Prospective pilot study to explore the melatonin level in brain tumor patients undergoing radiotherapy.

PURPOSE: Our aim was to assess if the radiotherapy dose decreased the melatonin levels as well as the quality of life and sleep in brain tumor patients. METHODS: We performed a follow-up study on melatonin levels in saliva and its urinary metabolite sulfatoxi-melatonine (STM) samples in patients with brain tumors treated with radiotherapy close to the pineal gland's area. We analyzed the cortisol, cortisone, and excrection of STM normalized by urinary creatinine. In some cases, a polysomnography (PSG) was performed. Quality of life questionnaires, distress scale, and sleepiness inventories were also administered. RESULTS: We included twelve patients (experimental arm) and eight healthy controls (control group). No differences were observed between experimental arm and control group at baseline. No differences were detected in the experimental arm before and after delivering the radiotherapy. No clinically significant differences were found according to the radiotherapy dose delivered. CONCLUSION: Melatonin levels and PSG outcomes do not change after receiving radiotherapy. The findings of this study do not show a statistically significant association between the treatment and the quality of life and sleep.

A Case about the Upgrade of Manufacturing Equipment for Insertion into an Industry 4.0 Environment.

Industry 4.0 is a synonym for the confluence of technologies that allows the integration of information technology, data science, and automated equipment, to produce smart industrial systems. The process of inserting new technologies into current conventional environments involves a wide range of disciplines and approaches. This article presents the process that was followed to identify and upgrade one station in an industrial workshop to make it compatible with the more extensive system as it evolves into the Industry 4.0 environment. An information processing kit was developed to upgrade the equipment from an automated machine to an Industry 4.0 station. The kit includes a structure to support the sensor and the data processing unit; this unit consisted of a minicomputer that records the data, graded the performance of the components, and sent the data to the cloud for storage, reporting, and further analysis. The information processing kit allowed the monitoring of the inspection system and improved the quality and speed of the inspection process.

Association between EBRT dose volume histograms and quality of life in prostate cancer patients.

AIM: To evaluate the association between dose-volume histogram (DVH) values in organs at risk (OAR) and patient-reported HRQoL outcomes. BACKGROUND: Data on the association between DVHs and health-related quality of life (HRQoL) in prostate cancer (PCa) patients are limited. MATERIALS AND METHODS: Five-year follow-up study of 154 patients with organ-confined (stage T1/T2) PCa treated with EBRT between January 2003 and November 2005. HRQoL was evaluated with the Expanded Prostate Cancer Index (EPIC). DVH for OARs (penile bulb, rectum and bladder) were created for all patients for whom data were available (119/154; 77%). The functional data analysis (FDA) statistical method was used. HRQoL data was collected prospectively and data analysis was performed retrospectively. RESULTS: Worsening of urinary incontinence and obstructive symptoms correlated with higher DVH dose distributions at 24 months. Increased rectal bleeding at months 24 and 60 correlated with higher DVH dose distributions in the 40-70 Gy range. Patients with deterioration in rectal incontinence presented a higher DVH distribution range than patients without rectal incontinence. Penile bulb DVH values and erectile dysfunction were not significantly associated. CONCLUSIONS: DVH parameters and post-radiotherapy HRQoL appear to be closely correlated, underscoring the importance of assessing DVH values prior to initiating EBRT to determine the risk of developing HRQoL related adverse effects. Advanced treatment modalities may be appropriate in high risk cases to minimize treatment-related toxicity and to improve treatment outcomes and HRQoL. Future studies are needed to better elucidate the association between pre-treatment DVH parameters in organs at risk and subsequent HRQoL.

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas.

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.

Second re-irradiation for DIPG progression, re-considering "old strategies" with new approaches.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive infiltrative glioma for which no curative therapy is available. Radiation therapy (RT) is the only potentially effective intervention in delaying tumor progression, but only transiently. At progression, re-irradiation is gaining popularity as an effective palliative therapy. However, at second progression, exclusive symptomatic treatment is usually offered. Here we report two patients with DIPG at second progression who were treated with a second re-irradiation course with good response. Importantly, treatment was well tolerated with no irradiation associated acute toxicity identified.

Outcome and prognostic factors in 110 consecutive patients with primary uterine leiomyosarcoma: A Rare Cancer Network study.

OBJECTIVE: Primary uterine leiomyosarcomas (ULMS) are rare, and the optimal treatment is controversial. We aimed to assess the outcome and prognostic factors in a multicenter population of women treated for primary ULMS. METHODS: We retrospectively collected data of 110 women treated in 19 institutions of the Rare Cancer Network (RCN). Inclusion criteria consisted of a pathology report confirming the diagnosis of ULMS, aged 18-80 years, complete International Federation of Gynecology and Obstetrics (FIGO) stage information, complete information on treatment, and a minimum follow-up of 6 months. Local control (LC) and locoregional control (LRC), overall survival (OS) and disease-free survival (DFS) rates were computed using the Kaplan-Meier method. Univariate analysis was implemented using the log rank test, and multivariate analysis using the Cox model. RESULTS: All patients underwent surgery. Seventy-five patients (68%) received adjuvant radiotherapy (RT), including brachytherapy in 18 (16%). Seventeen patients (15%) received adjuvant chemotherapy. Median follow-up was 58 (range, 6-240) months. Five-year OS and DFS rates were 50% and 34%, and LC and LRC rates were 88% and 72%, respectively. On multivariate analysis, independent favorable prognostic factors were younger age, FIGO stage I, small tumor size, previous uterine disease, and no vascular invasion for OS and DFS. FIGO stage was the only favorable factor influencing LRC. Adjuvant local or systemic treatments did not improve the outcomes. Eight patients treated with RT presented a grade 3 acute toxicity, and only one patient with grade 3 late toxicity. CONCLUSIONS: In this large population of primary ULMS patients, we found good results in terms of LC and LRC. Nevertheless, OS remains poor, mainly due to the occurrence of distant metastases. An early diagnosis seemed to improve the prognosis of the patients. Adjuvant local or systemic treatments, or more aggressive surgical procedures such as the Wertheim procedure, did not seem to impact the outcome.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

Localized prostate cancer treated with external beam radiation therapy: Long-term outcomes at a European comprehensive cancer centre.

AIMS AND BACKGROUND: To present survival and toxicity outcomes in patients with clinically localized, non-metastatic prostate cancer (PCa) treated with external beam radiotherapy (EBRT) combined with androgen deprivation therapy (ADT). MATERIALS AND METHODS: Retrospective study of 849 PCa patients (pts) treated from 1996 to 2005. Until August 2000, all patients (281) were treated with conventional dose EBRT (<76 Gy); subsequent pts received ≥76 Gy (565 pts). Median age was 70 years (range, 39-82). Most pts were intermediate (353; 42.8%) or high-risk (344; 41.7%). Mean PSA was 10.1 ng/ml. Median dose to the prostate was 75 Gy. Complete ADT was administered to 525 pts (61.8%). RESULTS: Median follow-up was 109.6 months (range, 68.3-193.4). Overall survival (OS) was 92.5% and 81.1% at 5 and 10 years; by risk group (low, intermediate, high), 5- and 10-year OS rates were 94.3% and 85.9%, 92.3% and 79.2%, and 91.9% and 80.2% (p = 0.728). Five- and 10-year BRFS was 94.1% and 80.6% (low risk), 86.4% and 70.9% (intermediate), and 85.2% and 71.4% (high) (p = 0.0666). Toxicity included rectitis: grade 1 (G1) (277 pts; 32.6%), G2 (108; 12.7%), and G3 (20; 2.6%) and urethritis: G1 (294; 34.6%); G2 (223; 26.2%), and G3 (11; 1.3%). By dose rate (<76 Gy vs. ≥76 Gy), 5 and 10-year BRFS rates were 83.1% and 68.3% vs. 88.4% and 74.8% (p = 0.038). CONCLUSIONS: Our results are comparable to other published series in terms of disease control and toxicity. These findings confirm the need for dose escalation to achieve better biochemical control and the benefits of ADT in high-risk PCa patients.

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial.

BACKGROUND: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING: Spanish National Health Investigation Fund, AstraZeneca.

Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation.

Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.

Radiation and concomitant chemotherapy for patients with glioblastoma multiforme.

Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide (TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy (hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

A Phase 2 Randomized Open-label Study of Oral Darolutamide Monotherapy Versus Androgen Deprivation Therapy in Men with Hormone-sensitive Prostate Cancer (EORTC-GUCG 1532).

BACKGROUND AND OBJECTIVE: Darolutamide is an androgen receptor inhibitor that increases overall survival in combination with androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive and nonmetastatic castration-resistant prostate cancer (PCa). This phase 2 study assessed the efficacy and safety of darolutamide as monotherapy without ADT in patients with eugonadal testosterone levels. METHODS: This was a 24-wk, open-label, randomized study of patients with hormone-sensitive, histologically confirmed PCa requiring gonadotropin-releasing hormone (GnRH); an Eastern Cooperative Oncology Group performance status score of 0/1; and life expectancy >1 yr. All patients received darolutamide 600 mg bid or a commercially available GnRH analog. The primary endpoint is a prostate-specific antigen (PSA) response, defined as a ≥80% decline at week 24 relative to baseline in the darolutamide study arm. The GnRH arm is used as an internal control. The secondary endpoints included changes in T levels, safety/tolerability, and quality of life. KEY FINDINGS AND LIMITATIONS: Among 61 men enrolled, the median (range) age was 72 yr (53-86 yr); 42.6% of them had metastases. In the darolutamide arm, the evaluable population with available PSA values at baseline and week 24 consisted of 23 patients. Twenty-three (100%) evaluable darolutamide patients achieved a PSA decline of >80% at week 24 (primary endpoint), with a median (range) decrease of -99.1% (-91.9%, -100%). Serum T levels increased by a median (range) of 44.3 (5.7-144.0) at week 24, compared with baseline. In the darolutamide arm, 48.4% of men reported drug-related adverse events (AEs; mostly grade 1 or 2). The most frequent treatment-emergent AEs included gynecomastia (35.5%), fatigue (12.9%), hot flush (12.9%), and hypertension (12.9%). Health-related quality of life measures are descriptive, and GnRH arm results will be presented as an internal reference. CONCLUSIONS AND CLINICAL IMPLICATIONS: Darolutamide monotherapy was associated with a significant PSA response in nearly all men with hormone-naïve PCa. Testosterone-level changes and most common AEs (gynecomastia, fatigue, hypertension, and hot flush) were consistent with potent androgen receptor inhibition. PATIENT SUMMARY: In this study, we report the first use of darolutamide, a novel antiandrogen, as monotherapy without androgen deprivation therapy (ADT). The study shows that darolutamide induce a profound suppression of prostate-specific antigen in all patients, with a safety profile different from that of ADT.

Results of the IROCA international clinical audit in prostate cancer radiotherapy at six comprehensive cancer centres.

To assess adherence to standard clinical practice for the diagnosis and treatment of patients undergoing prostate cancer (PCa) radiotherapy in four European countries using clinical audits as part of the international IROCA project. Multi-institutional, retrospective cohort study of 240 randomly-selected patients treated for PCa (n = 40/centre) in the year 2015 at six European hospitals. Clinical indicators applicable to general and PCa-specific radiotherapy processes were evaluated. All data were obtained directly from medical records. The audits were performed in the year 2017. Adherence to clinical protocols and practices was satisfactory, but with substantial inter-centre variability in numerous variables, as follows: staging MRI (range 27.5-87.5% of cases); presentation to multidisciplinary tumour board (2.5-100%); time elapsed between initial visit to the radiation oncology department and treatment initiation (42-102.5 days); number of treatment interruptions ≥ 1 day (7.5-97.5%). The most common deviation from standard clinical practice was inconsistent data registration, mainly failure to report data related to diagnosis, treatment, and/or adverse events. This clinical audit detected substantial inter-centre variability in adherence to standard clinical practice, most notably inconsistent record keeping. These findings confirm the value of performing clinical audits to detect deviations from standard clinical practices and procedures.

RNA sequencing and Immunohistochemistry Reveal ZFN7 as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP-negative Glioblastoma.

PURPOSE: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. EXPERIMENTAL DESIGN: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. RESULTS: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. CONCLUSIONS: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management.

Germline mutations in TP53, a tumor suppressor gene, are involved in the development of Li-Fraumeni syndrome, a rare disorder that predisposes carriers to multiple tumors. TP53 mutations have been associated with resistance to treatment and poor prognosis. A young female with the pathogenic germline TP53 mutation c.844C > T (p.R282W) was diagnosed with two metachronous breast tumors, one HER2-negative and the other HER2-positive. She was later diagnosed with synchronous glioblastoma, epidermal growth factor receptor-mutated lung adenocarcinoma, and HER2-negative breast cancer metastases. The patient was treated with local therapies, including brain surgery and radiotherapy, lung surgery, and a bilateral mastectomy, as well as with targeted systemic treatment. She proved to be highly sensitive to systemic therapy, and 13 years after the initial diagnosis of breast cancer and 6 years after the diagnosis of the two new primary tumors and recurrence of a prior cancer, she is alive with an excellent performance status. This surprising positive evolution may well be partly due to the pronged multidisciplinary approach to managing her disease and her extraordinary response to treatment: the lung adenocarcinoma showed excellent response to erlotinib; the breast cancer responded extremely well to eribulin and pegylated liposomal doxorubicin; and the glioblastoma has remained in response to surgery and radiotherapy. Despite harboring a TP53 mutation and having multiple tumors, this patient has shown an unexpectedly favorable evolution. The coordinated participation of a multidisciplinary team and the patient's own extraordinarily high sensitivity to systemic treatment played a major role in this evolution.

A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01).

BACKGROUND: Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome. METHODS: Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948). RESULTS: From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001). CONCLUSIONS: Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. KEY POINTS: 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities.

Primary extranodal lymphoma of the glands. Literature review and options for best practice in 2019.

Primary extranodal non-Hodgkin's lymphomas (EN-NHL) are a heterogeneous group of malignancies that involve numerous entities with significant difference in terms of tumor site locations, prognostic factors, biology expression, and therapeutic options. In the literature, many EN-NHL types were reported from limited series which only allowed narrow views for elucidating prognostic factors and defining the role of loco-regional therapies in the era of new systemic and biologically targeted therapies. The Rare Cancer Network (RCN), an international multidisciplinary consortium, has published a number of reports on several EN-NHL sites which included many gland locations. In this review, we will focus on the recent literature for a selected number of EN-NHL types in both exocrine and endocrine gland locations. We aim to provide renewed and clear messages for the best practice in 2019 for diagnosis, histopathology, treatments, and also their prognostic implications. We believe that better understanding of molecular and genetic characteristics of these particular diseases is crucial for an appropriate management in the era of personalized treatment developments.

Paraganglioma of the head and neck region, treated with radiation therapy, a Rare Cancer Network study.

BACKGROUND: Paraganglioma of the head and neck (HNPGL) are rare often benign tumors. Surgery and radiation therapy (RT) are the main treatment choices. We present an analysis of outcome and toxicity after RT from 13 institutions of the Rare Cancer Network. METHODS: Data were collected using a questionnaire concerning patients' characteristics, treatment, and outcome. A total of 81 patients with 82 HNPGL were analyzed. RESULTS: The median follow-up was 48 months (1-456). Sixty-two lesions were treated with conventional RT and 20 lesions with stereotactic RT. Local control (LC) was achieved in 69 out of 77 lesions. Late toxicity occurred in 17 patients. Patients treated with stereotactic RT experienced neither disease progression nor late toxicity. Four patients with a follow-up longer than 20 years experienced disease progression. CONCLUSION: RT for HNPGL offered good local control with acceptable toxicity. Stereotactic RT might offer better results. Long-term follow-up is required.

Atypical and malignant meningioma: outcome and prognostic factors in 119 irradiated patients. A multicenter, retrospective study of the Rare Cancer Network.

PURPOSE: To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas. METHODS AND MATERIALS: Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (+/-SD) age was 57.6 +/- 12 years. Surgery was macroscopically complete (Simpson Grades 1-3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 +/- 5.1 Gy (range, 40-66 Gy). Median follow-up was 4.1 years. RESULTS: The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor. CONCLUSIONS: In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease.