ABSTRACT
BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile remained unchanged since the previous analysis. CONCLUSIONS: Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in LARC patients, and should be considered as one of the best options of care for these patients.
ABSTRACT
Little is known about the prevalence and associated of morbidity of tendon problems. With only severe cases of tendon problems missing games, players that have their training and performance impacted are not captured by traditional injury surveillance. The aim of this study was to report the prevalence of Achilles and patellar tendon problems in elite male Australian football players using the Oslo Sports Trauma Research Centre (OSTRC) overuse questionnaire, compared to a time-loss definition. Male athletes from 12 professional Australian football teams were invited to complete a monthly questionnaire over a 9-month period in the 2016 pre- and competitive season. The OSTRC overuse injury questionnaire was used to measure the prevalence and severity of Achilles and patellar tendon symptoms and was compared to traditional match-loss statistics. A total of 441 participants were included. Of all participants, 21.5% (95% CI: 17.9-25.6) and 25.2% (95% CI 21.3-29.4) reported Achilles or patellar tendon problems during the season, respectively. Based on the traditional match-loss definition, a combined 4.1% of participants missed games due to either Achilles or patellar tendon injury. A greater average monthly prevalence was observed during the pre-season compared to the competitive season. Achilles and patellar tendon problems are prevalent in elite male Australian football players. These injuries are not adequately captured using a traditional match-loss definition. Prevention of these injuries may be best targeted during the off- and pre-season due to higher prevalence of symptoms during the pre-season compared to during the competitive season.
Subject(s)
Athletic Injuries/epidemiology , Soccer/injuries , Tendon Injuries/epidemiology , Achilles Tendon/injuries , Adolescent , Athletes , Australia , Humans , Male , Patellar Ligament/injuries , Prevalence , Young AdultABSTRACT
Anterior knee pain (AKP) is a frequent clinical presentation in jumping athletes and may be aggravated by sustained sitting, stair use, and loading of the quadriceps. Corticospinal activation of the quadriceps in athletes with AKP has not yet been investigated, but is important in guiding efficacious treatment. This cross-sectional study assessed corticospinal excitability (CSE) of the quadriceps in jumping athletes using transcranial magnetic stimulation (TMS). Groups consisted of Control (no knee pain); patellar tendinopathy (PT) [localized inferior pole pain on single-leg decline squat (SLDS)]; and other AKP (nonlocalized pain around the patella). SLDS (numerical score of pain 0-10), Victorian Institute of Sport Assessment Patellar tendon (VISA-P), maximal voluntary isometric contraction (MVIC), active motor threshold (AMT), CSE, and Mmax were tested. Twenty nine athletes participated; control n = 8, PTâ n = 11, AKPâ n = 10. There were no group differences in age (P = 0.23), body mass index (P = 0.16), MVIC (P = 0.38) or weekly activity (P = 0.22). PT had elevated CSE compared with controls and other AKP (P < 0.001), but no differences were detected between AKP and controls (P = 0.47). CSE appears to be greater in PT than controls and other AKP. An improved understanding of the corticospinal responses in different sources of knee pain may direct better treatment approaches.
Subject(s)
Cortical Excitability , Patellar Ligament/physiopathology , Pyramidal Tracts/physiopathology , Quadriceps Muscle/physiopathology , Tendinopathy/physiopathology , Adolescent , Adult , Basketball/physiology , Case-Control Studies , Cross-Sectional Studies , Electromyography , Female , Humans , Isometric Contraction , Knee Joint , Male , Musculoskeletal Pain/etiology , Tendinopathy/complications , Transcranial Magnetic Stimulation , Volleyball/physiology , Young AdultABSTRACT
Patellar tendinopathy (jumper's knee) has a high prevalence in jumping athletes. Excessive load on the patellar tendon through high volumes of training and competition is an important risk factor. Structural changes in the tendon are related to a higher risk of developing patellar tendinopathy. The critical tendon load that affects tendon structure is unknown. The aim of this study was to investigate patellar tendon structure on each day of a 5-day volleyball tournament in an adolescent population (16-18 years). The right patellar tendon of 41 players in the Australian Volleyball Schools Cup was scanned with ultrasound tissue characterization (UTC) on every day of the tournament (Monday to Friday). UTC can quantify structure of a tendon into four echo types based on the stability of the echo pattern. Generalized estimating equations (GEE) were used to test for change of echo type I and II over the tournament days. Participants played between eight and nine matches during the tournament. GEE analysis showed no significant change of echo type percentages of echo type I (Wald chi-square = 4.603, d.f. = 4, P = 0.331) and echo type II (Wald chi-square = 6.070, d.f. = 4, P = 0.194) over time. This study shows that patellar tendon structure of 16-18-year-old volleyball players is not affected during 5 days of cumulative loading during a volleyball tournament.
Subject(s)
Patellar Ligament/diagnostic imaging , Volleyball , Adolescent , Cumulative Trauma Disorders/diagnostic imaging , Female , Humans , Male , Patellar Ligament/injuries , Tendinopathy/diagnostic imaging , Time Factors , Ultrasonography , Volleyball/injuriesABSTRACT
The pathogenesis of tendinopathy and the primary biological change in the tendon that precipitates pathology have generated several pathoaetiological models in the literature. The continuum model of tendon pathology, proposed in 2009, synthesised clinical and laboratory-based research to guide treatment choices for the clinical presentations of tendinopathy. While the continuum has been cited extensively in the literature, its clinical utility has yet to be fully elucidated. The continuum model proposed a model for staging tendinopathy based on the changes and distribution of disorganisation within the tendon. However, classifying tendinopathy based on structure in what is primarily a pain condition has been challenged. The interplay between structure, pain and function is not yet fully understood, which has partly contributed to the complex clinical picture of tendinopathy. Here we revisit and assess the merit of the continuum model in the context of new evidence. We (1) summarise new evidence in tendinopathy research in the context of the continuum, (2) discuss tendon pain and the relevance of a model based on structure and (3) describe relevant clinical elements (pain, function and structure) to begin to build a better understanding of the condition. Our goal is that the continuum model may help guide targeted treatments and improved patient outcomes.
Subject(s)
Myalgia/physiopathology , Tendinopathy/diagnosis , Tendinopathy/physiopathology , Tendons/pathology , Collagen/physiology , Humans , Inflammation , Models, Biological , Myalgia/therapy , Tendinopathy/therapyABSTRACT
Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.
Subject(s)
Colorectal Neoplasms/genetics , Kisspeptins/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Genetic Association Studies , Humans , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prognosis , Signal TransductionABSTRACT
Epidermal growth factor receptor (EGFR) activation by radiation leads to increased cell proliferation and acts as a radioresistance mechanism. Neoadjuvant chemoradiation is the standard of care for locally advanced rectal cancer, and to date, no biomarkers of response have been found. We analyzed polymorphisms in the EGFR and its ligands, DNA repair genes and the thymidylate synthase in 84 stages II and III rectal cancer patients treated with neoadjuvant capecitabine plus radiotherapy. The rs11942466 polymorphism in the amphiregulin (AREG) gene region was associated with a pathological complete response (ypCR) (odds ratio: 0.26; 95% confidence interval: 0.06-0.79; P=0.014). The rs11615 C>T polymorphism in the ERCC1 gene also correlated with the ypCR as no patients with a C/C genotype achieved ypCR; P=0.023. This is the first work to propose variants within the AREG and the ERCC1 genes as promising predictive biomarkers of ypCR in rectal cancer.
Subject(s)
Chemoradiotherapy/methods , DNA Repair/genetics , Deoxycytidine/analogs & derivatives , ErbB Receptors/genetics , Fluorouracil/analogs & derivatives , Rectal Neoplasms/genetics , Rectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/therapeutic use , Capecitabine , Cohort Studies , Deoxycytidine/therapeutic use , Female , Fluorouracil/therapeutic use , Follow-Up Studies , Genetic Testing/methods , Genomics/methods , Humans , Ligands , Male , Middle Aged , Rectal Neoplasms/diagnosis , Treatment OutcomeABSTRACT
BACKGROUND: Pterygium Inversum Unguis (PIU) is a wing-like extended hyponychium associated with the absence of the distal groove. Although a rare condition, it has been described with different names, confusing both the investigator and the reader. OBJECTIVE: We propose a new nomenclature based on tissue origin and pathology, to account for these conditions. 1) Congenital Aberrant Hyponychium 2) Acquired Pterygium Inversum Unguis 3) Acquired Reversible Extended Hyponychium. MAIN OBSERVATIONS: We report a case of a 19-year-old male, with epidermal pigmentation abnormalities, who had painful fingertips of both index fingers and thumbs since he was 13. He therefore let his finger nails grow very long, minimizing painful contact with the hyponychium. Removal of the aberrant hyponychium revealed glomus bodies aggregates with increased nerve fibers. Subsequently after excision of the hyponychium, his pain was resolved. SUMMARY: Congenital, transient or permanent changes in the hyponychium should be named and classified according to tissue origin to avoid nomenclature confusion.
Subject(s)
Nails, Malformed/classification , Nails, Malformed/congenital , Nails/pathology , Biopsy , Diagnosis, Differential , Humans , Male , Nails, Malformed/pathology , Young AdultABSTRACT
In the epidermal growth factor receptor (EGFR) pathway, polymorphisms in EGFR and its ligand EGF have been studied as biomarkers for anti-EGFR treatment. However, the potential pharmacogenetic role of other EGFR ligands such as amphiregulin (AREG) and epiregulin (EREG) has not been elucidated. We studied 74 KRAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan. Twenty-two genetic variants in EGFR, EGF, AREG and EREG genes were selected using HapMap database and literature resources. Three tagging single-nucleotide polymorphisms in the AREG gene region (rs11942466 C>A, rs13104811 A>G, and rs9996584 C>T) predicted disease control in the multivariate analyses. AREG rs11942466 C>A and rs9996584 C>T were also associated with overall survival (OS). The functional polymorphism, EGFR rs712829 G>T, was associated with progression-free and OS. Our findings support that intergenic polymorphisms in the AREG gene region might help to identify colorectal cancer patients that will benefit from irinotecan plus anti-EGFR therapy.
Subject(s)
Amphiregulin/genetics , Biomarkers/metabolism , Camptothecin/analogs & derivatives , Colorectal Neoplasms/genetics , ErbB Receptors/antagonists & inhibitors , Polymorphism, Genetic , Base Sequence , Camptothecin/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , DNA Primers , Female , Humans , Irinotecan , Male , Neoplasm Metastasis , Polymorphism, Single Nucleotide , Real-Time Polymerase Chain ReactionABSTRACT
Crisóstomo Martínez from Valencia was a pioneering microscopist in 17th-century Europe. The first microscopic representations of skin in Spain appeared in an 18th-century work by Martín Martínez. Microbiology and histopathology progressed considerably in the late 19th century thanks to anatomists like Maestre de San Juan and surgeons like Federico Rubio Galí. The first Spanish pathologist to specialize in dermatology was Antonio Mendoza, a colleague of José Eugenio de Olavide at the Hospital San Juan de Dios in Madrid. Claudio Sala and Juan de Azúa also made significant contributions, including the description of pseudoepithelioma. Several disciples of Santiago Ramón y Cajal and Jorge FranciscoTello, such as Lorenzo Ruiz de Arcaute and Guillermo de la Rosa King, consolidated the dermatology laboratory, but the Civil War sent many into exile or deprived them of their professional status. Juan Rubió in Barcelona and Julio Rodríguez Puchol in Madrid were the immediate predecessors of today's dermatopathologists.
Subject(s)
Dermatology/history , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , Microbiology/history , Microscopy/history , Microscopy/instrumentation , Pathology, Clinical/history , SpainABSTRACT
BACKGROUND: The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). PATIENTS AND METHODS: Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m(2) with a loading dose of 400 mg/m(2) 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. RESULTS: The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18-27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%-86%), 62% (95% CI: 36%-82%), and 92% (95% CI: 67%-99%), respectively. CONCLUSION: CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. EUDRA CT NO: 2007-007029-38.
Subject(s)
Anus Neoplasms/drug therapy , Anus Neoplasms/radiotherapy , Drug-Related Side Effects and Adverse Reactions/pathology , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Anus Neoplasms/pathology , Cetuximab , Chemoradiotherapy/adverse effects , Cisplatin/administration & dosage , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/classification , Female , Fluorouracil/administration & dosage , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/radiotherapy , Radiotherapy/adverse effectsABSTRACT
OBJECTIVES: There is an established relationship between nightlife, substance use and violence. This study investigated this relationship when people are on holiday, and explored the differences in experiences between physical and verbal violence. STUDY DESIGN: A survey of young tourists at seven airport departure areas in Southern European resorts. METHODS: Questionnaires from 6502 British and German tourists were analysed exploring demographics, violence (verbal and physical), substance use, and reasons for resort and venue selection. RESULTS: Over two-thirds of respondents reported being drunk on their holiday, 12.4% had been involved in arguments and 2.9% had been involved in fights. Logistic regression highlighted more violence amongst visitors to Mallorca [arguments: adjusted odds ratio (AOR) 2.7; fights: AOR 2.0] compared with those visiting Portugal, males (arguments: AOR 1.3; fights: AOR 1.7), those who had used illicit drugs (arguments: AOR 1.5; fights: AOR 2.9), those who had been in fights at home in the last 12 months (arguments: AOR 2.2; fights AOR 2.9), and those who had frequently been drunk abroad (arguments: AOR 2.4; fights: AOR 2.5). Those aged 16-19 years, visiting Italy or Crete, who were drunk for fewer than half of the days of their stay, and who chose bars because they were frequented by drunk people were more likely to report having an argument. Fights were associated with cannabis use and were negatively associated with choosing bars with a friendly atmosphere. Economic status or frequency of visiting bars had no relationship with arguments or fights. CONCLUSIONS: Understanding and addressing the variables involved in violence when holidaying abroad is critical in targeting appropriate health promotion and harm reduction measures.
Subject(s)
Holidays , Social Environment , Substance-Related Disorders/epidemiology , Travel/psychology , Violence/statistics & numerical data , Adolescent , Adult , Alcoholic Intoxication/epidemiology , Europe/epidemiology , Female , Humans , Illicit Drugs , Male , Odds Ratio , Risk Factors , Surveys and Questionnaires , Travel/statistics & numerical data , Verbal Behavior , Young AdultABSTRACT
Introduction: In light of the impact of airway barrier leaks in COVID-19 and the significance of vitamin D in COVID-19 outcomes, including airway barrier protection, we investigated whether the very common dietary flavonoid quercetin could also be efficacious in supporting airway barrier function. Methods: To address this question, we utilized the widely used airway epithelial cell culture model, Calu-3. Results: We observed that treating Calu-3 cell layers with quercetin increased transepithelial electrical resistance while simultaneously reducing transepithelial leaks of 14C-D-mannitol (Jm) and 14C-inulin. The effects of quercetin were concentration-dependent and exhibited a biphasic time course. These effects of quercetin occurred with changes in tight junctional protein composition as well as a partial inhibition of cell replication that resulted in decreased linear junctional density. Both of these effects potentially contribute to improved barrier function. Quercetin was equally effective in reducing the barrier compromise caused by the pro-inflammatory cytokine TNF-α, an action that seemed to derive, in part, from reducing the elevation of ERK 1/2 caused by TNF-α. Discussion: Quercetin improved Calu-3 barrier function and reduced TNF-α-induced barrier compromise, mediated in part by changes in the tight junctional complex.
ABSTRACT
BACKGROUND: Alongside the benefits of Total-Body imaging modalities, such as higher sensitivity, single-bed position, low dose imaging, etc., their final construction cost prevents worldwide utilization. The main aim of this study is to present a simulation-based comparison of the sensitivities of existing and currently developed tomographs to introduce a cost-efficient solution for constructing a Total-Body PET scanner based on plastic scintillators. METHODS: For the case of this study, eight tomographs based on the uEXPLORER configuration with different scintillator materials (BGO, LYSO), axial field-of-view (97.4 cm and 194.8 cm), and detector configurations (full and sparse) were simulated. In addition, 8 J-PET scanners with different configurations, such as various axial field-of-view (200 cm and 250 cm), different cross sections of plastic scintillator, and multiple numbers of plastic scintillator layers (2, 3, and 4), based on J-PET technology have been simulated by GATE software. Furthermore, Siemens' Biograph Vision has been simulated to compare the results with standard PET scans. Two types of simulations have been performed. The first one with a centrally located source with a diameter of 1 mm and a length of 250 cm, and the second one with the same source inside a water-filled cylindrical phantom with a diameter of 20 cm and a length of 183 cm. RESULTS: With regards to sensitivity, among all the proposed scanners, the ones constructed with BGO crystals give the best performance ([Formula: see text] 350 cps/kBq at the center). The utilization of sparse geometry or LYSO crystals significantly lowers the achievable sensitivity of such systems. The J-PET design gives a similar sensitivity to the sparse LYSO crystal-based detectors while having full detector coverage over the body. Moreover, it provides uniform sensitivity over the body with additional gain on its sides and provides the possibility for high-quality brain imaging. CONCLUSION: Taking into account not only the sensitivity but also the price of Total-Body PET tomographs, which till now was one of the main obstacles in their widespread clinical availability, the J-PET tomography system based on plastic scintillators could be a cost-efficient alternative for Total-Body PET scanners.
ABSTRACT
BACKGROUND: The Jagiellonian Positron Emission Tomograph is the 3-layer prototype of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV photons emitted in [Formula: see text] annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures the precise labeling of the 511 keV photons. RESULTS: By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100[Formula: see text]. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons. CONCLUSION: A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.
ABSTRACT
Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⻲ had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⻲ (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL.
Subject(s)
Methotrexate , Methylenetetrahydrofolate Reductase (NADPH2) , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Child , Child, Preschool , Disease-Free Survival , Female , Genotype , Humans , Infant, Newborn , Kaplan-Meier Estimate , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Methotrexate/pharmacokinetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/metabolism , Pharmacogenetics , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
We present the update of the recommendations of the French society of oncological radiotherapy on radiotherapy of cutaneous cancers. The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomized trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and located in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumors (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radio- therapy (50 to 56Gy) for Merkel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.
Subject(s)
Skin Neoplasms/radiotherapy , Carcinoma, Basal Cell/radiotherapy , Carcinoma, Basal Cell/surgery , Carcinoma, Merkel Cell/radiotherapy , Carcinoma, Squamous Cell/radiotherapy , France , Humans , Lymphoma, T-Cell, Cutaneous/radiotherapy , Melanoma/pathology , Melanoma/radiotherapy , Palliative Care , Prognosis , Radiation Oncology , Radiotherapy Dosage , Radiotherapy, Adjuvant , Sarcoma, Kaposi/radiotherapy , Skin Neoplasms/pathology , Skin Neoplasms/surgeryABSTRACT
We present the update of the recommendations of the French society of oncological radiotherapy on hepatic tumours. Recent technological progress led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumours, as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. The tumour volume, its liver location close to the organs at risk determine the irradiation technique (repositioning method, total dose delivered, dose fractionation regimens). Tumour (and liver) breathing related motions should be taken into account. Strict dosimetric criteria must be observed with particular attention to the dose-volume histograms of non-tumoral liver as well as of the hollow organs, particularly in case of hypofractionated high dose radiotherapy "under stereotaxic conditions". Stereotactic body radiotherapy is being evaluated and is often preferred to radiofrequency for primary or secondary tumours (usually less than 5cm). An adaptation can be proposed, with a conformal fractionated irradiation protocol with or without intensity modulation, for hepatocellular carcinomas larger than 5cm.
Subject(s)
Carcinoma, Hepatocellular/radiotherapy , Liver Neoplasms/radiotherapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/secondary , France , Humans , Liver/radiation effects , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Organ Motion , Organs at Risk , Patient Positioning/methods , Radiation Oncology , Radiosurgery/methods , Radiotherapy Dosage , Radiotherapy, Conformal/methods , Radiotherapy, Image-Guided , Respiration , Tumor BurdenABSTRACT
Translational research in radiation oncology is undergoing intense development. An increasingly rapid transfer is taking place from the laboratory to the patients, both in the selection of patients who can benefit from radiotherapy and in the development of innovative irradiation strategies or the development of combinations with drugs. Accelerating the passage of discoveries from the laboratory to the clinic represents the ideal of any translational research program but requires taking into account the multiple obstacles that can slow this progress. The ambition of the RadioTransNet network, a project to structure preclinical research in radiation oncology in France, is precisely to promote scientific and clinical interactions at the interface of radiotherapy and radiobiology, in its preclinical positioning, in order to identify priorities for strategic research dedicated to innovation in radiotherapy. The multidisciplinary radiotherapy teams with experts in biology, medicine, medical physics, mathematics and engineering sciences are able to meet these new challenges which will allow these advances to be made available to patients as quickly as possible.