Multifunctional bioactive glasses with spontaneous degradation for simultaneous osteosarcoma therapy and bone regeneration.

For the treatment of tumor-related bone defects resulting from surgical resection, simultaneous eradication of residual tumor cells and repair of bone defects represent a challenge. To date, photothermal therapy based on photothermal materials is used to remove residual tumor cells under near infrared light. However, most of photothermal materials have no function for bone repair, and even if combined with bioactive materials to enhance osteogenesis, they still cause potential harm to the body due to inability to degrade or poor degradability. Herein, multifunctional bioactive glasses (PGFe5-1100, PGCu5-1100) based on phosphate glass doped with transition metal elements were prepared for photothermal ablation, bone regeneration, and controllable degradation. The glasses exhibited excellent photothermal effect, which was derived from the electron in-band transition after light absorption due to energy level splitting of doped transition metal element and the subsequent electron nonradiative relaxation. The photothermal performance can be controlled by laser power density, element doping content and glass melting temperature. Moreover, the hyperthermia induced by the glasses can effectively kill tumor cells in vitro. In addition, the glasses degraded over time, and the released P, Ca, Na, Fe could promote bone cell proliferation and osteogenic differentiation. Therefore, these results successfully demonstrated that transition metal element-doped phosphate glasses have multifunctional abilities of tumor elimination, bone regeneration, and spontaneous degradation simultaneously with better biosecurity and bioactivity, which is believed to pave the way for the design of novel biomaterials for osteosarcoma treatment.

Natural Chlorogenic Acid Planted Nanohybrids with Steerable Hyperthermia for Osteosarcoma Suppression and Bone Regeneration.

Surgical resection is the most common approach for the treatment of osteosarcoma. However, two major complications, including residual tumor cells and large bone defects, often arise from the surgical resection of osteosarcoma. Discovering new strategies for programmatically solving the two above-mentioned puzzles has become a worldwide challenge. Herein, a novel one-step strategy is reported for natural phenolic acid planted nanohybrids with desired physicochemical properties and steerable photothermal effects for efficacious osteosarcoma suppression and bone healing. Nanohybrids are prepared based on the self-assembly of chlorogenic acid and gold nanorods through robust Au-catechol interface actions, featuring precise nanostructures, great water solubility, good stability, and adjustable hyperthermia generating capacity. As expected, on the one hand, these integrated nanohybrids can severely trigger apoptosis and suppress tumor growth with strong hyperthermia. On the other hand, with controllable mild NIR irradiation, the nanohybrids promote the expression of heat shock proteins and induce prominent osteogenic differentiation. This work initiates a brand-new strategy for assisting osteosarcoma surgical excision to resolve the blockage of residual tumor cells elimination and bone regeneration.

Evaluation of Cell-detaching Effect of EDTA in Combination with Oxaliplatin for a Possible Application in HIPEC After Cytoreductive Surgery: A Preliminary in-vitro Study.

BACKGROUND: Ethylenediaminetetraacetic acid (EDTA), a commonly used compound in laboratory medicine, is known for its membrane-destabilization capacity and cell-detaching effect. This preliminary study aims to assess the potential of EDTA in removing residual tumor cell clusters. Using an in-vitro model, this effect is then compared to the cytotoxic effect of oxaliplatin which is routinely administered during HIPEC procedures. The overall cell toxicity and cell detaching effects of EDTA are compared to those of Oxaliplatin and the additive effect is quantified. METHODS: HT-29 (ATCC® HTB-38™) cells were treated with A) EDTA only B) Oxaliplatin only and C) both agents using an in-vitro model. Cytotoxicity and cell detachment following EDTA application were measured via colorimetric MTS assay. Additionally, detached cell groups were visualized using light microscopy and further analyzed by means of electron microscopy. RESULTS: When solely applied, EDTA does not exhibit any cell toxicity nor does it add any toxicity to oxaliplatin. However, EDTA enhances the detachment of adherent colon carcinoma cells by removing up to 65% (p<0.05) of the total initial cell amount. In comparison, the sole application of highly concentrated oxaliplatin induced cell mortality by up to 66% (p<0.05). While detached cells showed no mortality after EDTA treatment, cell clusters exhibited a decreased amount of extracellular and adhesive matrix in-between cells. When combined, Oxaliplatin and EDTA display a significant additive effect with only 30% (mean p <0.01) of residual vitality detected in the initial well. EDTA and Oxaliplatin remove up to 81% (p <0.01) of adhesive HT-29 cells from the surface either by cytotoxic effects or cell detachment. CONCLUSION: Our data support EDTA's potential to remove microscopical tumor cell clusters from the peritoneum and possibly act as a supplementary agent in HIPEC procedures with chemotherapy. While adding EDTA to HIPEC procedures may significantly decrease the risk of PM recurrence, further in-vivo and clinical trials are required to evaluate this effect.

[Notes on the cost-effectiveness of nutritional therapy with oral supplementation in the integral recovery of the patient with MRD]. / Apuntes sobre el coste-efectividad de la terapia nutricional con suplementación oral en la recuperación integral del paciente con DRE.

INTRODUCTION: The efficient management of health services requires obtaining the highest level of health possible with the available resources. The health economy has developed in recent years under the pressure of a more demanding population, older and with more comorbidities, in an environment of limited resources and greater financing difficulties. The Economics of Nutrition was born as a new discipline that addresses aspects related to the role of economics and nutrition in the health of healthy and sick populations. The economic analyzes are part of the evaluation tools for health interventions. Cost-effectiveness studies are the most frequently used. Cost-effectiveness studies have shown that the use of oral nutritional supplements offer clinical advantages for undernourished patients (reduction of morbidity and mortality) and economic benefits for the system (reduction of hospital stay, lower re-entry rates and cost savings). Oral nutritional supplementation in the integral recovery of the patient with malnutrition related to the disease is cost effective.

INTRODUCCIÓN: La gestión eficiente de los servicios sanitarios obliga a obtener el máximo nivel de salud posible con los recursos disponibles. La economía de la salud se ha desarrollado en los últimos años ante la presión de una población más demandante, de más edad y con más comorbilidades en un entorno de recursos limitados y mayores dificultades de financiación. La economía de la nutrición nace como una nueva disciplina que atiende aspectos relacionados con el papel de la economía y la nutrición en la salud de las poblaciones sanas y enfermas. Los análisis económicos forman parte de las herramientas de evaluación de las intervenciones sanitarias. Los estudios de coste-efectividad "los más frecuentemente utilizados" han demostrado que la utilización de los suplementos nutricional orales ofrece ventajas clínicas para los pacientes desnutridos (reducción de morbimortalidad) y económicas para el sistema (reducción de estancia hospitalaria, menores tasas de reingresos y ahorros de costes). La suplementación nutricional oral en la recuperación integral del paciente con desnutrición relacionada con la enfermedad es coste-efectiva.

NIR-responsive nanoplatform for pre/intraoperative image-guided carcinoma surgery and photothermal ablation of residual tumor tissue.

Local recurrence is common among patients with advanced cancer who have undergone surgery. Here, we developed a new surgical treatment for cancer based on a nanoparticle that loaded a near-infrared dye (IR780 iodide) and perfluorooctyl bromide into liposomes (NP-IR780). In an orthotopic breast cancer mouse model, NP-IR780 was demonstrated to have excellent tumor-targeting ability due to the selective tumor accumulation of IR780 iodide and the enhanced permeation and retention effect of the nanoparticle. With the excellent targeting ability, concurrent computed tomography and photoacoustic imaging were achieved for preoperative planning. In particular, NP-IR780 could serve as a tumor indicator for near-infrared fluorescence image-guided precise resection of lesions during surgery. Importantly, residual tumors could be ablated through intraoperative photothermal therapy without obvious recurrence. This work provides a theranostic strategy that significantly improved the survival of mice through pre/intraoperative image-guided tumor resection and subsequent photothermal therapy of residual lesions.

Management of the lateral neck in well differentiated thyroid cancer.

Lateral neck lymph node metastases in well differentiated thyroid cancer are common, ranging from 30% to 60%, with the majority of these foci identifiable only as microscopic deposits. A skilled ultrasound evaluation of the lymph nodes in the lateral neck is recommended for all patients presenting with newly diagnosed thyroid cancer undergoing surgical management. Ultrasound guided fine needle aspiration biopsy may be used to cytologically confirm suspected lateral neck nodal metastases prior to surgery. For patients with large volume nodal disease, extranodal extension, or multiple nodal metastases, computed tomography (CT) scan of the neck with contrast is an important additional imaging modality to accurately localize disease prior to surgery. Primary surgical management for lateral neck disease typically includes lateral neck dissection in conjunction with total thyroidectomy. Postoperative adjuvant radioactive iodine is typically recommended for patients with clinically evident nodal metastases, or for those with over 5 micrometastatic nodes. In the recurrent or persisting disease setting, complete surgical resection of local and regional disease remains the main treatment approach. However, sub-centimeter nodal disease may take an indolent course, and active surveillance may be a reasonable approach in selected clinical circumstances. Conversely, external beam radiation therapy (EBRT) may be considered for scenarios with unresectable disease, or microscopic residual disease following surgery in a clinically unfavorable setting. Two multi-kinase inhibitors (sorafenib and lenvatinib) are now FDA approved for treatment of RAI refractory thyroid cancer and now play an important role in the management of progressive, metastatic and surgically incurable disease.

Recurrence of Optimally Treated Malignant Peritoneal Mesothelioma with Cytoreduction and Heated Intraperitoneal Chemotherapy.

BACKGROUND: The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients. METHODS: We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan-Meier method. RESULTS: Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16-3.38). CONCLUSIONS: Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.

Chinese Data of Efficacy of Low- and High-Dose Iodine-131 for the Ablation of Thyroid Remnant.

BACKGROUND: Chinese data on the efficacy of low- and high-dose radioiodine for thyroid remnant are still absent. The aim of the study was to investigate whether a low dose of radioiodine is as effective as a high dose for remnant ablation in Chinese patients. METHODS: Patients presenting for radioiodine ablation in the authors' department were included. Inclusion criteria were aged ≥16 years, total or near-total thyroidectomy, tumor-node-metastasis (TNM) stage of pT1-3, any N stage, and M0. All patients were randomly allocated to either the high-dose group of 3700 MBq or the low-dose group of 1850 MBq for remnant ablation. The response to treatment was defined as successful or unsuccessful after a six- to nine-month interval. Ablation was considered to be successful if patients fulfilled the following criteria: no tracer uptake in the thyroid bed on diagnosis whole-body scanning and a negative level of serum thyroglobulin. RESULTS: There were 327 patients enrolled between January 2013 and December 2014. More than 95% had papillary thyroid cancer. Data could be analyzed for 278 cases (Mage = 44 years; 71.6% women), 155 in the low-dose group and 123 in the high-dose group. The rate of initial successful ablation was 84.2% in all patients, 82.6% in the low-dose group, and 86.2% in the high-dose group. There was no difference between the two groups (p = 0.509). CONCLUSIONS: In Chinese patients with differentiated thyroid carcinoma, the low dose of 1850 MBq radioiodine activity is as effective as a high dose of 3700 MBq for thyroid remnant ablation.

Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation.

INTRODUCTION: The impact of selective surgical resection for patients with esophageal cancer treated with definitive chemoradiation has not been clearly evaluated long-term. METHODS: NRG (National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, Gynecologic Oncology Group) Oncology Radiation Therapy Oncology Group 0246 was a multi-institutional, single-arm, open-label, nonrandomized phase II study that enrolled 43 patients from September 2003 to March 2008 with clinical stage T1-4N0-1M0 squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction from 19 sites. Patients received induction chemotherapy with fluorouracil (650 mg/m2/d), cisplatin (15 mg/m2/d), and paclitaxel (200 mg/m2/d) for two cycles followed by concurrent chemoradiation consisting of 50.4 Gy of radiation (1.8 Gy per fraction) and daily fluorouracil (300 mg/m2/d) with cisplatin (15 mg/m2/d) over the first 5 days. After definitive chemoradiation, patients were evaluated for residual disease. Selective esophagectomy was considered only for patients with residual disease after chemoradiation (clinical incomplete response) or recurrent disease on surveillance. RESULTS: This report looks at the long-term outcome of this selective surgical strategy. With a median follow-up of 8.1 years (minimum to maximum for 12 alive patients 7.2-9.8 years), the estimated 5- and 7-year survival rates are 36.6% (95% confidence interval [CI]: 22.3-51.0) and 31.7% (95% CI: 18.3-46.0). Clinical complete response was achieved in 15 patients (37%), with 5- and 7-yearr survival rates of 53.3% (95% CI: 26.3-74.4) and 46.7% (95% CI: 21.2-68.7). Esophageal resection was not required in 20 of 41 patients (49%) on this trial. CONCLUSIONS: The long-term results of NRG Oncology Radiation Therapy Oncology Group 0246 demonstrate promising efficacy of a selective surgical resection strategy and suggest the need for larger randomized studies to further evaluate this organ-preserving approach.

Microwave coagulation/ablation in combination with sorafenib suppresses the overgrowth of residual tumor in VX2 liver tumor model.

OBJECTIVES: Our study is to evaluate the effect of thermal ablation on residual VX2 tumor tissue and the efficiency of sorafenib as an adjuvant therapy after insufficient microwave coagulation (MWC) on a rabbit VX2 liver tumor model. METHODS: Thirty-seven rabbits with orthotic VX2 liver tumors were randomly divided into MWC group (n=11), combination treatment group (n=14), and control group (n=12). The therapeutic efficacy was evaluated by contrast enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), pathological and immunohistochemical examinations. Analysis of enhancement characteristics included enhancement level, pattern, and location. The necrotic degree of tumor was analyzed by semi-quantitative classification. The apparent diffusion coefficiency (ADC) was calculated using diffused weighted image (DWI). RESULTS: The tumor growth was accelerated in MWC group compared with control group and combination treatment group. A low metastasis rate was shown in combination treatment group compared with other two groups. The degree of necrosis in combination treatment group was greater than that in MWC group. The ADC value on DWI was higher compared with that of the control and MWC group, with statistical significance (P<0.05). With adjuvant therapy of sorafenib after insufficient ablation, the microvessel density (MVD) was lower than that of control group, whereas in MWC group the MVD was higher than that of control group, with statistical significance (P<0.05). CONCLUSION: Insufficient thermal ablation promotes residual tumor progression. While the adjuvant therapy of sorafenib serves as an effective way to suppress the overgrowth and neovascularization of residual tumor after insufficient thermal ablation.

The role of hyperthermic intraperitoneal chemotherapy using paclitaxel in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction.

BACKGROUND: We analyzed the role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) on the microscopic component of the disease in patients with a first recurrence of platinum-sensitive ovarian cancer after complete cytoreduction (CCR). PATIENTS AND METHODS: We analyzed the data of 54 patients who were operated on between January 2001 and July 2012 with the diagnosis of platinum-sensitive recurrent ovarian cancer. In all patients, it was possible to achieve a CCR. Patients were divided into two groups: group I (cytoreduction alone) consisted of 22 surgical patients and group II (cytoreduction and HIPEC) consisted of 32 patients. RESULTS: There were no significant differences in any of the preoperative variables studied. After a multivariate analysis of factors identified in the univariate analysis, only the presence of tumors with undifferentiated histology (hazard ratio 2.57; 95% CI 1.21-5.46; p < 0.05) was an independent factor associated with a reduced disease-free survival. The 1- and 3-year disease-free survival was 77 and 23% in patients from group I and 77 and 45% in patients from group II, respectively, with a tendency, but no significant differences (p = 0.078). There was no significant difference in postoperative morbidity between the two groups. CONCLUSIONS: The administration of HIPEC in patients in whom it is possible to achieve a CCR of the disease has not increased postoperative morbidity and mortality rates in our center. HIPEC with paclitaxel is effective in the treatment of microscopic disease in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction, although with no statistically significant difference.

Chemoradiotherapy for extrahepatic bile duct cancer with gross residual disease after surgery.

BACKGROUND: The purpose of the present study was to analyze the outcome of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients with gross residual disease after surgical resection. PATIENTS AND METHODS: We retrospectively analyzed 30 patients with EHBD adenocarcinoma who underwent chemoradiotherapy after palliative resection (R2 resection). Postoperative radiotherapy was delivered to the tumor bed including residual tumor and regional lymph nodes (range=40-55.8 Gy). Most patients underwent chemoradiotherapy concurrently with 5-fluorouracil (5-FU) or gemcitabine. RESULTS: The 2-year locoregional progression-free, distant metastasis-free and overall survival rates were 33.3%, 42.4% and 44.5%, respectively. High radiation dose≥50 Gy had a marginally significant impact on superior locoregional progression-free survival compared to 40 Gy (p=0.081). One patient developed grade 3 late gastrointestinal toxicity. CONCLUSION: Adjuvant chemoradiotherapy for EHBD cancer patients with gross residual disease after surgery was well-tolerated. There could be a chance for durable locoregional control and even long-term survival in selected patients.

Treatment of microscopic disease with hyperthermic intraoperative intraperitoneal chemotherapy after complete cytoreduction improves disease-free survival in patients with stage IIIC/IV ovarian cancer.

BACKGROUND: We analyze the efficacy of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) for microscopic residual disease in patients with stage IIIC/IV ovarian cancer after a complete cytoreduction of their disease. PATIENTS AND METHODS: We analyzed the data of 87 consecutive patients diagnosed with stage IIIC/IV ovarian cancer operated between December 1998 and July 2011. In every patient it was possible to achieve a complete cytoreduction of their disease. (Since January 2008, our center has incorporated the use of HIPEC in patients with peritoneal surface malignancies, including patients with peritoneal dissemination of primary ovarian cancer.) RESULTS: Of 87 patients, 52 were treated with HIPEC (paclitaxel 60 mg/m(2), 60 min, 42 °C). After a univariate analysis, factors associated with lower disease-free interval were: performing a gastrointestinal anastomosis, operative time greater than 270 min, poorly differentiated histology, and not being treated with HIPEC. After multivariate analysis, independent prognostic factors included not being treated with HIPEC [hazard ratio (HR) 8.77, 95 % CI 2.76-14.42, p < 0.01] and the presence of poorly differentiated tumors (HR 1.98, 95 % CI 1.45-8.56, p < 0.05). Disease-free survival at 1 and 3 years was 66 and 18 %, respectively, in patients without HIPEC and 81 and 63 %, respectively, in patients treated with HIPEC (p < 0.01). HIPEC administration did not alter the results obtained for disease-free survival in patients with undifferentiated tumors. CONCLUSIONS: The treatment of the microscopic disease following complete cytoreduction with HIPEC in patients with advanced ovarian cancer is effective and can prolong disease-free survival. This survival benefit was not seen in undifferentiated tumors.

Mucinous tumor of the appendix with limited peritoneal spread: is there a role for expectant observation?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is now the standard management for mucinous tumors of appendiceal origin at many centers. We examined the role of expectant observation (EO) in patients who had undergone an initial resection at the time of referral to our center and who had limited residual disease. METHODS: We performed a retrospective review of patients referred to Mount Sinai/Princess Margaret Hospitals, Toronto, for consideration of surgical management of peritoneal malignancy between January 1998 and December 2009. One hundred and three patients with primary mucinous appendiceal malignancy were identified. EO, consisting of regularly scheduled imaging and clinical review, was selected for asymptomatic patients with low-grade tumor and no/limited disease on imaging. Overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Management consisted of supportive care in 7 patients, systemic chemotherapy in 7, referral for CRS with HIPEC in 8, CRS without HIPEC at our center in 51, and EO in 30. In the CRS group, 5-year OS was 74 % and PFS was 56 %; both OS and PFS were predicted by extent of residual disease after cytoreduction (p = 0.014 and p = 0.011, respectively). In the EO group, 5-year OS and PFS were 95 and 82 %, respectively. Two patients in the EO group subsequently underwent CRS for progression on imaging. CONCLUSIONS: In well-selected patients who have undergone initial resection for low-grade mucinous tumor of the appendix with limited peritoneal spread, a formal program of observation can result in excellent 5-year OS and PFS. Longer-term follow-up will help define the benefits and risks of this approach.

Prognostic nomograms to predict oncological outcome of thyroid cancers.

CONTEXT: Thyroid cancers represent a conglomerate of diverse histological types with equally variable prognosis. There is no reliable prognostic model to predict the risks of relapse and death for different types of thyroid cancers. OBJECTIVE: The purpose of this study was to build prognostic nomograms to predict individualized risks of relapse and death of thyroid cancer within 10 years of diagnosis based on patients' prognostic factors. DESIGN: Competing risk subhazard models were used to develop prognostic nomograms based on the information on individual patients in a population-based thyroid cancer cohort followed up for a median period of 126 months. Analyses were conducted using R version 2.13.2. The R packages cmprsk10, Design, and QHScrnomo were used for modeling, developing, and validating the nomograms for prediction of patients' individualized risks of relapse and death of thyroid cancer. SETTING: This study was performed at CancerCare Manitoba, the sole comprehensive cancer center for a population of 1.2 million. PATIENTS: Participants were a population-based cohort of 2306 consecutive thyroid cancers observed in 2296 patients in the province of Manitoba, Canada, during 1970 to 2010. MAIN OUTCOME MEASURES: Outcomes were discrimination (concordance index) and calibration curves of nomograms. RESULTS: Our cohort of 570 men and 1726 women included 2155 (93.4%) differentiated thyroid cancers. On multivariable analysis, patient's age, sex, tumor histology, T, N, and M stages, and clinically or radiologically detectable posttreatment gross residual disease were independent determinants of risk of relapse and/or death. The individualized 10-year risks of relapse and death of thyroid cancer in the nomogram were predicted by the total of the weighted scores of these determinants. The concordance indices for prediction of thyroid cancer-related deaths and relapses were 0.92 and 0.76, respectively. The calibration curves were very close to the diagonals. CONCLUSIONS: We have successfully developed prognostic nomograms for thyroid cancer with excellent discrimination (concordance indices) and calibration.

Adjuvant chemoradiotherapy after curative resection for extrahepatic bile duct cancer: a long-term single center experience.

OBJECTIVES: To analyze the outcome of adjuvant chemoradiotherapy for patients with extrahepatic bile duct (EHBD) cancer, and to identify the prognostic factors for these patients. METHODS: Between January 1995 and December 2002, 86 patients with adenocarcinoma of EHBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 59 male and 27 female patients, and median age was 59 years (range, 34 to 73 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/d) was given on day 1 to 3 of each split course. The median follow-up period was 83 months for survivors. RESULTS: Forty-eight patients failed the treatment: locoregional recurrence in 20, distant metastasis in 38, and both locoregional and distant relapses in 10 patients. Five-year locoregional relapse-free survival rate was 70.3%. On multivariate analysis, resection margin status was the only significant prognosticator (P=0.0299). Five-year distant metastasis-free survival rate was 53.6%. Three or more involved lymph nodes had an adverse impact on distant metastasis-free survival (P=0.0334). Five-year overall survival rate was 44.7%, and poorly differentiated tumor was associated with inferior overall survival (P=0.0297). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival in patients with EHBD cancer. Resection margin status, number of involved lymph nodes, and histologic differentiation are associated with locoregional relapse, distant metastasis, and overall survival, respectively. Distant metastasis was the major pattern of failure, possibly due to the increased locoregional control by use of adjuvant chemoradiotherapy. Intensification of systemic treatment is warranted.

The prognostic value of grade of regression and oncocytic change in rectal adenocarcinoma treated with neo-adjuvant chemoradiotherapy.

BACKGROUND: Pathological staging and regression grading may affect the clinical outcome in rectal carcinoma patients treated with neoadjuvant chemoradiation (NACRT). Oncocytic change (OC) has also been described in the residual tumor. This study assesses the correlation of degree of pathological response and OC with clinical outcome. METHODS: Seventy-five cases of rectal adenocarcinoma undergoing NACRT followed by surgery were retrospectively analyzed for preoperative and post-operative staging, degree of tumor response to NACRT using the Dworak Regression score (DR) and Tumor Regression Grading (TRG) systems, as well as the proportion of cells showing OC. These parameters were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: Significant correlation was found between post-operative T and N stage and OS (P = 0.005 and 0.002, respectively); and post-operative and preoperative T stage with DFS (P = 0.002 and 0.02, respectively). Grouping patients by TRG scores (TRG1-3 vs TRG4-5) also proved to be a significant independent prognosticator for DFS (P < 0.001). The DR score groups and OC (<35% vs. >35%) were not statistically significant predictors of clinical outcome. CONCLUSIONS: Post-NACRT T and N staging and the TRG system are important prognostic indicators. The presence and extent of OC needs to be better understood and further investigated.

Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. A phase II trial.

BACKGROUND: The goal of this study was to determine the rational of radical surgery with intra-operative high-dose radiotherapy after chemoradiation (RT-CT) in extra cervical locally advanced cervical cancer (LACC) patients. METHODS: Between 2000 and 2007, 42 LACC (stage IIA bulky-IVA) patients were treated at the Gynecologic Oncology Unit of the C.R.O. of Aviano in a Phase II Clinical Trial. Radiotherapy was administered to the whole pelvic region (50.4 Gy in 28 fractions) in combination with cisplatin (60 mg/mq) plus 5FU (750 mg/mq for 4 days) on first and fifth week of RT. Radical surgery with Intra-Operative Radiation Therapy (IORT) was performed 6-8 weeks after the end of RT-CT treatment. RESULTS: After RT-CT, 35/42 patients (83%) underwent radical surgery and IORT treatment. At pathologic examination 8/35 (23%) patients showed complete response, while the rest (27/35) had residual disease either microscopic (17/27) or gross (10/27). The 5-year disease free survival (DFS) and the 5-year overall survival (OS) were 46% and 49% respectively. There were significant better DFS and OS when residual tumor was absent or limited to the cervix, respectively 78% versus 16% and 81% versus 20% (p < 0.001). All recurrences occurred within 24 months from treatment. CONCLUSIONS: RT-CT followed by surgery and IORT in LACC patients seems to be active in a subgroup of patients with pathological complete response to treatment or partial response with residual tumor limited to the cervix.

Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study.

PURPOSE: In 10-24% of patients with rectal cancer who are treated with neoadjuvant chemoradiation, no residual tumor is found after surgery (ypT0). When accurately selected, these complete responders might be considered for less invasive treatments instead of standard surgery. So far, no imaging method has proven reliable. This study was designed to assess the accuracy of diffusion-weighted MRI (DWI) in addition to standard rectal MRI for selection of complete responders after chemoradiation. METHODS: A total of 120 patients with locally advanced rectal cancer from three university hospitals underwent chemoradiation followed by a restaging MRI (1.5T), consisting of standard T2W-MRI and DWI (b0-1000). Three independent readers first scored the standard MRI only for the likelihood of a complete response using a 5-point confidence score, after which the DWI images were added and the scoring was repeated. Histology (ypT0 vs. ypT1-4) was the standard reference. Diagnostic performance for selection of complete responders and interobserver agreement were compared for the two readings. RESULTS: Twenty-five of 120 patients had a complete response (ypT0). Areas under the ROC-curve for the three readers improved from 0.76, 0.68, and 0.58, using only standard MRI, to 0.8, 0.8, and 0.78 after addition of DWI (P = 0.39, 0.02, and 0.002). Sensitivity for selection of complete responders ranged from 0-40% on standard MRI versus 52-64% after addition of DWI. Specificity was equally high (89-98%) for both reading sessions. Interobserver agreement improved from κ 0.2-0.32 on standard MRI to 0.51-0.55 after addition of DWI. CONCLUSIONS: Addition of DWI to standard rectal MRI improves the selection of complete responders after chemoradiation.

Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease that is often associated with several chromosomal and molecular abnormalities. Patients who have the Philadelphia (Ph) chromosome and associated BCR-ABL1 oncogene have a particularly poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only known curative treatment for Ph+ ALL and facilitating allo-HSCT in eligible patients is a key treatment goal. However, many patients relapse after allo-HSCT, particularly those with measurable residual disease prior to transplantation, and a significant percentage of patients are ineligible for allo-HSCT, particularly older patients. Hence, many patients require additional/alternative therapies to prolong survival. Studies are ongoing to determine the most effective first-line drug regimens for patients who subsequently undergo allo-HSCT and ineligible patients. Tyrosine kinase inhibitors targeted to Bcr-Abl are important novel therapies for Ph+ ALL. Although imatinib administered in combination with chemotherapy is established as the current first-line strategy, relapse is common, even among allo-HSCT recipients. Emerging data indicate that more potent multi-targeted kinase inhibitors (including dasatinib, nilotinib, and bosutinib) have promising efficacy in the first- or second-line setting. Here, the evidence base for existing drug treatments for Ph+ ALL is discussed and emerging therapeutic strategies are explored.