Gyriform infiltration as imaging biomarker for molecular glioblastomas.

BACKGROUND: Molecular glioblastomas (i.e. without the histological but with the molecular characteristics of IDH-wild-type glioblastoma) frequently lack contrast enhancement, which can wrongly lead to suspect a lower-grade glioma. Herein, we aimed to assess the diagnostic value of gyriform infiltration as an imaging marker for molecular glioblastomas. METHODS: Two independent investigators reviewed the MRI scans from patients with newly diagnosed gliomas for the presence of a gyriform infiltration defined as an elective cortical hypersignal on MRI FLAIR sequence. Diagnostic test performance of this sign for the diagnosis of molecular glioblastoma were calculated. RESULTS: A total of 426 patients were included, corresponding to 31 molecular glioblastoma, 294 IDH-wild-type glioblastoma, 50 IDH-mutant astrocytoma, and 51 IDH-mutant 1p19q-codeleted oligodendroglioma. A gyriform infiltration was observed in 16/31 (52%) molecular glioblastoma, 40/294 (14%) IDH-wild-type glioblastoma, and none of the IDH-mutant glioma. All the 56 gyriform-infiltration-positive tumors were IDH-wild-type and all but two had a TERT promoter mutation. The inter-rater agreement was good (κ = 0.69, p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 52%, 90%, 29%, 96%, respectively. The median overall survival was better for gyriform-infiltration-negative patients compared to gyriform-infiltration-positive patients in the whole series and in patients with non-enhancing lesions (n = 95) (25.6 vs 16.9 months, p = 0.005 and 20.2 months vs not reached, p < 0.001). CONCLUSION: Gyriform infiltration is a specific imaging marker of molecular glioblastomas that can help distinguishing these tumors from IDH-mutant lower-grade gliomas.

Returning to work after multimodal treatment in glioblastoma patients.

OBJECTIVE Although multimodal treatment for glioblastoma (GBM) has resulted in longer survival, uncertainties exist regarding health-related quality of life and functional performance. Employment represents a useful functional end point and an indicator of social reintegration. The authors evaluated the rate of patients resuming their employment and the factors related to work capacity. METHODS The authors performed a retrospective study of working-age patients treated with surgery and radiochemotherapy between 2012 and 2015. Data were collected before and after surgery and at 6, 12, 18, and 24 months. Employment was categorized according to the French Socio-Professional Groups and analyzed regarding demographic and clinical data, performance status, socio-professional category, radiological features, type, and quality of resection. RESULTS A total of 125 patients, mean age 48.2 years, were identified. The mean follow-up was 20.7 months with a median survival of 22.9 months. Overall, 21 patients (18.3%) went back to work, most on a part-time basis (61.9%). Of the patients who were alive at 6, 12, 18, and 24 months after diagnosis, 8.7%, 13.8%, 15.3%, and 28.2%, respectively, were working. Patients going back to work were younger (p = 0.03), had fewer comorbidities (p = 0.02), and had a different distribution of socio-professional groups, with more patients belonging to higher occupation categories (p = 0.02). Treatment-related symptoms (36.2%) represented one of the main factors that prevented the resumption of work. Employment was strongly associated with performance status (p = 0.002) as well as gross-total removal (p = 0.04). No statistically significant difference was found regarding radiological or molecular features and the occurrence of complications after surgery. CONCLUSIONS GBM diagnosis and treatment has a significant socio-professional impact with only a minority of patients resuming work, mostly on a part-time basis.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Waiting times before initiation of radiotherapy might not affect outcomes for patients with glioblastoma: a French retrospective analysis of patients treated in the era of concomitant temozolomide and radiotherapy.

Purpose of this study was to determine the effect of waiting time for radiotherapy on overall survival of patients with glioblastoma treated in the EORTC-NCIC trial at 18 centers in France. A total of 400 adult patients with glioblastoma who were treated between January 1, 2006 and December 31, 2006 were included. There were 282 patients with "minimum criteria" according to the EORTC-NCIC trial: (i) concurrent chemotherapy with temozolomide; and (ii) age between 18 and 70 years old. Among these patients, 229 were treated with adjuvant temozolomide and were classified as "maximal criteria". One-hundred and eighteen patients were in the "without minimal criteria" group. Waiting time from the first symptom (FS-RT), pathology diagnosis (P-RT), multidisciplinary meeting (MM-RT), surgery (S-RT), and CT scan for delineation (CT-RT) until the start of radiotherapy were recorded. Median follow-up for all patients was 327 days. Overall, median FS-RT, P-RT, MM-RT, CT-RT, and S-RT times were 77, 36, 32, 12, and 41 days, respectively. Median, and 12 and 24-month overall survival were 409 days, and 56.3 ± 2.1 % and 27.6 ± 2.6 %, respectively. Univariate analysis failed to reveal a difference in survival, irrespective of the delay. In multivariate analysis, independent favorable prognostic factors for overall survival were age (p ≤ 0.0001) and type of surgery (p = 0.0006). In this large series treated during the EORTC-NCIC protocol period, waiting time until radiotherapy did not seem to affect patient outcome.

Avoiding New Biopsies by Identification of IDH1 and TERT Promoter Mutation in Nondiagnostic Biopsies From Glioma Patients.

BACKGROUND: Biopsies in patients with a suspected glioma are occasionally nondiagnostic. OBJECTIVE: To explore the utility of molecular testing in this setting by determining whether IDH1 and TERT promoter (pTERT) mutations could be detected in nondiagnostic biopsies from glioma patients. METHODS: Using SNaPshot polymerase chain reaction, we retrospectively assessed IDH1 and pTERT mutation status in nondiagnostic biopsies from 28 glioma patients. RESULTS: The nondiagnostic biopsy (needle biopsy n = 25, open or endoscopic biopsy n = 3) consisted of slight glial cell hypercellularity, hemorrhage, and/or necrosis. After another biopsy (n = 23) or a subsequent surgical resection (n = 5) the diagnosis was an IDH1-wildtype (WT) pTERT-mutant glioma (glioblastoma n = 16, astrocytoma n = 4), an IDH1-mutant pTERT-mutant oligodendroglioma (n = 1), an IDH1-mutant pTERT-WT astrocytoma (n = 1), and an IDH1-WT pTERT-WT glioblastoma (n = 6). An IDH1 mutation was identified in the nondiagnostic biopsies of the 2 IDH-mutant gliomas, and a pTERT mutation in the nondiagnostic biopsies of 16 out of the 21 of pTERT mutant-gliomas (76%). Overall, an IDH1 and/or a pTERT mutation were detected in 17 out of 28 (61%) of nondiagnostic biopsies. Retrospective analysis of the nondiagnostic biopsies based on these results and on imaging characteristics suggested that a new biopsy could have been avoided in 6 patients in whom a diagnosis of "molecular glioblastoma" could have been done with a high level of confidence. CONCLUSION: In the present series, IDH1 and pTERT mutations could be detected in a high proportion of nondiagnostic biopsies from glioma patients. Molecular testing may facilitate the interpretation of nondiagnostic biopsies in patients with a suspected glioma.

Potential benefits of using non coplanar field and intensity modulated radiation therapy to preserve the heart in irradiation of lung tumors in the middle and lower lobes.

PURPOSE: Investigate whether the use of non coplanar fields and intensity modulated radiation therapy (IMRT) reduces the dose to the heart, in irradiation of middle and lower lung tumors. MATERIALS AND METHODS: Four plans are compared on 10 CT scans: (1) a reference plan, corresponding to coplanar plan of 3D conformal radiotherapy (3DCRT); (2) a 3DCRT(noncopl) plan, differing from reference plan by the change of one field in non coplanar fields; (3) an IMRT(copl) plan optimized on the same coplanar plan as reference plan; and (4) an IMRT(noncopl) plan optimized on the same non coplanar beams as 3DCRT(noncopl) plan. The equivalent uniform dose (EUD) for PTV was 74 Gy in 37 fractions. RESULTS: In all plans, the 95% isodose surface covers at least 99% of the PTV with very similar conformity index values. A significant reduction in EUD, V30, V40 and V50 is observed for heart when either non coplanar fields or IMRT is used. IMRT also reduces the lung NTCP, V5, V13, V20 and V30 values and esophagus NTCP. CONCLUSION: Both the use of non coplanar fields and IMRT dramatically reduces the dose received by the heart. The largest benefit is seen when the two techniques are combined.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.

PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

Preoperative radiotherapy for rectal adenocarcinoma: Which are strong prognostic factors?

PURPOSE: This retrospective 12-year study evaluated the prognostic value of initial and postoperative staging of rectal tumors. METHODS AND MATERIALS: Between 1985 and 1996, 297 patients were treated with preoperative radiotherapy (39 Gy in 13 fractions) and surgery for Stage T2-T4N0-N1M0 rectal adenocarcinoma. Pretreatment staging included a clinical examination and endorectal ultrasonography (EUS) since 1988. Clinical staging was performed by digital rectal examination and rigid proctoscopy. EUS was performed in 236 patients. Postoperative staging was performed by examination of the pathologic specimen. RESULTS: The median follow-up was 49 months. The overall 5-year survival rate was 67%, with a local failure rate of 9%. The rate of sphincter preservation was 65%. The clinical examination findings were strong prognostic factor for both cT stage (p < 0.001) and cN stage (p < 0.006) but had poor specificity for cN stage (only 25 lymph nodes detected). In both univariate and multivariate analyses, EUS had a statistically significant prognostic value for uT (p < 0.014) but not for uN (p < 0.47) stage. In contrast, pT and pN stages were strong prognostic factors (p < 0.001 and p < 0.001, respectively). CONCLUSION: Pretreatment staging, including clinical examination and EUS, seemed accurate enough to present a high prognostic value for the T stage. EUS was insufficient to stage lymph node involvement. Owing to its lack of specificity, uN stage was not a reliable prognostic factor. An improvement in N staging is necessary and essential. Despite downstaging, postoperative staging remained a very strong prognostic factor for both T and N stages.

Early stage follicular lymphoma: what is the clinical impact of the first-line treatment strategy?

BACKGROUND: Less than 20% of patients with follicular lymphoma (FL) present with Ann Arbor Stage I or II disease at diagnosis. Numerous therapeutic options exist, however radiation therapy is considered the standard of care for early-stage disease based on single-institution or retrospective series. Our aim was to revisit the outcome of patients with localized FL in the rituximab era. PATIENTS AND METHODS: We analyzed the characteristics and outcomes of 145 early-stage FL patients, who were retrospectively divided into six groups according to their initial treatment: watchful waiting (WW), chemotherapy alone (CT), radiotherapy alone (RT), combined radiotherapy and chemotherapy (RT-CT), rituximab alone (Ri), and immunochemotherapy (Ri-CT). RESULTS: Of the 145 patients, 84 (57.9%) had stage I disease and 61 (42.1%) stage II. The complete response (CR) rate varied from 57% for the Ri group to 95% for the RT-CT group. Overall survival (OS) at 7.5 y of patients treated after 2000 was better than that of those treated prior to 2000. OS did not significantly differ from one treatment to another. In contrast, a significant difference was found for progression-free survival (PFS) at 7.5 y, which favored Ri-CT (60%) therapy versus the others (p=0.00135). CONCLUSION: Delayed therapy initiation was associated with a similar OS than that observed in patients receiving immediate intervention. The "watchful waiting" strategy may thus be proposed as first-line therapy, similar to stage III and IV FL patients with a low tumor burden. However, when treatment is required, immunochemotherapy appears to be the best option.

Histological features and treatment approach of trichoblastic carcinomas: from a case report to a review of the literature.

BACKGROUND: Trichoblastic carcinoma (or malignant trichoblastoma) is a rare malignant cancer of adnexal structures with morphological features that in some cases are reminiscent of a trichoblastoma. Trichoblastic carcinoma is underdiagnosed as it is a rather recent entity which is still not recognized as such by all pathologists. The differential diagnosis with basal cell carcinoma is often difficult to make and the optimal treatment has not yet been established. CASE REPORT: We report the case of a 43-year-old patient who underwent surgical excision and adjuvant radiotherapy for a growing mass of 40 × 48 mm located in the lumbar right paraspinal skin. The pathological findings demonstrated a trichoblastic carcinoma. The clinicopathological profile, the histogenesis, and the difficulties related to the histopathological diagnosis and treatment of this rare entity are discussed in this article. CONCLUSION: Although the published reports on this disease are few, surgery should be considered the standard therapeutic approach for trichoblastic carcinomas. Selected cases presenting clinical features of local aggressiveness can safely be treated with adjuvant irradiation to improve local control. However, acute and particularly late toxicities need to be taken into account in the decision.

Standard-fractionated radiotherapy for optic nerve sheath meningioma: visual outcome is predicted by mean eye dose.

PURPOSE: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM. METHODS AND MATERIALS: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test. RESULTS: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision. CONCLUSIONS: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.

Impact of 18F-fluoro-2-deoxyglucose positron emission tomography on treatment strategy and radiotherapy planning for stage I-II Hodgkin disease: a prospective multicenter study.

PURPOSE: To quantify the impact of preradiotherapy 18F-fluoro-2-deoxyglucose positron-emission tomography (FDG-PET) on treatment strategy and radiotherapy planning for patients with Stage I/II Hodgkin disease included in a large prospective multicenter study. PATIENTS AND METHODS: Conventional computed tomography and FDG-PET were performed just before the planned radiotherapy. The radiotherapy plan was first elaborated under blinded conditions for FDG-PET data. Then, the medical staff was asked to confirm or not confirm the treatment strategy and, if appropriate, to modify the radiotherapy plan based on additional information from FDG-PET. RESULTS: Between January 2004 and January 2006, 137 patients were included (124 were available for analysis) in 11 centers (108 adults, 16 children). All but 1 patient had received chemotherapy before inclusion. Prechemotherapy work-up included FDG-PET for 61 patients, and data were available for elaboration of the first radiotherapy plan. Based on preradiotherapy FDG-PET data, the radiotherapy was cancelled in 6 patients (4.8%), and treatment plan modifications occurred in 16 patients (12.9%): total dose (11 patients), CTV volume (5 patients), number of beam incidences (6 patients), and number of CTV (6 patients). The concordance between the treatment strategies with or without preradiotherapy FDG-PET was 82.3%. Concordance results were not significantly different when prechemotherapy PET-CT information was available. CONCLUSION: Preradiotherapy FDG-PET for treatment planning in Hodgkin lymphoma may lead to significant modification of the treatment strategy and the radiotherapy planning in patients with Stage I or II Hodgkin disease, even in those who have undergone FDG-PET as part of the prechemotherapy work-up.

Long-term survival of 106 stage III ovarian cancer patients with minimal residual disease after second-look laparotomy and consolidation radiotherapy.

OBJECTIVE: Attempts to increase survival in stage III ovarian cancer patients with minimal residual disease at second-look laparotomy have included consolidation radiotherapy. We present long-term survival of 106 consecutive patients treated between 1983 and 1993 in 4 French institutions for stage III ovarian adenocarcinoma with first-look debulking, cisplatin-based chemotherapy, second-look surgery with a residual disease <1 cm and consolidation radiotherapy. METHODS: Median age was 52 years. Residual disease after first look surgery was <1 cm for 40.5% of patients. Median number of chemotherapy cycles was 6 (range 4-12). Residual disease <1 cm at second-look laparotomy was observed in 79% of the patients, with 33% of patients in complete histologic remission. Residual disease <1 cm was obtained in all patients after tumor excision during second-look surgery. Radiation was performed using a linear accelerator with a whole abdomen dose of 22.5 Gy, an additional 22 Gy pelvic boost for 71 patients, and an additional 12 Gy lombo-aortic boost for 33 patients. RESULTS: Median follow-up was 14 years. Radiation was stopped for acute toxicity in 11 patients. Long-term toxicities included radiation enteritis in 21 patients with 9 patients requiring surgery for bowel obstruction. Four deaths were related to enteritis complications. Overall survival at 5 and 10 years was respectively 53% and 36%. CONCLUSION: This sequential treatment with final consolidation abdominopelvic radiotherapy is an effective treatment for a selected group of stage III ovarian cancer patients with a high intestinal toxicity incidence.

Prognostic factors of squamous cell carcinoma of the anal margin treated by radiotherapy: the Lyon experience.

BACKGROUND: To report our patient experience with squamous cell carcinoma of the anal margin and to evaluate the prognostic factors influencing outcome. MATERIALS AND METHODS: Between 1980 and 2001, 26 patients with anal margin squamous cell carcinoma were treated in Lyon-Sud: 7 T1, 14 T2, 4 T3, and 1 T4 with 20 N0, 3 N1, and 3 N2. The anal canal was invaded in five patients. Treatment consisted of definitive external irradiation in 14 patients and adjuvant irradiation (after a local excision) in 12 patients. External irradiation was combined with chemotherapy in seven patients, brachytherapy in four patients, and both brachytherapy and chemotherapy in one patient. RESULTS: The local control rate was initially 61.4%, and it was 80.8% after salvage treatment. The 5-year overall and specific survival rates were 71 and 88.3%, respectively. Three factors correlated with specific survival: cell differentiation (P=0.038) and T (P=0.001) and N category (P=0.0005). A salvage abdominoperineal resection was successfully employed in five of seven local recurrences. Four grade 3 and two grade 4 toxicities were observed. Sphincter preservation was possible in 66% of alive patients. CONCLUSION: Our results confirm the dominating place of definitive irradiation and radiochemotherapy in the treatment of anal margin squamous cell carcinoma. The indications for abdominoperineal resection must be limited to local relapse. The prognosis of squamous cell carcinoma is correlated to T and N staging and cell differentiation.