EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.

PET-based prognostic survival model after radiotherapy for head and neck cancer.

PURPOSE: The aims of this multicentre retrospective study of locally advanced head and neck cancer (LAHNC) treated with definitive radiotherapy were to (1) identify positron emission tomography (PET)-18F-fluorodeoxyglucose (18F-FDG) parameters correlated with overall survival (OS) in a training cohort, (2) compute a prognostic model, and (3) externally validate this model in an independent cohort. MATERIALS AND METHODS: A total of 237 consecutive LAHNC patients divided into training (n = 127) and validation cohorts (n = 110) were retrospectively analysed. The following PET parameters were analysed: SUVMax, metabolic tumour volume (MTV), total lesion glycolysis (TLG), and SUVMean for the primary tumour and lymph nodes using a relative SUVMax threshold or an absolute SUV threshold. Cox analyses were performed on OS in the training cohort. The c-index was used to identify the highly prognostic parameters. A prognostic model was subsequently identified, and a nomogram was generated. The model was externally tested in the validation cohort. RESULTS: In univariate analysis, the significant PET parameters for the primary tumour included MTV (relative thresholds from 6 to 83% and absolute thresholds from 1.5 to 6.5) and TLG (relative thresholds from 1 to 82% and absolute thresholds from 0.5 to 4.5). For the lymph nodes, the significant parameters included MTV and TLG regardless of the threshold value. In multivariate analysis, tumour site, p16 status, MTV35% of the primary tumour, and MTV44% of the lymph nodes were independent predictors of OS. Based on these four parameters, a prognostic model was identified with a c-index of 0.72. The corresponding nomogram was generated. This prognostic model was externally validated, achieving a c-index of 0.66. CONCLUSIONS: A prognostic model of OS based on primary tumour and lymph node MTV, tumour site, and p16 status was proposed and validated. The corresponding nomogram may be used to tailor individualized treatment.

Adaptive radiotherapy for head and neck cancer.

INTRODUCTION: Large anatomical variations can be observed during the treatment course intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), leading to potential dose variations. Adaptive radiotherapy (ART) uses one or several replanning sessions to correct these variations and thus optimize the delivered dose distribution to the daily anatomy of the patient. This review, which is focused on ART in the HNC, aims to identify the various strategies of ART and to estimate the dosimetric and clinical benefits of these strategies. MATERIAL AND METHODS: We performed an electronic search of articles published in PubMed/MEDLINE and Science Direct from January 2005 to December 2016. Among a total of 134 articles assessed for eligibility, 29 articles were ultimately retained for the review. Eighteen studies evaluated dosimetric variations without ART, and 11 studies reported the benefits of ART. RESULTS: Eight in silico studies tested a number of replanning sessions, ranging from 1 to 6, aiming primarily to reduce the dose to the parotid glands. The optimal timing for replanning appears to be early during the first two weeks of treatment. Compared to standard IMRT, ART decreases the mean dose to the parotid gland from 0.6 to 6 Gy and the maximum dose to the spinal cord from 0.1 to 4 Gy while improving target coverage and homogeneity in most studies. Only five studies reported the clinical results of ART, and three of those studies included a non-randomized comparison with standard IMRT. These studies suggest a benefit of ART in regard to decreasing xerostomia, increasing quality of life, and increasing local control. Patients with the largest early anatomical and dose variations are the best candidates for ART. CONCLUSION: ART may decrease toxicity and improve local control for locally advanced HNC. However, randomized trials are necessary to demonstrate the benefit of ART before using the technique in routine practice.

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

[Testicular cancer: a model to optimize the radiological follow-up]. / Cancer testicutaire: un modèle pour optimiser le suivi radiologique.

Despite being rare cancers, testicular seminoma and non-seminoma play an important role in oncology: they represent a model on how to optimize radiological follow-up, aiming at a lowest possible radiation exposure and secondary cancer risk. Males diagnosed with testicular cancer undergo frequently prolonged follow-up with CT-scans with potential toxic side effects, in particular secondary cancers. To reduce the risks linked to ionizing radiation, precise follow-up protocols have been developed. The number of recommended CT-scanners has been significantly reduced over the last 10 years. The CT scanners have evolved technically and new acquisition protocols have the potential to reduce the radiation exposure further.

Setup margins and geometric uncertainties in intensity-modulated radiation therapy in treating pituitary adenomas: the experience of Lyon Sud Hospital.

PURPOSE: The authors retrospectively evaluated the setup uncertainties in Intensity-Modulated Radiation Therapy (IMRT) for pituitary adenomas and verified the margins used in daily practice (3 mm). MATERIALS AND METHODS: Craniocaudal (CC), anteroposterior (AP) and laterolateral (LL) displacements were measured during the first 3 days of treatment and then weekly by comparing two orthogonal images obtained by an electronic system of portal imaging with Digitally Reconstructed Radiographs (DRRs). Setup Margins (SM) were defined according to the International Commission on Radiation Units (ICRU)-62 formula, the Stroom equation and the van Herk equation. The systematic (Σ) and random (σ) errors of the population were calculated as standard deviation (SD) of the population mean and the mean of SDs for every patient, respectively. RESULTS: Twenty patients were treated by IMRT for pituitary adenomas, and a total of 231 measurements were obtained. Σ and σ were 0.6 and 1.3 mm, 0.8 and 1 mm, 1.2 and 1.5 mm in the AP, LL and CC direction, respectively. Larger setup margin was 2.4, 2.7 and 4 mm in the AP, LL and CC direction, respectively (van Herk formula). CONCLUSIONS: IMRT is a highly sophisticated treatment technique that requires precise definition and optimisation of local setup errors and, finally, of the irradiated volumes. The role of image-guided RT in these kinds of treatments should be prospectively evaluated.

The PROCAINA (PROstate CAncer INdication Attitudes) Project (Part I): a survey among Italian radiation oncologists on postoperative radiotherapy in prostate cancer.

PURPOSE: Radiotherapy (RT) has an established role in the postoperative treatment of prostate cancer patients with extracapsular extension, positive surgical margins or a detectable post-operative prostate-specific antigen (PSA). Despite the large number of patients treated with postoperative RT, some issues about optimal technique, doses, volumes, timing and association with androgen deprivation are still subject of debate. The aim of this survey was to determine the patterns of choice of Italian radiation oncologists in two different clinical cases of postoperative prostate cancer patients. STUDY DESIGN: During the 2010 National Congress of the Italian Association of Radiation Oncology (AIRO), four clinical cases were presented to the attending radiation oncologists. Two of them were cases of postoperative prostate cancer, differing in T stage of the primary tumour according to the TNM classification, preoperative staging procedures, preoperative PSA (iPSA), Gleason score of biopsies and definitive pathological specimen after surgery and postoperative PSA. For each clinical case, the radiation oncologists were asked to: (a) give indication to new pre-treatment procedures for staging; b) give indication to postoperative treatment; (c) to define specifically, where indicated, the total dose, type of fractionation, treatment volumes, type of technique, type of image-guided setup control; (d) indicate whether adjuvant hormonal therapy should be prescribed; (e) define criteria that mostly influenced the prescription. A descriptive statistical analysis was then performed. RESULTS: A total of 300 questionnaires were distributed amongst radiation oncologists attending the congress; 128 were completed and considered for this analysis (41%). Some important differences were shown in prescribing and performing postoperative radiotherapy, and some significant differences with international guidelines and data available from the literature were also reviewed and discussed. CONCLUSIONS: Despite the results of clinical trials, significant differences still exist among Italian radiation oncologists in deciding postoperative treatment in prostate cancer patients. These patients probably deserve a more uniform approach based on updated, detailed and evidence-based recommendations.

The role of radiotherapy in adult medulloblastoma: long-term single-institution experience and a review of the literature.

Medulloblastoma (MB) occurs infrequently in adult patients and standard treatment is still controversial. We report our long-term, single-institution experience of adult MB and a review of the literature. We analysed adult patients with histologically proved MB treated by postoperative radiotherapy. Primary endpoints were local control (LC), disease-free survival (DFS), and overall survival (OS). Acute toxicity was reported according to CTC-NCI score vers. 3.0 and specific neuropsychological assessment analysis was performed to define late brain toxicity. From 1990-2008, 13 patients were treated by craniospinal (CSI, 12/13) or cranial irradiation (1/13, because of bad clinical conditions). Median follow up was 101 months (64-218). Complete radiological response was observed in 12/13 patients and a partial response in 1/13. Ten-year LC, OS, and DFS were 91, 76, and 84%, respectively. Two patients died because of local and spinal progression after 13 and 62 months. Acute G3 haematological toxicity (RTOG score) was observed for one patient only. The neuropsychological analysis did not reveal late toxicity related to brain radiotherapy. This experience confirms the efficacy and safety of radiotherapy in adult MB patients, resulting in very interesting 10-year LC and OS.

Does weight loss predict accuracy of setup in head and neck cancer patients treated with Intensity-Modulated Radiation Therapy?

PURPOSE: This prospective study reports the impact of weight loss on setup of head and neck (H&N) cancer patients treated by Intensity-Modulated Radiation Therapy (IMRT). MATERIALS AND METHODS: Setup errors of H&N cancer patients treated by IMRT from January to June 2010 were prospectively analysed and statistically related to weight loss. A mixed linear model was used for statistical evaluations. Setup margins of our institute were also calculated. RESULTS: Twenty-two patients and 128 pairs of Electronic Portal Images (EPI) were analysed. Setup errors varied between -0.6 and +0.6, -0.7 and +0.8 and -0.2 and +0.8 in the anterior-posterior, superior-inferior and right-left direction, respectively. Median and mean weight loss were 2.1 and 3.1 kg (range 0-12 kg), respectively; median and mean percent of weight loss were 2.95% and 4.64% (range 0.3-19.7%), respectively. No statistical relation was seen between weight loss and the setup errors. CONCLUSIONS: Weight loss is not a good clinical parameters for predicting an increase of setup errors. Other clinical and/or anthropometrical features should be prospectively evaluated in order to assess the need for re-planning.

A multicenter LArge retrospectIve daTabase on the personalization of stereotactic ABlative radiotherapy use in lung metastases from colon-rectal cancer: The LaIT-SABR study.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) has been shown to increase survival in oligometastatic disease, but local control of colorectal metastases remains poor. We aimed to identify potential predictive factors of SBRT response through a multicenter large retrospective database and to investigate the progression to the polymetastatic disease (PMD). MATERIAL AND METHODS: The study involved 23 centers, and was approved by the Ethical Committee (Prot. Negrar 2019-ZT). 1033 lung metastases were reported. Clinical and biological parameters were evaluated as predictive for freedom from local progression-free survival (FLP). Secondary end-point was the time to the polymetastatic conversion (tPMC). RESULTS: Two-year FLP was 75.4%. Two-year FLP for lesions treated with a BED < 00 Gy, 100-124 Gy, and ≥125 Gy was 76.1%, 70.6%, and 94% (p = 0.000). Two-year FLP for lesion measuring ≤10 mm, 10-20 mm, and >20 mm was 79.7%, 77.1%, and 66.6% (p = 0.027). At the multivariate analysis a BED ≥125 Gy significantly reduced the risk of local progression (HR 0.24, 95%CI 0.11-0.51; p = 0.000). Median tPMC was 26.8 months. Lesions treated with BED ≥125 Gy reported a significantly longer tPMC as compared to lower BED. The median tPMC for patients treated to 1, 2-3 or 4-5 simultaneous oligometastases was 28.5, 25.4, and 9.8 months (p = 0.035). CONCLUSION: The present is the largest series of lung colorectal metastases treated with SABR. The results support the use of SBRT in lung oligometastatic colorectal cancer patients as it might delay the transition to PMD or offer relatively long disease-free period in selected cases. Predictive factors were identified for treatment personalization.

(68Ga)-PSMA-PET/CT for the detection of postoperative prostate cancer recurrence: Possible implications on treatment volumes for radiation therapy.

PURPOSE: The aim of this study was to define the pattern of relapse of postoperative prostate cancer in patients by using 68Ga-labeled prostate-specific membrane antigen positron-emission tomography/computed tomography ([68Ga]-PSMA PET/CT). MATERIAL AND METHODS: Forty patients received a (68Ga)-PSMA PET/CT for biochemical failure. Following the Radiation Therapy Oncology Group (RTOG) guidelines, the pelvic clinical target volume has been contoured. Bone metastases were considered as outside the clinical target volume. Two subgroups of patients were defined, patients having relapse: (1) inside, or (2) outside the clinical target volume. RESULTS: Globally, eight patients out of 32 presented with a positive lymph node failure inside the clinical target volume according to RTOG guidelines (25%), 22 patients had nodal relapses outside this clinical target volume (68.75%) and in two patients nodal relapses occurred both inside and outside of the clinical target volume (6.25%). Overall, 36 positive lymph node lesions were identified: of these, 23 nodal relapses were identified within the clinical target volume contoured according to RTOG and/or at the lomboaortic level (63%). To cover 95% of these 23 relapses, a hypothetical clinical target volume should encompass the nodal regions of the RTOG-defined clinical target volume as well as the paraaortic lymph node level up to T12-L1. CONCLUSION: Most of the patients in the present study, presented with distant lymph node and/or bone metastases. Therefore, larger target volumes should be adopted to treat at least 95% of lymph node regions at risk for an occult relapse.

Early-stage Favourable Anal Cancer: A Retrospective Analysis of Clinical Outcomes of a Moderately Low Dose Elective Nodal Intensity-modulated Radiotherapy Schedule.

In this retrospective study we evaluated the long-term results of 35 early-stage favourable T1-2 N0 M0 anal cancer patients treated with intensity-modulated radiotherapy techniques combining low dose prophylactic inguinal-pelvic irradiation with dose-escalated boost. Optimal locoregional control and good tolerance makes this treatment a valuable alternative to brachytherapy boost and involved-field radiotherapy plans.

A PET-based nomogram for oropharyngeal cancers.

PURPOSE: In the context of locally advanced oropharyngeal cancer (LAOC) treated with definitive radiotherapy (RT) (combined with chemotherapy or cetuximab), the aims of this study were: (1) to identify PET-FDG parameters correlated with overall survival (OS) from a first cohort of patients; then (2) to compute a prognostic score; and (3) finally to validate this scoring system in a second independent cohort of patients. MATERIALS AND METHODS: A total of 76 consecutive patients (training cohort from Rennes) treated with chemoradiotherapy or RT with cetuximab for LAOC were used to build a predictive model of locoregional control (LRC) and OS based on PET-FDG parameters. After internal calibration and validation of this model, a nomogram and a scoring system were developed and tested in a validation cohort of 46 consecutive patients treated with definitive RT for LAOC in Lausanne. RESULTS: In multivariate analysis, the metabolic tumour volume (MTV) of the primary tumour and the lymph nodes were independent predictive factors for LRC and OS. Internal calibration showed a very good adjustment between the predicted OS and the observed OS at 24 months. Using the predictive score, two risk groups were identified (median OS 42 versus 14 months, p < 0.001) and confirmed in the validation cohort from Lausanne (median OS not reached versus 26 months, p=0.008). CONCLUSIONS: This is the first report of a PET-based nomogram in oropharyngeal cancer. Interestingly, it appeared stronger than the classical prognostic factors and was validated in independent cohorts markedly diverging in many aspects, which suggest that the observed signal was robust.

Overview of the predictive value of quantitative 18 FDG PET in head and neck cancer treated with chemoradiotherapy.

18 F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) allows to quantify the metabolic activity of a tumor (glycolysis) and has become a reference tool in oncology for the staging, restaging, radiotherapy planning and monitoring response in many cancers. Quantitative analyses have been introduced in order to overcome some of the limits of the visual methods, allowing an easier and more objective comparison of the inter- and intra-patients variations. The aims of this review were to report available evidences on the clinical value of quantitative PET/CT parameters in HNC. Forty-five studies, for a total of 2928 patients, were analyzed. Most of the data available dealt with the intensity of the metabolism, calculated from the Standard Uptake Value (SUV). Metabolic Tumor Volume (MTV) was well correlated with overall survival and disease free survival, with a higher predictive value than the maximum SUV. Spatial distribution of metabolism and textural analyses seems promising.

Role of external beam radiotherapy in the treatment of relapsing meningioma.

The role of radiotherapy in the treatment of relapsing meningiomas is not well established. Data of patients treated with radiotherapy for a relapsing meningioma were retrospectively analyzed. Overall survival (OS) was the primary endpoint of the analysis. Local control and acute and late toxicity rates have been also reported. From April 1986 to February 2011, 37 patients with a diagnosis of recurrent meningioma were treated. Median age was 64 years (range 36-79). A total of 18, 10, 5 and 4 patients were affected by relapsing benign, atypical, malignant meningiomas and meningiosarcomas, respectively (WHO classification). Median dose was 60 Gy (range 46-66 Gy). The median follow-up was 42 months (range 3-300 months). OS at 1, 3, 5 and 8 years was 81, 55.6, 43.9 and 25.8%, respectively (median OS 45 months). A strong statistical trend was observed toward better OS rates in patients treated with radiotherapy at first recurrence compared to those treated at the second (or more) recurrence (OS 50.5 vs. 30.8%, p=0.055). A statistical impact of the histology (WHO I vs. II, III and IV) on 5-year OS was also observed (OS 60 vs. 30%, 0 and 0%, p=0.010). Radiotherapy has been well tolerated, with no G2-4 neurological toxicity (RTOG toxicity score). Conventional radiation therapy has an important role in multidisciplinary approach in the treatment of recurrence of meningiomas. The histological type and the timing of the radiotherapy are prognostic factors in terms of survival.

Clinical similarities: an innovative approach for supporting medical decisions.

Taking decisions in the medical domain is a very complex task. The context is strongly affected by uncertainty and the possible undesired side effects of the treatments have to be carefully considered. Currently, these decisions are based on the physician's own experience and the evidences of the published literature, according, when available, with the philosophy of Evidence Based Medicine. The main issues of this approach are that the own experience can be different, and the results in the literature are sometimes contrasting. For helping physicians while taking medical decisions, we are proposing an innovative approach based on the idea of the clinical similarity. Given a set of clinical variables, the proposed approach selects patients that are similar, presenting to the physician the respective decisions taken and the corresponding clinical effects.

Does hormone therapy modify the position of the gold markers in the prostate during irradiation? A daily evaluation with kV-images.

PURPOSE: Gold markers are frequently used for a better daily repositioning of the prostate before irradiation. The purpose of this work was to analyze if the combination of an androgen deprivation with the external irradiation could modify the position of the gold markers in the prostate. PATIENTS AND METHODS: Ten patients have been treated for a prostate cancer, using three implanted gold markers. The variations of the intermarker distances in the prostate were measured and collected on daily OBI(®) kilovoltage images acquired at 0° and 90°. Five patients had a 6-month androgen deprivation started before the external irradiation (H group) and five did not (NH group). RESULTS: A total number of 1062 distances were calculated. No distance variation greater than 3.7mm was seen between two markers, in any of the two groups. The median standard deviations of the daily intermarker distance differences were 0.7mm (range 0.3-1.2mm) for the H group and 0.6mm (range 0.2-1.2mm) for the NH group. The intermarker distances variations were noted as greater than -2mm, between -2mm and 2mm and greater than 2mm in 16.4, 83.4 and 0.2% for the H group and 1.3, 98.5 and 0.2% for the NH group, respectively. CONCLUSION: The distance variations remained less than 4mm in both groups and for all the measurements. In the NH group, the variation of the distance between two markers remained below 2mm in 98.5%. In the H group, the presence of a reduction of distance above 2mm in 16.4% of measurements could indicate the shrinkage of the prostate volume.

[Multidisciplinary management of rectal cancer]. / État des lieux du traitement multidisciplinaire du cancer du rectum.

In the last 10 years, a number of important European randomized published studies investigated the optimal management of rectal cancer. In order to define an evidence-based approach of the clinical practice based, an international consensus conference was organized in Italy under the endorsement of European Society of Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO) and European Society of Therapeutic Radiation Oncology (ESTRO). The aim of this article is to present highlights of multidisciplinary rectal cancer management and to compare the conclusions of the international conference on 'Multidisciplinary Rectal Cancer Treatment: looking for an European Consensus' (EURECA-CC2) with the new National Comprehensive Cancer Network (NCCN) guidelines.