[Re-irradiation of bone marrow compression on a focus of extra medullary hematopoiesis: Presentation of a case]. / Ré-irradiation de compression médullaire sur foyer d'hématopoïèse extra médullaire : présentation d'un cas.

We present the case of a 40-year-old patient with ß-Thalassemia major who underwent decompressive palliative radiotherapy on symptomatic intracanal extra medullary hematopoiesis on three occasions between 2016 and 2020. We delivered normo-fractionated radiotherapy at a dose of 10Gy in five fractions on vertebrae T4 to T10 and L3 to S2, 20Gy in ten fractions on vertebrae C7 to T11, and 12Gy in six fractions on vertebrae C7 to T9. The treatment was well tolerated with complete recovery of the symptomatology during the first two irradiations, and almost complete recovery after the 3rd irradiation.

Autologous bone plug-sliding with core decompression and bone marrow aspirate concentrate application: a joint-preserving surgical technique for corticosteroid-induced osteonecrosis of femoral head.

This study aimed to describe a surgical procedure for the management of corticosteroid-induced osteonecrosis of the femoral head (ONFH) and report its clinical results. The technique included harvesting a bone plug from the lateral femoral neck, core decompression, and bone marrow aspirate concentrate (BMAC) application; the procedure was completed by press-fit insertion of the autologous bone plug in the debrided area. Autologous bone plug-sliding with core decompression and bone marrow concentrate aspirate application provides good clinical outcomes in the management of ONFH. A retrospective review was performed using records of patients operated on between October 2019 and June 2021. Only patients with Ficat-Arlet stage-2 ONFH, who underwent the procedure described, were included. Twenty- nine hips (18 patients) were included and evaluated clinically and radiologically. Clinical evaluation included the Harris hip score (HHS) and Visual analogue scale (VAS) for pain, while radiological evaluation included direct radiographs. The average age was 39.8 years (± 11.7, range: 24-65 years). The average follow-up was 13.5 months (± 3.4, range: 8-19 months). There were improvements in the VAS pain and Harris hip scores in all patients. Average HHS increased from 61.90 to 87.45 (p < 0.001), while the average VAS pain score decreased from 7.14 to 3.27 (p < 0.001). No complications were encountered in any of the patients during the follow-up. None of the patients had femoral head collapse on the latest radiograph or required total hip replacement. The combination of the novel autologous bone plug-sliding method with conventional regenerative methods is a successful treatment choice for ONFH.

Refractory ventricular tachycardia treated by a second session of stereotactic arrhythmia radioablation.

Purpose: Stereotactic arrhythmia radioablation (STAR) is an effective treatment for refractory ventricular tachycardia (VT), but recurrences after STAR were recently published. Herein, we report two cases of successful re-irradiation of the arrhythmogenic substrate. Cases: We present two cases of re-irradiation after recurrence of a previously treated VT with radioablation at a dose of 20 Gy. The VT exit was localized on the border zone of the irradiated volume, which responded positively to re-irradiation at follow-up. Conclusion: These two cases show the technical feasibility of re-irradiation to control recurrent VT after a first STAR.

Quality assurance of radiotherapy in the ongoing EORTC 1420 "Best of" trial for early stage oropharyngeal, supraglottic and hypopharyngeal carcinoma: results of the benchmark case procedure.

INTRODUCTION: The current phase III EORTC 1420 Best-of trial (NCT02984410) compares the swallowing function after transoral surgery versus intensity modulated radiotherapy (RT) in patients with early-stage carcinoma of the oropharynx, supraglottis and hypopharynx. We report the analysis of the Benchmark Case (BC) procedures before patient recruitment with special attention to dysphagia/aspiration related structures (DARS). MATERIALS AND METHODS: Submitted RT volumes and plans from participating centers were analyzed and compared against the gold-standard expert delineations and dose distributions. Descriptive analysis of protocol deviations was conducted. Mean Sorensen-Dice similarity index (mDSI) and Hausdorff distance (mHD) were applied to evaluate the inter-observer variability (IOV). RESULTS: 65% (23/35) of the institutions needed more than one submission to achieve Quality assurance (RTQA) clearance. OAR volume delineations were the cause for rejection in 53% (40/76) of cases. IOV could be improved in 5 out of 12 OARs by more than 10 mm after resubmission (mHD). Despite this, final IOV for critical OARs in delineation remained significant among DARS by choosing an aleatory threshold of 0.7 (mDSI) and 15 mm (mHD). CONCLUSIONS: This is to our knowledge the largest BC analysis among Head and neck RTQA programs performed in the framework of a prospective trial. Benchmarking identified non-common OARs and target delineations errors as the main source of deviations and IOV could be reduced in a significant number of cases after this process. Due to the substantial resources involved with benchmarking, future benchmark analyses should assess fully the impact on patients' clinical outcome.

[Predictive assays for responses of tumors and normal tissues in radiation oncology]. / Outils pour la prédiction de la réponse tumorale et des tissus sains en oncologie radiothérapie.

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the target volume. Tumor sensitivity to radiotherapy may be particularly inconstant depending on location, histology, somatic genetic parameters and the capacity of the immune system to infiltrate the tumor. In addition, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better predict the tumor response but also the radiation-induced late effects.

[Individual modification of the dose, volume and fractionation of breast radiotherapy]. / Personnalisation de la dose, du volume et du fractionnement de la radiothérapie du sein.

Randomized trials demonstrated similar overall survival between mastectomy and breast-conservative surgery followed by adjuvant radiation therapy. Breast-conservative surgery, with adjuvant radiation therapy, with or without neoadjuvant systemic therapy has become the standard of care for women with early or locally advanced breast cancer. Nevertheless, certain cardiac, lung or cutaneous toxicities may alter the long-term body image and the quality of life of a limited number of patients who consider having had "overtreatment" or treatment outside the best knowledge of science. In case of low-risk breast cancer, several trials have evaluated the carcinologic outcome in absence of radiation therapy after breast-conservative surgery. Local recurrences increased in case of breast-conservative surgery alone but without impact on overall survival. Multiple debates have emerged in order to select the most appropriate evaluation criteria. Finally, a large consensus has considered that reducing local recurrences is important but with modern technologies and after identifying patients of individual radiosensitivity. Indeed, in case of a low absolute risk of local recurrence, radiation therapy techniques have been developed to allow a focal treatment especially for patients with high risk of developing late effects. This kind of compromise takes into account the reduction risk of local recurrences but also the probability of developing radiation-induced cutaneous sequelae. In the same way, for patients considered at high risk of recurrence, the huge volumes need specific techniques to better cover the targets while protecting the surrounding critic organs such as heart and lung. Intensity-modulated radiation therapy and the local high boost may help to decrease local recurrences of these more extended and aggressive diseases while considering the individual radiosensitivity that paves the way of long-term sequelae. In this article, we detail a personalized approach of breast radiation therapy considering the absolute risk of local recurrences and the probability of radiation-induced toxicity appearance.

Isodose 20 Gy found as a threshold dose for radiation recall dermatitis.

Radiation recall is a rare phenomenon that can be observed in the field of radiotherapy, months or years after irradiation when a patient is exposed to certain pharmaceutical agents. In this report, we relate a case of radiation recall dermatitis induced after the application of a topical natural cream, 2 years after the initial radiotherapy treatment. Skin reactions were severe and limited to the irradiated volume, whereas a large part of the skin where the cream was applied outside the radiation field was strictly normal. More precisely, the radiation recall dermatitis matched with the isodose 20 Gy, whereas no recall reaction was observed in the lower dose areas (5, 10 or 15 Gy) despite these areas were also largely exposed to the cream. In conclusion, this is the first report that could provide a threshold dose for the occurrence of a radiation recall dermatitis, which was not observed below 20 Gy, in the context of this topical reagent.

[Chemoradiation for oesophageal cancer: A critical review of the literature]. / Chimioradiothérapie des cancers de l'œsophage : revue critique de la littérature.

Locally advanced oesophageal cancer treatment requires a multidisciplinary approach with the combination of chemotherapy and radiotherapy for preoperative and definitive strategy. Preoperative chemoradiation improves the locoregional control and overall survival after surgery for locally advanced oesophageal cancer. Definitive chemoradiation can also be proposed for non-resectable tumours or medically inoperable patients. Besides, definitive chemoradiation is considered as an alternative option to surgery for locally advanced squamous cell carcinomas. Chemotherapy regimen associated to radiotherapy consists of a combination of platinum derived drugs (cisplatinum or oxaliplatin) and 5-fluorouracil or a weekly scheme combination of carboplatin and paclitaxel according to CROSS protocol in a neoadjuvant strategy. Radiation doses vary from 41.4Gy to 45Gy for a preoperative strategy or 50 to 50.4Gy for a definitive treatment. The high risk of lymphatic spread due to anatomical features could justify the use of an elective nodal irradiation when the estimated risk of microscopic involvement is higher than 15% to 20%. An appropriate delineation of the gross tumour volume requires an exhaustive and up-to-date evaluation of the disease. Intensity-modulated radiation therapy represents a promising approach to spare organs-at-risk. This critical review of the literature underlines the roles of radiotherapy for locally advanced oesophageal cancers and describes doses, volumes of treatment, technical aspects and dose constraints to organs-at-risk.

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.

(18F)-FDG PET/CT parameters to predict survival and recurrence in patients with locally advanced cervical cancer treated with chemoradiotherapy.

PURPOSE: To identify predictive (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based parameters for locoregional control, disease-free survival and overall survival, by testing different thresholds of metabolic tumor volume and total lesion glycolysis in patients with locally-advanced cervical cancer. PATIENTS AND METHODS: Thirty-seven patients treated with standard chemoirradiation underwent a pretreatment (18F)-FDG-PET/CT. Using different thresholds of maximum standardized uptake value, the following PET parameters were computed: maximum standardized uptake value, mean standardized uptake value, metabolic tumor volume and total lesion glycolysis for primary tumor and lymph nodes and a new parameter combining the metabolic tumor volume and the distance between lymph nodes and the primary tumor, namely metabolic node distance. Correlation between PET and clinical parameters with clinical outcome (overall survival, disease-free survival, and locoregional control) was assessed using univariate and multivariate analyses (Cox model). RESULTS: In univariate analyses, PET/CT parameters associated with overall survival and disease-free survival were: metabolic tumor volume and total lesion glycolysis of the primary tumor, total lesion glycolysis of lymph nodes and metabolic node distance. The most predictive threshold segmentation for metabolic tumor volume and total lesion glycolysis was 48% of maximum standardized uptake value for the primary tumor and 30% for the lymph nodes. In multivariate Cox analysis, the total lesion glycolysis of primary tumor 48% and metabolic node distance were the two independent risk factors for overall survival (P<0.01), disease-free survival (P<0.01) and locoregional control (P=0.046). CONCLUSION: Total lesion glycolysis of primary tumor and distance between the invaded positive lymph node and the primary tumor seem to have the highest predictive value when compared to classical clinical prognostic parameters and may be useful to identify high risk groups at time of diagnosis and to tailor the therapeutic approach in locally-advanced cervical cancer.

[Lung dose constraints for normo-fractionated radiotherapy and for stereotactic body radiation therapy]. / Doses aux organes à risque en radiothérapie conformationnelle et en radiothérapie stéréotaxique : les poumons.

Radiation-induced lung disease (RILD) is common after radiation therapy and represents cornerstone toxicities after treatment of thoracic malignancies. From a review of literature, the objective of this article was to summarize clinical and non-clinical parameters associated with the risk of RILD in the settings of normo-fractionated radiotherapy and stereotactic body radiation therapy (SBRT). For the treatment of lung cancers with a normo-fractionated treatment, the mean lung dose (MLD) should be below 15-20Gy. For a thoracic SBRT, V20Gy<10% and MLD<6Gy are recommended. One should pay attention to central tumors and respect specific dose constraints to the bronchial tree. The recent technological improvements may represent an encouraging way to decrease lung toxicities. Finally, our team developed a calculator in order to predict the risk of radiation pneumonitis.

Dose-dependent effects of adiponectin on ADAMTS-9 gene expression in human chondrocytes.

OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), comprising of 19 members is a family of peptidases. They have several vital functions in physiological and pathological processes in organisms. ADAMTS-9 has aggrecanolytic activity and is responsible for degradation of aggrecan mainly in articular cartilage. It is known that adiponectin is the most abundantly secreted adipokine (adipocytokines), and the characteristics of adiponectin have not been elucidated yet. It was assumed that adiponectin has anti-inflammatory effect before. However, an inflammatory feature of adiponectin was shown in researches. In our study, the effect of adiponectin on ADAMTS-9 gene expression in primary human chondrocytes was investigated. METHODS: Primary human chondrocytes were exposed to adiponectin at 1, 4, 8 and 12 µg/ml doses for certain time period. Total RNA was isolated and reverse-transcribed by random primer after incubation. ADAMTS-9 and ß-actin genes expression levels were determined using real-time polymerase chain reaction (qRT-PCR). RESULTS: The highest upregulation of ADAMTS-9 gene expression level was found at 12 µg/ml dose of adiponectin and 48 h incubation. CONCLUSION: Adiponectin is the key element in the maintenance of cartilage homeostasis. Similarly, the involvement of adiponectin in articular inflammatory diseases was demonstrated in detail. These findings bring adiponectin into central place in the research to develop adiponectin based new therapy methods for arthritic diseases. Together with these findings, our results suggest that adiponectin may be involved in the degradation of articular cartilage by increasing ADAMTS-9 gene expression (Tab. 1, Fig. 3, Ref. 35).

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.

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.

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.

Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial.

BACKGROUND: We present here final clinical results of the COHORT trial and both translational sub-studies aiming at identifying patients at risk of radiation-induced subcutaneous fibrosis (RISF): (i) radiation-induced lymphocyte apoptosis (RILA) and (ii) candidates of certain single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS: Post-menopausal patients with stage I-II breast cancer (n = 150) were enrolled and assigned to either concurrent (arm A) or sequential radiotherapy (RT)-letrozole (arm B). Among them, 121 were eligible for RILA and SNP assays. Grade ≥2 RISF were the primary end point. Secondary end points were lung and heart events and carcinologic outcome. RILA was performed to predict differences in RISF between individuals. A genome-wide association study was performed to identify SNPs associated with RILA and RISF. Analyses were done by intention to treat. RESULTS: After a median follow-up of 74 months, 5 patients developed a grade ≥2 RISF. No significant difference was observed between arms A and B. Neither grade ≥2 lung nor symptomatic cardiac toxicity was observed. Median RILA value of the five patients who had grade ≥2 RISF was significantly lower compared with those who developed grade ≤1 RISF (6.9% versus 13%, P = 0.02). Two SNPs were identified as being significantly associated with RILA: rs1182531 (P = 4.2 × 10(-9)) and rs1182532 (P = 3.6 × 10(-8)); both located within the PHACTR3 gene on chromosome 20q13.33. CONCLUSIONS: With long-term follow-up, letrozole can safely be delivered concomitantly with adjuvant breast RT. Translational sub-studies showed that high RILA values were correlated with patients who did not develop RISF. REGISTERED CLINICAL TRIAL: NCT00208273.

Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.

BACKGROUND: Predicting outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is an area of uncertainty. It influences the decision-making for regional nodal irradiation (RNI). The aim of the NORA (NOdal RAdiotherapy) survey was to examine the patterns of RNI. METHODS: A web-questionnaire, including several clinical scenarios, was distributed to 88 EORTC-affiliated centers. Responses were received between July 2013 and January 2014. RESULTS: A total of 84 responses were analyzed. While three-dimensional (3D) radiotherapy (RT) planning is carried out in 81 (96%) centers, nodal areas are delineated in only 51 (61%) centers. Only 14 (17%) centers routinely link internal mammary chain (IMC) and supraclavicular node (SCN) RT indications. In patients undergoing total mastectomy (TM) with ALND, SCN-RT is recommend by 5 (6%), 53 (63%) and 51 (61%) centers for patients with pN0(i+), pN(mi) and pN1, respectively. Extra-capsular extension (ECE) is the main factor influencing decision-making RNI after breast conserving surgery (BCS) and TM. After primary systemic therapy (PST), 49 (58%) centers take into account nodal fibrotic changes in ypN0 patients for RNI indications. In ypN0 patients with inner/central tumors, 23 (27%) centers indicate SCN-RT and IMC-RT. In ypN1 patients, SCN-RT is delivered by less than half of the centers in patients with ypN(i+) and ypN(mi). Twenty-one (25%) of the centers recommend ALN-RT in patients with ypN(mi) or 1-2N+ after ALND. Seventy-five (90%) centers state that age is not considered a limiting factor for RNI. CONCLUSION: The NORA survey is unique in evaluating the impact of SLNB/ALND status on adjuvant RNI decision-making and volumes after BCS/TM with or without PST. ALN-RT is often indicated in pN1 patients, particularly in the case of ECE. Besides the ongoing NSABP-B51/RTOG and ALLIANCE trials, NORA could help to design future specific RNI trials in the SLNB era without ALND in patients receiving or not PST.

Flexor tendons repair: effect of core sutures caliber with increased number of suture strands and peripheral sutures. A sheep model.

BACKGROUND: Surgeons have aimed to achieve strong repair so as to begin early active rehabilitation programs for flexor tendon injury. Multi-strand suture techniques were developed to gain improved gap resistance and ultimate force compared with the respective two-strand techniques. In vivo studies indicate that multiple strands may cause ischemia during the intrinsic healing process by decreasing the total cross-sectional area of the injured site, unless the total cross-sectional area of the sutures is not decreased. HYPOTHESIS: The hypothesis was to design an in vitro study to understand the biomechanical relationship between suture calibers of core sutures with increased number of suture strands and peripheral suture on final repair strength. MATERIALS AND METHODS: Sixty fresh sheep forelimb flexor digitorum profundus tendons were randomly placed into three groups (A, B, and C), each containing 20 specimens, for tendon repair. Two-, four-, and eight-strand suture techniques were respectively used in Groups A, B, and C. A simple running peripheral suture technique was used in Subgroups A2, B2, and C2. For each repaired tendon, the 2-mm gap-formation force, 2-mm gap-formation strength, maximum breaking force and maximum breaking strength were determined. RESULTS: Differences in 2-mm gap-formation force and 2-mm gap-formation strength were found between Subgroups A1 and A2, B1 and B2, and C1 and C2. Between Groups A and B, A and C, and B and C, there was no difference as well. CONCLUSION: Both the number of strands and the ratio between the total suture volume and tendon volume at the repair site are important for ideal repair. If the total cross-sectional area of the sutures is equal in 2-strand, 4-strand, and 8-strand procedure, there is no difference in the strength of the repair. A decrease in caliber size suture requires more passes to achieve the same strength. Instead, it is much better to use peripheral suture techniques to improve the strength of the repair with larger diameter 2-strand core sutures.

[Postoperative radiation therapy in lung carcinom]. / La radiothérapie postopératoire a-t-etlle une place dans le cancer pulmonaire ?

Locally advanced non-small-cell lung carcinoma (NSCLC) is a very heterogeous disease, the role of postoperative radiation therapy (PORT) in pN2 patients with completly resected NSCLC remains controversial. Although an improvment in local control has been described in several studies, the effect on survival has been contradictory or inconclusive. Retrospective evaluation suggest a positive effect of PORT in high risk patients with pN2 disease: RI-resected NSCLC, bulky and multilevel N2. However further evaluation of PORT in prospectively randomized studies in completely resected pN2 NSCLC is needed.