of renal function has to be performed taking into account that the impairment of renal function is initially silent and only later may be clinically dramatic. When clinically indicated, the reduction or, in cases of severe nephrotoxicity, the suspension of chemotherapy should be considered to avoid the progressive deterioration of the compromised glomerular and/or tubular function., (© 2017 The British Pharmacological Society.)

Introduction: Recent studies indicated tumors may be comprised of heterogeneous molecular subtypes and incongruent molecular portraits may emerge if different areas of the tumor are sampled. This study explored the impact of intra-tumoral heterogeneity in terms of activation/phosphorylation of FDA approved drug targets and downstream kinase substrates., Material and Methods: Two independent sets of liver metastases from colorectal cancer were used to evaluate protein kinase-driven signaling networks within different areas using laser capture microdissection and reverse phase protein array., Results: Unsupervised hierarchical clustering analysis indicated that the signaling architecture and activation of the MAPK and AKT-mTOR pathways were consistently maintained within different regions of the same biopsy. Intra-patient variability of the MAPK and AKT-mTOR pathway were <1.06 fold change, while inter-patients variability reached fold change values of 5.01., Conclusions: Protein pathway activation mapping of enriched tumor cells obtained from different regions of the same tumor indicated consistency and robustness independent of the region sampled. This suggests a dominant protein pathway network may be activated in a high percentage of the tumor cell population. Given the genomic intra-tumoral variability, our data suggest that protein/phosphoprotein signaling measurements should be integrated with genomic analysis for precision medicine based analysis.

Background: As the early detection and total destruction of gliomas are essential for longer survival, we attempted to synthesize a quantum dot (QD) that is capable of recognizing glioma cells for imaging and photodynamic therapy., Methods: Using a one-pot aqueous approach, near infrared-emitting CdTe was produced. After detection of its physicochemical characteriistics, it was conjugated with RGD. The emission images were observed with confocal microscopy. To test its toxicity, CdTe-RGD at various concentrations was separately added to a human glioma cell line (U251) and a mouse embryo fibroblast cell line (3T3) (control) for incubation in dark conditions. To test its photodynamic effect, the U251 and 3T3 cells were then irradiated for 5-60 min, using a 632.8-nm laser., Results: This QD (Φ = 3.75 nm, photoluminescence (PL) peak wavelength = 700 nm, photoluminescence quantum yield (PLQY) = 20 %), was a spherical crystal with excellent monodispersity. Under a confocal microscope, U251 cells were visualized, but not the 3T3 cells. In dark conditions, the survival rates of both U251 and 3T3 cells were above 85 %. After laser irradiation, the survival rate of U251 cells decreased to 37 ± 1.6 % as the irradiation time and the CdTe-RGD concentration were increased., Conclusions: With good physicochemical characteriistics and low toxicity, this QD-RGD has broad prospects for use in the biomedical imaging and photodynamic therapy of gliomas.

Introduction: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma. Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children. Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.

Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy., Implications for Practice: The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients., (©AlphaMed Press.)

Background: In case of Krukenberg tumor (KT) of gastric origin it is controversial and debated whether radical surgery in case of synchronous KT or metastasectomy in case of metachronous ones is associated with additional benefits. Role of perioperative treatments is unclear., Methods: Among 2515 female patients who were diagnosed with gastric cancer between January 1990 and December 2012 from 9 Italian centers, 63 presented simultaneously or developed KT as recurrence., Results: Thirty patients presented with synchronous KT, while 33 developed metachronous ovarian metastases during follow-up. The differences between the two groups were analyzed and compared. The median age of 63 patients was 48.0 years (range 31-71). Resection was possible in 53 patients (20 synchronous and 33 metachronous). Twelve patients in the synchronous group and 15 patients of the metachronous group underwent hyperthermic intraperitoneal chemotherapy after resection of KT. All of them underwent adjuvant chemotherapy after KT resection. The median survival for all population was 23 months (95 % confidence interval, 7-39 months). The median survival time in the metachronous group was 36 months, which was significantly longer than that in the synchronous group, 17 months, p < 0.0001., Conclusions: KT remains a clinical challenge for gastric cancer therapy. The extent of disease and feasibility of removal of the metastatic lesion must be carefully evaluated prior to surgery to define the patients group who could benefit most from a resection associated with perioperative treatments.

Background: Imiquimod 3.75% reduces 92.2% of all actinic keratosis (AK) lesions, assumed to include both subclinical and clinical lesions, across a large sun-exposed field such as the full face or balding scalp., Objective: To evaluate the efficacy of imiquimod 3.75% using the reduction in lesions from Lmax (the maximum lesion count during treatment) in subgroups of patients with low and high AK lesion counts., Methods: Patients from two 14-week, placebo-controlled, double-blind studies were subgrouped according to whether they had ≤ 10 or >10 AK lesions at baseline. Treatment was applied to the full face or balding scalp during two 2-week treatment cycles separated by a 2-week treatment-free interval., Results: Overall, 167 patients had ≤ 10 lesions and 152 patients had >10 AK lesions at baseline. With imiquimod 3.75%, the median percentage reduction in AK lesions from Lmax to end of study was similar in patients with ≤ 10 and >10 baseline lesions (91.5% and 93.0% respectively). The median absolute reduction in AK lesions from Lmax to end of study was 24.0 for patients with >10 baseline lesions and 10.0 for those with ≤ 10 baseline lesions. The median percentage and absolute reductions in lesions from Lmax were significantly greater with imiquimod 3.75% vs. placebo (P < 0.0001)., Conclusions: Imiquimod 3.75% is effective regardless of disease severity as shown in this study by the reduction of over 90% of lesions from Lmax in patients with low or high AK lesion counts., (© 2014 European Academy of Dermatology and Venereology.)

Background: Actinic keratoses (AKs) are precursors to invasive squamous cell carcinoma and can progress if untreated. Limited data support the use of ingenol mebutate to treat AKs on more than one area of the body simultaneously., Objective: To investigate safety, efficacy and treatment satisfaction when treating separate areas simultaneously or sequentially with different concentrations of ingenol mebutate gel., Methods: In this phase IIIb study (NCT01787383), patients with clinically visible, non-hyperkeratotic AKs on two separate treatment areas (face/scalp and trunk/extremities) were randomized to simultaneous or sequential treatment with ingenol mebutate gel (0.015% and 0.05%). Endpoints included composite local skin response (LSR) score 3 days after first application, complete AK clearance and percentage reduction in AKs at week 8., Results: There were no statistically significant differences between simultaneous (n = 101) and sequential (n = 98) groups in composite LSR score (10.4 vs. 9.7), complete clearance (52.7% vs. 46.9%) or percentage reduction in AKs (83.4% vs. 79.1%). Mean composite LSR scores on face/scalp and trunk/extremities were similar for both groups. Adverse event (AE) incidence was comparable between groups, the most common treatment-related AEs being pruritus and pain at the application site., Conclusion: Treating AKs with ingenol mebutate simultaneously or sequentially gave similar results in terms of tolerability (LSR score, AEs) and efficacy (complete clearance). Therefore, the physician and patient can select the most convenient treatment regimen, with confidence in achieving a similar outcome., (© 2015 LEO Pharma A/S. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons, Ltd. on behalf of European Academy of Dermatology and Venereology.)

Background and Purpose: 13-cis-Retinoic acid represents a well-established clinical strategy for the management of minimal residual disease of high risk neuroblastoma (NB) patients. However, the clinical efficacy on the overall survival of these patients remains limited, addressing the issue of better understanding the molecular mechanisms and intracellular pathways mediating Retinoic Acid (RA) clinical effects., Experimental Approach: This work investigates the mechanism underlying the sensitivity/resistance to RA in NB by taking advantage of the paired SK-N-AS/rAS-ST cells showing different responsivity to ATRA. The subline rAS-ST was selected by inducing resistance to the novel retinoid ST1926 in the NB SK-N-AS cell line., Key Results: Resistance to ST1926 was neither dependent on cellular uptake nor on multi-drug resistance phenotype. Rather, both delayed/lower DNA damage and apoptosis appeared involved in reduced sensitivity of rAS-ST cells to ST1926. This subline showed enhanced responsivity to ATRA compared to the wt counterpart, that was associated with enhanced RARα/β expression, DNA damage, G2 accumulation, PI3K/AKT pathway inhibition, cellular differentiation and delayed telomerase inhibition, without involvement of either p27/p53 or caspase-mediated apoptosis., Conclusions and Implications: The present data add important information to the understanding of RA sensitivity in NB, providing further insights towards a more efficacious clinical use of this drug., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Basal cell carcinoma (BCC) is the most common skin cancer worldwide. Most occur on the head and neck, where cosmetic and functional outcomes are critical. BCC can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for the majority of high-risk lesions. Aggressive, recurrent or unresectable tumors can be difficult to manage. Until recently, no approved systemic therapy was available for locally advanced or metastatic BCC inappropriate for surgery or radiotherapy. Vismodegib provides a systemic treatment option. However, a consensus definition of advanced BCC is lacking. A multidisciplinary panel with expertise in oncology, dermatology, dermatologic surgery and radiation oncology proposes a consensus definition based on published evidence and clinical experience.

Platinum compounds are widely used in the treatment of pediatric tumors such as neuroblastoma, germ-cell tumors, osteosarcoma, retinoblastoma, hepatoblastoma, brain tumors (low-grade gliomas and medulloblastoma/PNET), and relapsed and refractory lymphomas. The three major platinum compounds (cisplatin, carboplatin, and oxaliplatin) have a similar pharmacokinetics profile and mechanism of action, but the differences in their chemical structure are responsible for their different antitumor activity and toxicity. In this review, we have described the main characteristics of cisplatin, carboplatin, and oxaliplatin, focusing on their toxic effects and possible strategies to prevent them to improve the clinical outcomes in pediatric cancer patients. The underlying mechanism of each platinum-related toxicity is shown together with the clinical manifestations. Furthermore, possible preventive strategies are suggested to reduce the negative impact of platinum compounds on the quality of life of children with cancer. Cisplatin seems to be mostly ototoxic and nephrotoxic, carboplatin mainly produces myelosuppression, whereas oxaliplatin induces predominantly peripheral sensory neurotoxicity. In contrast, nausea and vomiting can be linked to all platinum compounds, although cisplatin exerts the strongest emetic effect. A correct knowledge of pharmacokinetics and toxicological profile of platinum compounds may aid physicians prevent their toxicity on auditory, nervous, renal, and bone marrow function, improving the quality of life of pediatric cancer patients.

Background & Aims: Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points., Methods: Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant., Results: The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002, <0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS., Conclusions: D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Hypersensitivity reactions (HSRs) may occur in children with cancer during the use of almost all chemotherapeutic drugs. HSRs may also produce a negative impact on treatment intensity and, as a consequence, worsen patients' outcome. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring in children with cancer treated with chemotherapeutic drugs and their impact on treatment efficacy, in order to outline possible adequate prevention and management strategies., Methods: Data were collected by searching for relevant studies about incidence, clinical features and management of hypersensitivity reactions that may occur with the use of chemotherapeutic agents in children aged 0-18 years, published from January 1976 to December 2012 in the PubMed database., Results: In children with cancer treated with chemotherapeutic drugs (especially platinum compounds, methotrexate, L-asparaginase), HSRs commonly present with mild/moderate to severe clinical patterns. Multiple factors appear to affect reaction rates, including route, rate of administration, previous exposure, drug form, presence of excipients. The occurrence of hypersensitivity to a chemotherapeutic agent can include the avoidance of re-exposure. For sensitized patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitization or treatment with a related compound., Conclusions: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions to antineoplastic drugs are commonly encountered. Clinicians must not underestimate the potential risk and occurrence of HSRs in the pediatric population. Knowledge of the different presentations of these reactions can help to develop strategies for the prevention and the management of HSRs in order to ensure treatment outcome, to improve the quality of patient care and to reduce healthcare costs.

Wiskott-Aldrich syndrome (WAS) is characterized by primary immunodeficiency, thrombocytopenia and eczema. Patients with WAS have an increased risk to develop tumors. Non-Hodgkin lymphoma (NHL) represents the most common malignancy occurring in WAS-affected patients, diffuse-large-B-cell lymphoma is the most frequently encountered variant. We describe a case of a patient with WAS and NHL in the pharynx, an atypical tumor site presentation. The patient was successfully treated with a reduced dose chemotherapy regimen plus anti-CD20 monoclonal antibody. He is in complete remission 3 years from the start of treatment., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the digestive tract. They have recently been recognized as a separate nosological entity and the literature on these stromal tumors has rapidly expanded., Materials and Methods: The surgical records of 50 patients with primary GISTs treated at the Digestive Surgery Department of the Catholic University of Rome from January 1993 to December 2010 were reviewed and the prognostic factors were analyzed., Results: Surgery was performed in all patients with curative intent. The median age at presentation was 66.5 years (range, 28-81). Adjuvant therapy was administered in 26 (52%) cases. Median follow-up was 71 months (range, 5-208). There was an 8% recurrence rate. The actuarial 5-year overall and disease-free survival rates were 66.3% and 57.2%, respectively. High mitotic rate (P <0.001), tumor size greater than 10 cm (P = 0.007) and tumor rupture (P = 0.05) were the only prognostically significant negative factors for overall survival in multivariate analysis., Conclusions: The present study confirmed the important role of aggressive surgical management of GISTs to offer these patients the most appropriate treatment for long-term survival.

Purpose: The number of oral anticancer agents has greatly increased in recent years. It is a well-known fact that food intake can induce significant variations in the bioavailability of these drugs. The aim of this review is to describe the interactions between diet and oral anticancer drugs in terms of the possible effects of such interactions on reducing the antineoplastic activity of the drug or increasing its side effects., Methods: This was an analytical study of the numerous mechanisms leading to changes in the bioavailability of oral antineoplastic agents due to diet., Results: Food-drug interactions can induce a delay, decrease or increase in the absorption of the oral chemotherapeutic agent. The concomitant intake of food and antineoplastic drugs influence the pharmacokinetic and pharmacodynamic drug processes depending on the composition of the food consumed and the specific interactions of the food with transport mechanisms (p-glycoprotein, multidrug resistance proteins) and intestinal enzymatic systems (cytochrome P450)., Conclusions: In prescribing an oral anticancer agent, clinicians must consider the possibility that the consumption of specific food items has the potential to interfere with the pharmacokinetics and pharmacodynamics of the prescribed drug.

Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.

Aims and Background: Merkel cell carcinoma (MCC) is a rare skin tumor occurring mostly in older people. Postoperative radiotherapy is strongly recommended to improve local control. A case of a MCC treated by radiotherapy associated with imiquimod (Aldara) is presented. A possible physiopathological rationale for this concomitant treatment is also given., Materials and Methods: We treated a diabetic 82-year-old man presenting with a MCC of the right zygomatic area. Despite surgery, postoperative ultrasonography showed a firm, painless residual mass of about 11 x 10 cm, fixed to the deep tissues. Parotid and zygomatic areas were treated along with the ipsilateral laterocervical lymph nodes. The total dose to the planning target volume was 50.4 Gy (1.8 Gy/day). Imiquimod was applied once a day to the zygomatic area with macroscopic infiltration and to the surrounding erythema., Results: During the combination treatment, the patient showed acute G3 skin toxicity (RTOG) and a scab that resolved after a 3-week interruption of the radiotherapy and imiquimod treatment. When the scab was removed, the underlying skin appeared completely re-epithelialized. Imiquimod was suspended and treatment was continued only with irradiation. During this second phase of the treatment, the patient developed G2 dermatitis and G2 stomatitis. Clinical and instrumental re-evaluation showed a complete response 7 months after the end of radiotherapy, with very good local tropism., Conclusion: This case report suggests the possible effective use of immunomodulators, in this case imiquimod, combined with radiation therapy for cutaneous malignancies such as MCC. Skin tolerance should be an important issue to consider.

Nausea and vomiting are respectively the first and third most relevant chemotherapy-associated side effects in pediatric oncology, despite the introduction of new antiemetic agents. Symptoms change according to the antineoplastic agents used, and are influenced by age since emotional and psychological aspects play an important role. Studies conducted on new antiemetic therapies usually focus on adult populations affected by tumors, whereas there are very few series including pediatric patients, who are even more severely affected by this specific side effect.

Over the last 40 years, a significant advance has been made in the treatment of childhood and adult cancers. However, the increase of the survival rate points out medium- and long-term adverse effects that constitute a serious limitation for the quality of life in adults survived from a childhood cancer. Cardiovascular disease is an important cause of morbidity and mortality in adults treated with chemo- and radiotherapy for childhood cancers. Although some antitumor treatments are potentially cardiotoxic, anthracycline therapy and radiotherapy are mostly responsible for long-term cardiac damage. Anthracycline toxicity is generally limited to the myocardium, while radiation can cause injury to all components of the heart. The purpose of this review is to discuss the mechanisms of action of anthracyclines, their cardiotoxicity, the feasibility of screening, and the prevention of cardiac damage after treatment in childhood.

E-3-(4'-Hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid (ST1926) is a novel orally available compound belonging to the class of synthetic atypical retinoids. These agents are attracting growing attention because of their unique mechanism of antitumor action that appears different from that of classical retinoic acid. This study aims at investigating the antitumor activity of ST1926 in neuroblastoma (NB) preclinical models. In vitro, ST1926 was more cytotoxic than both its prototype, CD437 and all-trans-retinoic acid (ATRA) and it was active in the SK-N-AS cell line, which is refractory to ATRA. We showed that unlike ATRA, ST1926 does not induce morphological differentiation in NB cells where it produces indirect DNA damage, cell cycle arrest in late S-G2 phases and p53-independent programmed cell death. DNA damage was not mediated by oxidative stress and was repaired by 24h after drug removal. The SK-N-DZ cell line appeared the most sensitive to the proapoptotic activity of ST1926, probably because both the extrinsic and intrinsic pathways appear involved in the process. Studies with Z-VAD-FMK, suggested that ST1926 might also mediate caspase-independent apoptosis in NB cells. In vivo, orally administered ST1926, appeared to inhibit tumor growth of NB xenografts with tolerable toxicity. Overall, our results support the view that ST1926 might represent a good drug candidate in this pediatric tumor.

The purpose of this study was to evaluate cisplatin-induced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls (p<0.05). When tiopronin was added, DPOAE responses were significantly increased compared to those obtained with the administration of cisplatin alone (p<0.05). The cochleogram showed that tiopronin had a significant protective effect in the basal half and in the lower half of the middle turn. We conclude that tiopronin, a drug effective in protecting against cisplatin nephrotoxicity, is also effective in protecting against cisplatin ototoxicity.

A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees. Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto-vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects.

The aim of the present study was to investigate both vestibular and cochlear cisplatin toxicity. Twelve albino guinea pigs were divided into an experimental (n=8) and a control saline group (n=4) and were treated with cisplatin at a daily dose of 2.5 mg/kg for 6 consecutive days. Vestibular dysfunction was evaluated by computing the gain of the vestibular ocular reflex (VOR) evoked by stimulation in the horizontal (HVOR) and vertical (VVOR) planes. Changes in cochlear function were characterised as compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. The onset of vestibular functional impairment was observed on the third day, although the VOR gain decrease was not significant. The impairment of the vestibular function progressed until the sixth day becoming statistically significant particularly at VVOR mid frequencies of stimulation. At these frequencies both macula and crista ampullaris functions are involved. Concomitantly a progressive auditory threshold shift was observed at all stimulus frequencies. The decline of the auditory function was statistically significant from the third day of treatment and it was more evident at high frequencies. Morphological observations showed a massive loss of outer hair cells and a degeneration of the organ of Corti in the basal/middle turns and only a slight loss of hair cells of the cristae ampullares and maculae. In conclusion, functional and morphological data provide evidence that the toxic effect of cisplatin is more pronounced in the organ of Corti than in the vestibular epithelium.

Hypersensitivity reactions to carboplatin are rare but sometimes life-threatening events may occur requiring discontinuation of treatment. In our study, we describe clinical features and diagnostic procedures of carboplatin-associated reactions in children affected by low-grade astrocytoma and treated with multiple courses of carboplatin. In 6 out of 29 children, we reported allergic events. We also report a desensitization protocol for carboplatin administration, which allowed the patients to receive effective treatment without adverse reactions.

Purpose: BBR 3464 is a promising new trinuclear platinum complex that has been shown to circumvent the resistance to cisplatin in a panel of tumor cell lines and xenografts with acquired or intrinsic resistance to cisplatin. The in vitro and in vivo antitumor activity of BBR 3464 was evaluated and compared with that of cisplatin in neuroblastoma., Methods: In in vitro studies, the short- and long-term cytotoxicities, cell cycle perturbations, the ability to induce apoptosis, the intracellular platinum accumulation and DNA platination were evaluated in three neuroblastoma cell lines exposed to appropriate drug concentrations for 1 h. In in vivo studies, BBR 3464 was administered i.v. at doses of 0.30 and 0.35 mg/kg three times at intervals of 4 days (q4dx3), and cisplatin was administered i.v. according to two different schedules (at 2 and 4 mg/kg three times at intervals of 4 days and at 6 and 12 mg/kg as single doses)., Results: In a short-term growth inhibition assay, BBR 3464 was shown to be up to 100-fold more potent than cisplatin and it was even more potent in a clonogenic assay. The difference in the antitumor effect of BBR 3464 on the different cell lines was evident in both assays, while cisplatin exerted a comparable antitumor activity in all lines tested. Cell cycle analysis demonstrated a longer-lasting block in G2/M phase induced by BBR 3464 without the early S phase accumulation induced by cisplatin. The higher potency of BBR 3464 appeared to be unrelated to the induction of apoptosis, that was lower or at most comparable to cisplatin. Cellular platinum accumulation and platinum-DNA adduct formation following BBR 3464 exposure was higher than following cisplatin exposure. These differences may have resulted from a different mechanism of action and may explain the lack of cross-resistance with cisplatin. In xenografts of neuroblastoma, BBR 3464 was confirmed to be very potent as compared to cisplatin (MTD 0.35 mg/kg and 4 mg/kg for BBR 3464 and cisplatin, respectively). The efficacy of BBR 3464 was superior to that of cisplatin when both drugs were administered on a fractionated schedule (q4dx3), while BBR 3464 appeared equally active to 12 mg/kg cisplatin administered as a single dose., Conclusions: Our findings indicate that BBR 3464 has a definite antitumor effect in neuroblastoma lines and may be a candidate for early clinical trials in children with neuroblastoma.

BBR3464 is a new platinum-based drug non cross-resistant with cisplatin. To characterise the cellular basis of BBR3464 cytotoxicity as opposed to cisplatin, we performed a comparative study of the two drugs in cisplatin-resistant neuroblastoma and astrocytoma cells. In both model systems, BBR3464 proved to be more potent than cisplatin and was able to overcome cisplatin resistance. The higher potency exhibited by BBR3464 correlated with an increased cellular platinum accumulation and DNA-adduct formation. At equitoxic doses, BBR3464 induced apoptosis to a lesser extent than cisplatin and failed to overcome the decreased susceptibility to cisplatin-induced apoptosis in cisplatin-resistant cells. Cell cycle analysis showed a dose-dependent G2/M arrest by BBR3464. In astrocytoma cells, cisplatin treatment resulted in the upregulation of p53, p21 and bax, while only p21 induction was observed after BBR3464 treatment. In cisplatin-resistant cells, the reduced sensitivity to cisplatin paralleled a resistance to the induction of p53/p21 pathway by cisplatin, while the same doses of BBR3464 induced p21 to a similar extent in the resistant cells as in the parental cells. In conclusion, BBR3464 induces a cellular response that is different from cisplatin, supporting the view that the two drugs act through different mechanisms. Our data indicate that BBR3464 may be a promising agent in the treatment of tumours unresponsive to cisplatin and with a non-functional p53.

Objective: In recent years many authors have been focused on N2 non-small cell lung cancer patients to determine whether the rate of resectability and long term survival can be improved by a combined preoperative treatment, with significant results. Following these experiences, we planned an induction therapy trial to assess the impact on downstaging, resectability and survival of concurrent radio-chemotherapy on N2 non-small cell lung cancer patients., Methods: Between January 1990 and August 1995, 82 N2 non-small cell lung cancer patients (44 IIIA and 38 IIIB) received preoperative chemo-radiotherapy with a single cycle of Carboplatin (90 mg/m2 per day for days 1-4), concurrent with radiotherapy (daily radiation dose of 180 cGray for a total of 5040). After surgery, all patients received multi-drug chemotherapy with Carboplatin 300 mg/m2 per day on day 1 and VP-16 100 mg/m2 per day on days 1, 2 and 3, for a total of 6 monthly cycles. Patients with unresectable tumors underwent to this multi-drug chemotherapy, directly., Results: Two patients were excluded from the study. When the remaining 80 patients had a 'clinical' re-staging, 41 (51.3%) showed a major response, 36 (45%) had minimal or none response, and 3 (3.7%) had progression of disease. Forty-one patients were judged to be resectable, 11 staged IIIB, and 30 IIIA; 2 patients of the IIIB group refused surgery. Of the 39 operated cases, 37 were completely resected (resectability rate: 94.8%). We report one perioperative death due to respiratory failure and two major complications. The overall actuarial 5 year survival is 24.5%. Downstaging was observed in 22 patients (56.4%), with three patients (7.7%) having no evidence of tumor in the specimen, 16 (41%) having sterilization of all lymph nodes, and three (7.7%) having sterilization of mediastinal nodes but positive N1 nodes. The 5-year actuarial survival is 53% for patients who had complete resection and 0% for patients with no resection (P = 0.0000)., Conclusions: The following conclusions are possible: preoperative radiotherapy and chemotherapy with Carboplatin is well tolerated by patients, does not increase postoperative complications and produces an high rate of response. There is an high resection rate for patients who respond to the therapy. Patients with major response who undergo complete surgical resection had statistically significant improved survival compared with patients whose disease was not resected.