Radiation-induced circulating miRNA expression in blood of head and neck cancer patients.

In recent years, scientists have found evidence confirming the aberrant expression of miRNAs in cancer patients compared to healthy individuals. The growing interest in the identification of non-invasive and specific diagnostic and prognostic molecular markers has identified microRNAs as potential candidates in cancer diagnosis, prognosis and treatment response. In the present study, we have analyzed the expression profile of circulating miR-21, -191 and -421 in peripheral blood of head and neck cancer patients (HNC) to investigate a possible modulation of mRNA levels by radiation and to identify the role of mRNA as biomarkers of cancer prognosis. Results showed a modulation of the microRNA expression at different time points after radiotherapy, suggesting that treatment may influence the release of circulating miRNAs depending also on the time interval elapsed since radiotherapy. The expression levels of miR-21, -191 and -421 were higher in blood of patients treated with radiotherapy alone after 6 months from the end of therapy and high levels of them seemed to correlate with the remission of the disease. The trends shown in this study confirmed that miRNAs could be useful prognosis markers and could provide preliminary data for further evaluation in predicting patients' response to radiotherapy by developing miRNA-based treatments to improve the sensitivity of cancer cells to radiotherapy.

Morphological Analysis of Amoeboid-Mesenchymal Transition Plasticity After Low and High LET Radiation on Migrating and Invading Pancreatic Cancer Cells.

BACKGROUND/AIM: Cell migration and invasion are fundamental components of tumor cell metastasis that represent the biggest threat to the survival and quality of life of cancer patients. There is clear evidence that ionizing radiation can differently modulate migration and invasiveness of cancer cells depending on the cell lines, the doses and the radiation types investigated. This suggests that motile cells are able to adopt different migration strategies according to their molecular characteristics and external signals. MATERIALS AND METHODS: In this study, a morphological analysis was performed on pancreatic cancer Aspc-1 cells to evaluate the amoeboid-mesenchymal mobility transition in several experimental conditions considering the role played by factors released by normal and tumor cells, in basal conditions and after low and high Linear Energy Transfer (LET) irradiation. RESULTS AND CONCLUSION: The migratory behavior of Aspc-1 cells is modulated by factors released by normal fibroblasts and tumor cells, and this is in turn modulated by both the radiation dose and the radiation quality.

Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy.

BACKGROUND: To evaluate the benefit of oral nutritional supplements (ONS) in addition to nutritional counseling in head and neck cancer (HNC) patients undergoing radiotherapy (RT). METHODS: In a single-center, randomized, pragmatic, parallel-group controlled trial (ClinicalTrials.gov: NCT02055833; February 2014-August 2016), 159 newly diagnosed HNC patients suitable for to RT regardless of previous surgery and induction chemotherapy were randomly assigned to nutritional counseling in combination with ONS (N = 78) or without ONS (N = 81) from the start of RT and continuing for up to 3 months after its end. Primary endpoint was the change in body weight at the end of RT. Secondary endpoints included changes in protein-calorie intake, muscle strength, phase angle and quality of life and anti-cancer treatment tolerance. RESULTS: In patients with the primary endpoint assessed (modified intention-to-treat population), counseling plus ONS (N = 67) resulted in smaller loss of body weight than nutritional counseling alone (N = 69; mean difference, 1.6 kg [95%CI, 0.5-2.7]; P = 0.006). Imputation of missing outcomes provided consistent findings. In the ONS-supplemented group, higher protein-calorie intake and improvement in quality of life over time were also observed (P < 0.001 for all). The use of ONS reduced the need for changes in scheduled anti-cancer treatments (i.e. for RT and/or systemic treatment dose reduction or complete suspension, HR=0.40 [95%CI, 0.18-0.91], P = 0.029). CONCLUSION: In HNC patients undergoing RT or RT plus systemic treatment, and receiving nutritional counseling, the use of ONS resulted in better weight maintenance, increased protein-calorie intake, improved quality of life and was associated with better anti-cancer treatment tolerance.

Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions.

The differential diagnosis between recurrence of gliomas or brain metastases and this phenomenon is important in order to choose the best therapy and predict the prognosis but is still a big problem for physicians. The new emerging MRI, CT, and PET diagnostic modalities still lack sufficient accuracy. Radiolabeled choline and amino acids have been reported to show great tumor specificity. We studied the uptake kinetics of [18F]fluoromethyl-choline (FCH) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) by the T98G human glioblastoma cells from 20 to 120 min after irradiation either with photons at 2-10-20 Gy or with carbon ions at 2 Gy (at the National Centre for Oncological Hadrontherapy (CNAO), Pavia, Italy). We also evaluated the cell death and morphology changes induced by radiation treatment. Both FET and FCH are able to trace tumor behavior in terms of higher uptake for increased doses of radiation treatment, due to the upregulation of cells attempts to repair nonlethal damage. Our data suggest that both FCH and FET could be useful to analyze the metabolic pathways of glioblastoma cells before and after radiotherapy. Physicians will have to consider the different kinetics pathways of uptake concerning the two radiopharmaceuticals.

Pulsed Electromagnetic Field with Temozolomide Can Elicit an Epigenetic Pro-apoptotic Effect on Glioblastoma T98G Cells.

Treatment with pulsed electromagnetic fields (PEMFs) is emerging as an interesting therapeutic option for patients with cancer. The literature has demonstrated that low-frequency/low-energy electromagnetic fields do not cause predictable effects on DNA; however, they can epigenetically act on gene expression. The aim of the present work was to study a possible epigenetic effect of a PEMF, mediated by miRNAs, on a human glioblastoma cell line (T98G). We tested a PEMF (maximum magnetic induction, 2 mT; frequency, 75 Hz) that has been demonstrated to induce autophagy in glioblastoma cells. In particular, we studied the effect of PEMF on the expression of genes involved in cancer progression and a promising synergistic effect with temozolomide, a frequently used drug to treat glioblastoma multiforme. We found that electromagnetic stimulation in combination with temozolomide can elicit an epigenetic pro-apoptotic effect in the chemo- and radioresistant T98G glioblastoma cell line.

The Prognosis of Patients with Liver Metastases from Colorectal Cancer still Depends on Anatomical Presentation more than on Treatments.

BACKGROUND: The best management of liver metastases from colorectal cancer is still debated and little is known about the true impact of treatments on survival. MATERIALS AND METHODS: The study involved 122 patients (77 males), aged 64.0 ± 11.0 years (range: 27.8-86.1) at diagnosis of liver metastatization (synchronous in 59). All underwent chemotherapy and at least one procedure of radiofrequency ablation; 53 also had partial hepatic resections. Demographics, tumor characteristics and survival outcomes from liver metastatization were analyzed with univariate and multivariate techniques. This analysis was performed also taking into account relative survival as the best estimate of specific survival. RESULTS: The analysis with observed survival selected the categorized number of involved lymph nodes in the colorectal specimens as the only statistically significant predictor, while the analysis with relative survival also showed site of the primary tumor (above the sigmoid colon or otherwise) and number of liver metastases as significant factors. The standardized mortality ratio was 9.673 (95% CI: 7.668-11.663) and a total of 201.85 years of life were lost in comparison with the survival of the reference population. CONCLUSIONS: The computation of relative survival ­ better than observed survival ­ selected a more adequate number of predictors, making investigation of even limited series of patients with confounding factors reliable. The finding that prognosis was mainly dependent on the anatomical presentation of the primary tumor and of liver metastases ­ instead of treatments ­ could explain the still contrasting opinions on the role of the available therapies in this field.

Successful T-cell-depleted haploidentical hematopoietic stem cell transplantation in a child with dyskeratosis congenita after a fludarabine-based conditioning regimen.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure for marrow failure associated with dyskeratosis congenita (DC). Data on transplants from alternative donors are limited. We describe a boy with DC and severe aplastic anemia who underwent haploidentical T-cell depleted HSCT using a reduced-intensity conditioning regimen. He underwent engraftment without toxicity or GVHD. His posttransplant course was complicated by EBV reactivation, treated with rituximab and EBV-specific T lymphocytes. After 26 months, he is in complete chimerism, with normal blood count and no sign of GVHD or pulmonary dysfunction. To the best of our knowledge, this is the first report of DC successfully treated with allogeneic HSCT from a haploidentical family donor.

Late oral mucosa alterations after radiotherapy for head and neck cancer assessed by exfoliative cytology.

AIM: Late oral mucosa changes after radiotherapy for head and neck cancer have been poorly studied. This study aimed to determine long-term effects of radiotherapy on oral mucosa using exfoliative oral cytology. PATIENTS AND METHODS: Fifty patients with cancer were enrolled, five of whom in order to validate microscopic analysis. Smears were collected at programmed visit; a score was used to rank possible cytological alterations. Presence of inflammation was also microscopically described and compared to blood count tests. RESULTS: Epithelial cells revealed a peculiar 'folding' phenotype, not related to chemotherapy, total dose, or to the effective dose delivered to mucosa. Inflammation described was related to the score for 'folding' cells; moreover, score decreased in the presence of a higher lymphocyte count, while it was not altered by neutrophil count. CONCLUSION: We suggest application of exfoliative cytology to study radiation injury and the variability of individual response of oral mucosa to radiation.

HLA-haploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia.

We report the outcome of 12 consecutive pediatric patients with Fanconi anemia (FA) who had neither an HLA-identical sibling nor an HLA-matched unrelated donor and who were given T cell-depleted, CD34(+) positively selected cells from a haploidentical related donor after a reduced-intensity, fludarabine-based conditioning regimen. Engraftment was achieved in 9 of 12 patients (75%), and the cumulative incidence of graft rejection was 17% (95% confidence interval [CI], 5% to 59%). Cumulative incidences of grades II to IV acute and chronic graft-versus-host disease were 17% (95% CI, 5% to 59%) and 35% (95% CI, 14% to 89%), respectively. The conditioning regimen was well tolerated, with no fatal regimen-related toxicity and 3 cases of grade III regimen-related toxicity. The cumulative incidence of transplant-related mortality was 17% (95% CI, 5% to 59%). The 5-year overall survival, event-free survival, and disease-free survival were 83% (95% CI, 62% to 100%), 67% (95% CI, 40% to 93%), and 83% (95% CI, 62% to 100%), respectively. These data demonstrate that a fludarabine-based conditioning regimen, followed by infusion of high doses of T cell-depleted stem cells, is able to ensure engraftment with good overall survival and disease-free survival, confirming the feasibility of haploidentical hematopoietic stem cell transplantation in FA. To the best of our knowledge, this is the largest series of hematopoietic stem cell transplantation from a haploidentical related donor in FA patients reported to date.

Predictive factors for oropharyngeal mycosis during radiochemotherapy for head and neck carcinoma and consequences on treatment duration. Results of mycosis in radiotherapy (MIR): a prospective longitudinal study.

BACKGROUND AND PURPOSE: Oropharyngeal mycosis (OPM) is a complication of radiotherapy (RT) treatments for head and neck (H&N) cancer, worsening mucositis and dysphagia, causing treatment interruptions and increasing overall treatment time. Prophylaxis with antifungals is expensive. Better patient selection through the analysis of prognostic factors should improve treatment efficacy and reduce costs. MATERIALS AND METHODS: A multicentre, prospective, controlled longitudinal study, with ethics committee approval, examined H&N cancer patients who were candidates for curative treatments with radio-chemotherapy. Patients were divided in groups according to OPM appearance: before the starting of RT (cases), during RT (new cases) and never (no cases). RESULTS: Of 410 evaluable patients, 20 were existing cases, 201 new cases and 189 did not report OPM. In our study OPM appears in 42.4% of people >70years and in 58.2% of younger individuals (p=0.0042), and in 68.6% of women versus 50.8% of men (p=0.0069). Mucositis and dysphagia were higher and salivation reduced among people with OPM (p<0.0000). Patients with OPM had longer hospitalization (p=0.0002) and longer (>12days) treatment interruptions (p=0.0288). CONCLUSIONS: Patients with OPM had higher toxicity and a greater number of long treatment interruptions. Analyses of prognostic factors can help clinicians understand OPM distribution and select patients with the highest probability of OPM for antifungal prophylaxis.

New frontiers for astrocytic tumours.

Glioblastoma multiforme, the most common type of primary brain tumour, remains an unsolved clinical problem. A great deal of work has been done in an effort to understand the biology and genetics of glioblastoma multiforme, but clinically effective treatments remain elusive. It is well known that malignant gliomas develop resistance to chemo- and radiotherapy. In this review we evaluated the literature data regarding therapeutic progress for the treatment of astrocytic tumours, focusing our attention on new frontiers for glioblastoma. The research studies performed in in vitro and in vivo models show that the application of hyperthermia using magnetic nanoparticles is safe and could be a promising tool in the treatment of glioblastoma patients. Our efforts are focused towards new fields of research, for example nanomedicine and the study of the uptake and cytotoxic effects of magnetic nanoparticles. The improvement of the quality of life of patients, by increasing their survival rate is the best result to be pursued, since these tumours are considered as ineradicable.

Cell death forms and HSP70 expression in U87 cells after ionizing radiation and/or chemotherapy.

BACKGROUND: Several types of cell death can induce the activation of the immune system by releasing factors of damage. AIM: To identify different cell death modalities using U87 glioblastoma cell line after radio-chemotherapy treatments by analyzing the expression of HSP70 after γ-ray irradiation and temozolomide treatment. MATERIALS AND METHODS: U87 cell line was irradiated with 2, 4, 8, 10 and 20 Gy, treated with 200 µM of temozolomide, or subjected to combined treatments of these. RESULTS: Forty-eight hours after treatment, apoptosis was more prevalent than necrosis, especially after γ-radiation with a somewhat dose-dependent trend. Temozolomide did not seem to induce significant modifications of the pattern of cell death and protein expression. Temozolomide-induced cell death was lower or equal to that obtained with high dose radiotherapy. A low synergism between the two treatments was observed. CONCLUSION: This cell line showed a marked radioresistance to conventional clinical doses, showing attempts to repair the induced damage, while temozolomide treatment showed no cytotoxic effects.

Prolonged survival in advanced thymoma: Effectiveness of sequential multiple lines of chemotherapy in an inoperable case.

A standard therapeutic approach for advanced malignant thymoma has yet to be defined given the rarity of this condition. We present a patient with advanced thymoma, evaluated as inoperable at diagnosis due to multiple serosal metastases. The strong constitution and determination of the patient allowed treatment with six distinct and subsequent chemotherapy regimens, all administered on an outpatient basis. A survival of 64 months from diagnosis was achieved. A favorable clinical response was obtained after the first three treatment lines, with the disappearance of all lesions on both computed tomography and positron emission tomography (PET) images. However, this result was not confirmed by surgical exploration of the thorax, undertaken with the aim of radical excision of possible residual disease. The presence of multiple pleural nodules, not evident on the imaging techniques, prevented even limited tumor debulking. The chemotherapy lines administered following detection of the lessions, stabilized the disease for a further 2 years, while a satisfactory quality of life was maintained. Only in the last months did the tumor progress and signs of cardiotoxicity appear, with the latter constituting the eventual cause of death. This case is important since the medical literature does not indicate non-cross-resistant regimens for advanced thymoma following second-line chemotherapy, and the sequence of regimens presented in this case study may serve as a feasible outline program. Moreover, we highlight the known possibility of false-negative PET studies, which can occur despite the claimed glucose avidity of thymoma tissue.

Tumors of the gastroesophageal junction have intermediate prognosis compared to tumors of the esophagus and stomach, but share the same clinical determinants.

The issue of whether carcinoma of the gastroesophageal junction (GEJ) should be considered a distal esophageal, a proximal gastric or an independent tumor, at least with regards to clinical evaluation and management remains controversial. This study included 613 retrospective consecutive patients with carcinoma of the upper digestive tract, 64 of the esophagus, 58 of the GEJ and 491 of the stomach. The prognostic impact of the main clinical and histological parameters was analyzed in relation to relative survival as an estimate of the excess mortality. Relative survival and standardized mortality ratio (SMR) were calculated from the observed survival and the expected survival of the general population with identical age, gender and calendar years of observation. Multivariate analyses were applied to the proportional hazards model of the relative survival. The excess mortality, expressed by the relative survival and SMR of the patients with GEJ carcinoma are intermediate compared to those of patients with esophageal and gastric tumors. However, prognosis is not determined by tumor location, histology or administration of adjuvant chemotherapy, but mainly by stage and radical surgical resection. Gender has a minor but significant prognostic effect and age showed a slight inverse correlation with excess mortality. In conclusion, the excess mortality related to the tumors of the upper digestive tract is determined by stage, radical resection, gender and age. The intermediate prognosis of GEJ tumors mainly depends on a particular combination of such elementary determinants.

Concurrent intra-arterial carboplatin administration and radiation therapy for the treatment of advanced head and neck squamous cell carcinoma: short term results.

BACKGROUND: The aim of the present study was to evaluate the survival, efficacy and safety of a modified RADPLAT-like protocol using carboplatin instead of cisplatin. METHODS: Fifty-six patients with primary head and neck squamous cell carcinoma received 4 cycles of intra-arterial carboplatin (350 mg/m2 per cycle every 2 weeks), with concurrent three-dimensional conformal radiation therapy. RESULTS: Two major and 4 minor complications were observed. Forty-five of the 56 patients (80%) completed the protocol, while 11 (20%) patients had to discontinue the intra-arterial infusions due to the occurrence of severe haematological toxicity, but were able to complete radiotherapy. Forty-four (98%) of the 45 patients who completed the protocol and 10 (91%) of the 11 who did not, were free of disease at the end of the treatment, for a comprehensive 96% of CR overall. After a median 23.55 months (range: 2 to 58 months) of follow-up, 40 patients (71%) are alive and disease-free, 1 (2%) is alive but affected by disease and 15 (27%) have died of the disease or other causes. CONCLUSION: Intra-arterial carboplatin administration with concurrent three-dimensional conformal radiation therapy seems to be a promising alternative to RADPLAT in the treatment of advanced head and neck tumours. Haematological and non-haematological toxicities are virtually similar, but carboplatin has the advantage in that it is not nephrotoxic and can be used at very high doses without any significant increase in the extent of side effects.

Usability of institutional cancer web sites: an Italian case study.

In order to evaluate if and to what extent Italian speaking cancer patients can benefit from information available on cancer web sites, an "in vitro" usability (ISO definition) study has been carried out. It investigated the usability of the web sites of the most representative Italian Institutions in the oncological field for the adult patients needing to find information about head and neck cancer. Specific evaluation criteria from the literature were used. The results point out some problems about accessibility, in line with other studies, and about the usefulness of the contents, in particular in the web sites of care delivery institutions: a grey present situation, but there are already grounds for significant improvement. Institutions and organizations must not waste the opportunity of being valuable sources in order to build the so called "informed patient," and the usability of their web sites could make the difference.

Curative and organ-preserving treatment with intra-arterial carboplatin induction followed by surgery and/or radiotherapy for advanced head and neck cancer: single-center five-year results.

BACKGROUND: This study evaluated the feasibility, toxicity, response rate and survival of neoadjuvant superselective intra-arterial infusion of high dose carboplatin in advanced head and neck cancer. METHODS: Forty-six patients with primary head and neck squamous cell carcinoma received 3 cycles of intra-arterial carboplatin (300 to 350 mg/m2 per cycle every 2 weeks), followed by radiotherapy or surgery plus radiotherapy. RESULTS: No complications or severe toxicity occurred. Sixteen patients (35%) were complete responders, 20 (43%) partial responders while 10 (22%) did not respond to treatment. After completion of the multimodality treatment, 38/46 patients (83%) were complete responders. After a 5-year follow-up period, 18/46 patients (39%) are alive and disease-free, 3 (6,5%) have died of a second primary tumor and 25 (54.5%) have died of the disease. CONCLUSION: Intra-arterial carboplatin induction chemotherapy is a safe, well-tolerated technique that discriminates between responders and non-responders and so may have prognostic significance in planning further integrated treatments aimed to organ preservation for advanced head and neck carcinomas.

The multiple faces of the e-patient, if not disabled.

The term e-health entered common speech a few years ago , while the term "e-patient" has recently appeared on the healthcare scenario. The aim of the present paper is to describe the nature of the so called "e-patient" from different points of view, through a review, not systematic, of the literature. A profile, though not totally exhaustive, of the current e-patient has been drawn, in an attempt to report uncertainties and worries that should not be underestimated. Comments are provided on the asymmetry between the evaluation effort around the internet world and corresponding face-to-face world. Disabled patients are almost excluded from the e-patient family due to the inaccessibility of most of the health related web sites.

MOPPEBVCAD chemotherapy with limited and conditioned radiotherapy in advanced Hodgkin's lymphoma: 10-year results, late toxicity, and second tumors.

PURPOSE: MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with limited radiotherapy was devised in 1987 to reduce late toxicity and second tumor incidence while trying to improve effectiveness through increases of dose intensity and dose density. Late results, toxicity, and second tumor incidence were reviewed in all the patients treated. EXPERIMENTAL DESIGN: The drugs of three previous alternating regimens [CAD (lomustine, melphalan, and vindesine), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and ABV (doxorubicin, bleomycin, and vinblastine)] were intensified and hybridized, the cumulative dose of mechlorethamine was lowered, and irradiation was delivered to no more than two sites either bulky or partially responding to chemotherapy. RESULTS: A total of 307 previously untreated advanced-stage patients underwent MOPPEBVCAD chemotherapy. Radiotherapy was delivered to 118 of 307 patients (38%). Remission was complete in 290 patients (94%). With a median follow-up of 114 months, 10-year overall, disease-free, and failure-free survival rates were 79%, 84%, and 71%, respectively. Forty-two patients relapsed and 60 died. The causes of death were Hodgkin's lymphoma in 36 patients, second neoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2, and unknown in 6. Sixteen second tumors (of which nine were myelodysplasia and/or acute leukemia) were diagnosed in all. Outside this series of 307 patients, MOPPEBVCAD obtained complete responses in 12 of 15 relapsed and 9 of 9 refractory patients who had previously been treated with other regimens. CONCLUSIONS: Clinical response and long-term results are very satisfactory, whereas the second tumor incidence was lower than would have been expected with MOPP analogues. Given its response/late toxicity balance, MOPPEBVCAD does not undermine the leading role of ABVD as first-line regimen but can be indicated as a very effective second-line conventional therapy.