Addressing the post-irradiation hypothalamic-pituitary endocrine abnormalities of brain tumors in pediatric patients.

PURPOSE: Hypothalamic-pituitary axis is susceptible to radiotherapy, causing endocrine disorders to childhood cancer survivors. We conducted a systematic review in order to assess the radiation-induced toxicity that leads to hormone secretion abnormalities and their severity in children with brain tumors. METHODS: The data were collected by relevant studies on PubMed and EMBASE. Articles up to December 2016 were included. We selected studies which focused on children patients (<18 yr old) with brain tumors treated with radiotherapy and the consequences for their endocrine system. RESULTS: Growth hormone (GH) deficiency was the most common post-irradiation abnormality among children cancer survivors, followed by gonadotrophin (GT), thyroid stimulating hormone (TSH), corticotropin (ACTH) and prolactin (PRL) disorders. CONCLUSIONS: The age of the patient, total radiotherapy dose, number of fractions, fraction size and the duration of treatment seem to determine the severity of these disturbances.

3D conformal radiotherapy in primary nasopharyngeal cancer: effectiveness and prognostic factors.

PURPOSE: To assess the efficacy and safety of using 3D conformal radiation therapy (3DCRT) to treat nasopharyngeal cancer (NPC) in a Caucasian cohort and evaluate factors with prognostic value. METHODS: Between September 2001 and November 2012, 44 NPC patients with a mean age of 57 years underwent 3DCRT at the University Hospital of Ioannina. Nineteen patients (43%) presented with WHO type 1 and 2 histology. Thirty two patients (73%) had advanced-stage disease (stage III/IV). Thirty-one patients (70%) received chemotherapy. The mean total radiotherapy dose prescribed to the planning target volume (PTV) was 67.2 Gy. The daily dose was 1.8 Gy. RESULTS: With a median follow up of 43 months (range 8.4-125), the 4-year local relapse-free (LRFS), nodal relapse-free (NRFS), distant metastases-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 90, 87, 91, 80 and 82%, respectively. Histology was a significant prognostic factor concerning overall survival, with worst prognosis in patients with WHO type 1/2 compared to type 3. Age <70 years, absence of retropharyngeal lymph node metastasis, complete response after treatment and the completion of ≥4 cycles of concurrent weekly cisplatin favored overall survival. Fifteen patients (34%) developed grade 3 late side effects (xerostomia: 6, soft tissue fibrosis: 6, hearing loss: 2, brachial plexus neuralgia: 1). CONCLUSION: 3DCRT in our Caucasian cohort, characterized by predominantly advanced-stage disease, combined with chemotherapy, is an effective treatment modality approach in patients with NPC with excellent tolerance.

Prognostic factors in glioblastoma patients managed with radiotherapy combined with temozolomide.

PURPOSE: No consensus on clinicopathologic prognostic factors that predict the outcome of patients with newly diagnosed glioblastoma multiforme (GBM) managed with resection, postoperative radiotherapy (RT) and adjuvant temozolomide (TMZ) exists today. The purpose of this study was to assess the outcome, compliance and toxicity in GBM patients treated with TMZ at our Center, as well as to evaluate factors with prognostic significance. METHODS: 91 GBM patients were enrolled in this retrospective study (2004-2012). 3D-conformal RT was given to a median total dose of 60Gy (daily dose 2Gy). Eighty nine (98%) of the patients received concurrent TMZ (75mg/m²) and 74 (81%) received adjuvant TMZ (150-200mg/m² for 5 days every 28 days) up to 12 cycles. RESULTS: At a mean follow up of 18.6 months, the median overall survival (OS) was 15.1 months. Grade 3/4 haematologic toxicity was observed in 19.8% of the patients while 4 patients (4.4%) experienced grade 3/4 non haematologic toxicity. In univariate analysis, significant correlation was found between OS and no/minor neurologic deficit at diagnosis (p=0.02), acute onset of symptoms (p=0.04) and 6 cycles of adjuvant TMZ (p<0.001). The addition of more than 6 cycles of TMZ did not offer any statistically significant survival benefit. In multivariate analysis, only the absence of major neurologic deficit remained associated with overall survival (p=0.016). CONCLUSION: 3D conformal RT with TMZ achieved acceptable disease control with satisfactory compliance and toxicity. Intact neurologic function was associated with superior outcome, as a surrogate of low tumor burden, early treatment start and/or indolent tumor biology.

Radiotherapy for prevention of heterotopic ossification of the elbow: a systematic review of the literature.

BACKGROUND: Heterotopic ossification is a pathological process characterized by abnormal formation of bone in nonskeletal tissue. Radiotherapy for heterotopic ossification of the elbow is questionable because of possible adverse effects. METHODS: A systematic review of the literature was conducted in MEDLINE, Scopus, ISI Web of Science, National Institute for Health and Clinical Excellence, National Guideline Clearinghouse, System for Information on Grey Literature in Europe, ClinicalTrials.gov, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews up to April 2012. All published articles assessing interventions including radiotherapy for prevention of heterotopic ossification in the elbow of adult patients were considered. Information was recorded by the first two authors, and disagreements in interpretation were resolved by consensus. RESULTS: In total, 27 studies using radiotherapy for elbow heterotopic ossification were identified (1 randomized clinical trial, 1 case-control study, and 25 case reports and case series) in the literature. Most of them used a single dose of 7.0 Gy. The randomized clinical trial was stopped early because of severe adverse effects (pseudarthrosis) caused by radiation. The case-control study showed that radiotherapy did not effectively prevent recurrence of heterotopic ossification. The case reports and case series mentioned only sparse adverse events. CONCLUSION: The use of radiation therapy for prevention of heterotopic ossification of the elbow is supported by weak evidence.

Interior Design: A New Perspective in Supportive Care of Patients with Acute Onset of Debilitating Diseases.

Background: Upon the onset of a debilitating rapidly evolving condition (such as cancer or a rapidly progressing myopathy, neuropathy, respiratory disease, or a severe traumatic injury), individuals have limited time to find a new home or make radical structural modifications in their residence. How the affected patients can continue sharing the same house with their families, while meeting their own special requirements, is thus rising as a critical issue. Household and daily routine rearrangements, either temporary or permanent, may be necessary, to ameliorate the life of patients with impairments, lasting for months or even years. Objectives: Interior design may provide a highly efficient "living" palliation for debilitating medical conditions directly at patients' home-site. Methods: Research of relevant literature, using keywords "debilitating conditions," "home care," "end of life care," "care of advanced cancer patients," "care of patients with mental disorders," "home care of covid-19 affected patients," and "care of patients with degenerative illnesses." Results: We found that patients and their relatives may not be aware of the probable interior design solutions to their daily life challenges, imposed by a disease-related impairment. In parallel, interior design experts may equally be unaware of these issues, as well as of who needs the available solutions.Similarly, medical and architectural sciences are not connected, eventually failing to meet patients' everyday needs. Conclusions: Interior architecture and health scientists are called to cooperate, aiming to provide a highly efficient and meaningful support to patients and families affected by unforeseen debilitating medical conditions.

ICAM-1 expression in patients with advanced non-small cell lung cancer treated with radiotherapy.

PURPOSE: To investigate the possible clinical relevance of ICAM-1 molecule in patients with advanced non-small cell lung cancer (NSCLC) treated with radiotherapy. METHODS: The expression of ICAM-1 was examined immunohistochemically on tissue specimens of 62 patients with pathologically confirmed NCSLC. The median age at diagnosis was 62 years (range 49-84) with a male predominance (87.8%). All patients had stage III disease at presentation. The median follow up was 15.5 months (range 7-44). Obtained expression data were weighted against clinical and pathological parameters. RESULTS: Thirty-seven patients (60%) had no ICAM-1 staining, 16 patients (26%) had weak staining, while 6 patients (10%) expressed moderate staining and only 3 patients (5%) showed strong ICAM-1 staining. Moderate and high expressions were mostly observed in adenocarcinomas and undifferentiated carcinomas (n=8), that are considered more aggressive than squamous cell carcinoma (n=1). The median overall survival (OS) was 15 months (range 11-20). There seemed to exist an inverse association between ICAM-1 expression and OS, since there was a trend in median survival in favor of no ICAM-1 expression (p=0.083). Moreover, in patients with no ICAM-1 expression, there was observed a statistically significant difference in OS, favoring the squamous cell subtype (p=0.006). Nevertheless, ICAM-1 expression did not confer any statistical significance regarding smoking status (p=0.128), metastatic potential (p=0.574) as well as with the site of metastasis (p=0.964). CONCLUSION: Our findings may serve as a helping resource for further investigations of ICAM-1 as a molecular marker that could characterize treatment response and survival of tumor subpopulations.

Induction chemotherapy with docetaxel and cisplatin followed by concomitant chemoradiotherapy in patients with inoperable non-nasopharyngeal carcinoma of the head and neck.

BACKGROUND: Induction chemotherapy (IC) followed by concomitant chemoradiotherapy (CCRT) has the potential of being an ideal multi-modality approach for improving the prognosis of patients with squamous cell carcinoma of the head and neck (SSCHN). PATIENTS AND METHODS: Thirty-four patients with locally advanced SCCHN were treated with 3 cycles of IC, consisting of docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks, followed 3-4 weeks later by definitive radiotherapy (70 Gy) and concomitant weekly cisplatin 40 mg/m2. RESULTS: After a median follow-up of 27.7 months, 6-month progression-free survival (PFS), the primary study end-point, was 84%. The median PFS was 16.4 months and median overall survival 24.4 months. The majority of the patients completed 3 cycles to moderate toxicity. Anemia, nausea/vomiting and mucositis were the prominent toxicities during CCRT. Retrospective analysis of a panel of biomarkers suggested that excision repair cross-complementation group 1 (ERCC1) protein expression was associated with shorter PFS. CONCLUSION: IC followed by CCRT, as administered in the present study, is a feasible and well-tolerated therapeutic approach. However, its real impact on the prognosis of SCCHN patients has to be demonstrated in a randomized study comparing this treatment to CCRT alone.

Development and validation of simple step protein precipitation UHPLC-MS/MS methods for quantitation of temozolomide in cancer patient plasma samples.

Temozolomide (TEMODAL™) (TMZ) is an antineoplastic agent that is primarily used for the treatment of glioblastoma and anaplastic gliomas, two aggressive forms of brain cancer. Due to the poor prognosis of brain tumour patients, there is an increasing body of research into improving the stability and delivery of TMZ past the blood brain barrier using carrier molecules. These require accurate determination of TMZ levels for biodistribution and pharmacokinetic evaluation. Unfortunately, current methodologies for the determination of TMZ in human plasma suffer from low reproducibility, recovery, sensitivity or cost ineffective procedures associated with extensive sample cleaning. To surpass these disadvantages, we developed two bioanalytical methods with high sensitivity and excellent recovery for the determination of TMZ in human plasma at minimum cost. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used and both methods were validated under US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) guidelines. The two methods had minor differences in the sample pre-treatment and each method was developed and applied in separate laboratories. Theophylline was selected as internal standard (IS). Calibration curves were linear over the range of 10-500 ng/mL with extraction recovery ranging from 77.3 to 97.3% while all validation parameters met the acceptance criteria and proved the methods' reliability. The validated methods were successfully applied to plasma samples donated from cancer patient following treatment with temozolomide.

Combination treatment for glioblastoma with temozolomide, DFMO and radiation.

PURPOSE: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with dismal prognosis. This tumor is characterized by extensive heterogeneity, thus is difficult to treat and every established or new treatment faces significant hazard of resistance. Temozolomide (TMZ), an oral alkylating agent, is the first-line treatment for GBM, but resistance to TMZ is a major problem. Herewith, we investigated the combined effect of TMZ, difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, and radiation in GBM cell lines. METHODS: We used the U87G, U251MG and T98G GBM cell lines. A linac 6MV accelerator (Varian Medical Systems) was used for cell irradiation. Viability and proliferation of the cells were examined with trypan blue exclusion assay, crystal violet and xCELLigence system. Cell cycle and activation of caspase-8 were evaluated with flow cytometry. RESULTS: The combination treatment resulted in a consistent higher suppression of proliferation in all cell lines treated and induced a significant higher cell cycle arrest in G2/M phase in U251MG and T98G cell lines. In U251MG cells caspase-8 was increased with each treatment alone, however the combination treatment had lower level of caspase-8 induction, suggesting a co-existence of another mechanism of cell death apart from apoptosis. In T98G cells the combination treatment increased the activation of caspase-8. CONCLUSION: Combination treatment with DFMO, TMZ and radiation significantly reduced cell viability in all cell lines tested. Given that both TMZ and DFMO can be administered orally and are related to minimal toxicities, this combination treatment may be a novel treatment strategy for GBM that deserves further investigation.

Malignant orbital schwannoma with massive intracranial recurrence.

BACKGROUND: A 62 year old male presented with progressive diplopia, left orbital pain and impairment of visual acuity. METHOD AND FINDINGS: Neuroradiological investigation disclosed an orbital tumour. The lesion was totally excised. Histopathology examination revealed a malignant peripheral nerve sheath tumour (MPNST). The tumour recurred with intracranial extension. The patient died 13 months after the initial diagnosis. CONCLUSIONS: To our knowledge, this is the first reported example of a massive intracranial recurrence of an orbital MPNST. The epidemiological features, clinical course and treatment of these lesions are discussed.

Subtotal gastrectomy for diffused hemorrhagic gastritis induced by radiation, following liver resection for hilar cholangiocarcinoma. A case report.

INTRODUCTION: A rare case of hemorrhagic gastritis induced by radiation is presented, which was resistant to conservative treatment and required subtotal gastrectomy. PRESENTATION OF CASE: A 56-year-old male was initially undergone right hepatectomy, resection of the extrahepatic biliary tree, hilar lymph node dissection and hepatico-jejunostomy due to advanced hilar cholangiocarcinoma. Because of the extent of the disease, chemo-radiotherapy was administered. The patient received a total radiotherapy dose of 57.6Gy in 32 sessions. Unfortunately, diffused hemorrhagic gastritis induced by radiation was developed, which was resistant to conservative treatment (endoscopic hemostasis, transfusion). A subtotal gastrectomy was performed. The patient is in good condition 45 months after the liver resection, but with local recurrence. CONCLUSION: In resistant situations to conservative treatment and recurred bleeding of diffused hemorrhagic gastritis induced by radiation, surgical management may have a role.

Paclitaxel, cisplatin, leucovorin, and continuous infusion fluorouracil followed by concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck: a Hellenic Cooperative Oncology Group Phase II Study.

The primary objective of this phase II study was to access the complete response (CR) rate to a new innovative induction regimen in patients with locally advanced head and neck cancer (LA-HNC). From October 2000 until October 2003 a total of 38 eligible patients (33 men and 5 women) entered the study. The large majority of them presented with a performance status of 0-1 and with clinical stage IV disease. Treatment consisted of three cycles of induction chemotherapy (IC) with paclitaxel 175 mg/m2 in a 3-h infusion on d 1, leucovorin (LV) 200 mg/m2 over 20 min immediately followed by FU 400 mg/m2 bolus and then 600 mg/m2 as a 24-h continuous infusion on d 1 and 2 and a cisplatin 75 mg/m2 over 1-h infusion on d 2 every 3 wk. This was then followed by radiation (70 Gy) and weekly cisplatin 40 mg/m2. After the completion of IC, 6/38 (16%) patients had CR. The CR rate was increased to 66% post-concomitant chemoradiotherapy (CCRT). Neutropenia (37.5%), pain (62%), nausea/vomiting (21%), and alopecia (79%) were the most frequent side effects during IC. The most pronounced toxicities during chemoradiotherapy were stomatitis (62.5%) and xerostomia (53%). Median time to progression was 11.0 mo and median survival 16.7 mo. One- and 2-yr survival rates were 73% and 38%, respectively. In conclusion, this novel induction regimen is active, is well tolerated, and can be successfully followed by CCRT with weekly cisplatin. CCRT should remain standard treatment for patients with LA-HNC. Novel induction combinations, such as that reported in the present study, should be evaluated in combination with CCRT only in the context of clinical trials.

Diffusion tensor and dynamic susceptibility contrast MRI in glioblastoma.

OBJECTIVE: We prospectively investigated the correlation between diffusion tensor (DTI), dynamic susceptibility contrast (DSC) perfusion MRI metrics and Ki-67 labelling index in glioblastomas. METHODS: We studied seventeen patients who were operated on for glioblastoma. DTI and DSC MRI were performed within a week prior to surgical excision. Lesion/normal ratios were calculated for the apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and relative mean transit time (rMTT) ratio. In the excised tumour specimens Ki-67 antigen expression was evaluated by the MIB-1 immunostaining method. RESULTS: A significant correlation was observed between Ki-67 index and ADC ratio (r = -0.528, p = 0.029) and FA ratio (r = 0.589, p = 0.012). rCBV and rMTT presented a trend towards significant correlation with Ki-67 index (r = 0.628, p = 0.07 and r = 0.644, p = 0.06 respectively). There was a trend towards better survival for patients with gross total tumour excision and FA values lower than 0.48 (p = 0.1 and p = 0.09 respectively). No significant correlation was found between ADC ratio, rCBV, rCBF, rMTT and overall survival. CONCLUSION: ADC ratio, FA ratio, rCBV and rMTT tumour/normal tissue ratios may represent indicators of glioma proliferation. FA values may hold promise for predicting survival in patients with glioblastoma.

Myocardial perfusion imaging with (99 m)Tc-tetrofosmin SPECT in breast cancer patients that received postoperative radiotherapy: a case-control study.

PURPOSE: To evaluate the cardiac toxicity of radiotherapy (RT) in breast cancer (BC) patients employing myocardial perfusion imaging (MPI) with Tc-99 m Tetrofosmin-single photon emission computer tomography (T-SPECT). MATERIALS AND METHODS: We studied 46 BC female patients (28 patients with left and 18 patients with right BC) treated with postoperative RT compared to a control group of 85 age-matched females. The median time of RT to SPECT was 40 months (6-263). RESULTS: Abnormalities in the summed stress score (SSS) were found in 54% of left BC patients, 44.4% of right BC patients, and 32.9% of controls. In left BC patients there were significantly more SSS abnormalities compared to controls (4.0 ± 3.5 vs 2.6 ± 2.0, p = 0.05) and possible trend of increased abnormalities of right BC patients (3.7 ± 3.0 vs 2.6 ± 2.0, p = 0.14). Multiple regression analysis showed more abnormalities in the MPI of left BC patients compared to controls (SSS, p = 0.0001); Marginal toxicity was also noted in right BC patients (SSS, p = 0.045). No additional toxicity was found in patients that received adjuvant cardiotoxic chemotherapy. All T-SPECT abnormalities were clinically silent. CONCLUSION: The study suggests that radiation therapy to BC patients result in MPI abnormalities but without apparent clinical consequences.

Pure small cell carcinoma of the prostate: a case report and literature review.

Primary small cell carcinoma of the prostate (SCPCa) is a rare pathologic entity with unique clinical features and a poor prognosis. We present a case of a patient diagnosed with pure SCPCa treated with a combined chemo-radiotherapeutic approach. Pathological findings showed that the neoplastic cells exhibited positivity for pancytokeratin, synaptophysin, thyroid transcription factor-1 and CD56. Immunostaining for prostate-specific antigen was negative, while serum prostate-specific antigen was within normal limits. We review the available literature to gain additional information about diagnosis, treatment and prognosis of pure SCPCa.

Long-term clinical outcome of patients treated with beta-brachytherapy in routine clinical practice.

BACKGROUND: Only limited data exist regarding the long-term efficacy of beta-brachytherapy (beta-VBT) in routine clinical practice and the impact of the prolonged (>6 months) combined antiplatelet therapy after beta-VBT. Our aim is to examine the long-term clinical efficacy of routine beta brachytherapy (beta-VBT) followed by indefinite administration of combined antiplatelet therapy in patients at high restenotic risk. METHODS: Sixty-one patients with 65 lesions [de novo: 41, in-stent restenotic (ISR): 24] underwent intracoronary beta-VBT and were followed prospectively. All patients received indefinite administration of aspirin and clopidogrel, underwent routine angiography 6 months later and were followed-up clinically for 43.7 months (range: 32 to 52 months). RESULTS: Acute success was achieved in 60/61 (98.4%) patients. Lesion length was 36.1 (+/-17.6) mm for the de novo and 22.0 (+/-9.8) mm for the ISR (p=0.001). Stents were implanted in 35/41 de novo and 7/24 ISR lesions (p<0.01). Six-month binary restenosis after successful beta-VBT was 35.9% (23/64). During follow-up patients with de-novo lesions who received a new stent during index procedure had a higher incidence of major cardiac events than patients with ISR lesions without a new stent (log rank test, p=0.02). Acute and late thrombotic events were reported at 6 patients, all with de novo lesions and stent implantation. CONCLUSIONS: Beta-VBT plus stenting in de novo lesions is related to an unacceptable high rate of thrombotic complications and clinical restenosis despite prolonged administration of combined antiplatelet therapy. Brachytherapy remains a reasonable option for patients with ISR lesions until full data from large randomized trials comparing drug eluting stents with brachytherapy are available.

Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A Hellenic Cooperative Oncology Group phase II study.

BACKGROUND: Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control. PATIENTS AND METHODS: Untreated patients with stage IIB-IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m(2) followed by paclitaxel 175 mg/m(2) as 3-h infusion on day 1 and cisplatin 75 mg/m(2) on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m(2). RESULTS: From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet. CONCLUSION: IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.