Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this ...subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.
Display omitted
•SIX1/2 mutations in blastemal type Wilms tumors induce a proliferation signature•DROSHA/DGCR8 microprocessor mutations lead to a broad decrease in miRNA processing•TP53 mutations are associated with aneuploidy, chromothripsis, and high lethality•IGF2 and MYCN/FBXW7 alterations are frequent in blastemal type tumors
Blastemal type Wilms tumors are associated with poor prognosis. Wegert et al. identify recurrent mutations in SIX1 and SIX2 that correlate with high proliferation and in DROSHA and DGCR8 that affect miRNA biogenesis, as well as a high frequency of IGF2 overexpression in these tumors.
We analyzed the role of sleep position in obstructive sleep apnea syndrome (OSAS). The polysomnograms of 120 patients with sleep apnea syndrome were analyzed. We associated the apnea hypopnea index ...(AHI) of the supine position with the AHI of the other positions. Patients were stratified in a group of positional patients (PP) (AHI supine >or= 2 x AHI other positions) and a group of non-positional patients (NPP). In 55.8% of our patients, OSAS was position dependent. PP patients were significantly (6.7 years) younger. BMI and AHI were higher in the NPP group, but the difference was not significant. Level of obstruction in the upper airway (retropalatinal vs retrolingual vs both levels) as assessed by sleep endoscopy was not significantly different between the two groups. Total sleep time (TST) was equal in both groups, but the average time in supine position was 37 min longer in the PP group. This study confirms the finding that in more than 50% of patients, OSAS is position dependent. Apart from age, no patient characteristics were found indicating the position dependency. Overall AHI does not identify positional OSAS.
Purpose We investigated induction carboplatin based chemotherapy in patients with nonorgan confined urothelial carcinoma who were considered unfit for cisplatin. A comparison was made with patients ...who received induction cisplatin based combination chemotherapy. Materials and Methods We identified 167 patients with nonorgan confined urothelial carcinoma who received induction cisplatin based combination chemotherapy (126) or gemcitabine and carboplatin (41) at our hospital between 1990 and 2010. Of the patients 124 completed 4 cycles of cisplatin based combination chemotherapy or gemcitabine and carboplatin. Clinical response (ycTNM) was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. Radical cystectomy and bilateral extended pelvic lymph node dissection were performed in 106 patients. A pathological complete response was defined as no evidence of disease (ypT0N0). Disease specific survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed. Results Complete clinical response rates did not differ significantly among the treatment groups. A pathological complete response was seen in 33.7% of specimens in the cisplatin based combination chemotherapy group vs 30.3% in the gemcitabine and carboplatin group (p = 0.808). We found no significant difference in disease specific survival between patients who started cisplatin based combination chemotherapy and those who started gemcitabine and carboplatin. For patients who completed 4 cycles and underwent radical cystectomy there was also no significant difference in disease specific survival between the groups. On multivariate analysis a pathological complete response was the only variable significantly associated with disease specific survival (p <0.045). Conclusions Induction gemcitabine and carboplatin for nonorgan confined urothelial carcinoma achieves clinical and pathological response rates, and survival outcomes comparable to those of the cisplatin based combination chemotherapy schemes. Our data suggest that a carboplatin based regimen can be considered a reasonable alternative for cisplatin unfit patients in the preoperative setting.
Background
The COVID‐19 pandemic had global catastrophic effects on the management of non‐communicable diseases including paediatric cancers. Restrictions during the start of 2020 complicated timely ...referrals of patients to specialized centres. We aimed to evaluate the pandemic’s impact on the number of new diagnoses, disease characteristics and management delay for paediatric renal tumour patients included in the SIOP‐RTSG‐UMBRELLA study, as compared with data from a historical SIOP‐RTSG trial (2005–2009).
Methods
The number of intensive care admissions, population mobility rates and national lockdown periods/restrictions were used as proxies of the pandemic’s severity and impact on societies. Clinical and tumour data were extracted from the SIOP‐RTSG‐UMBRELLA study and from historical SIOP‐RTSG trials.
Results
During the first lockdown in Europe, the number of newly diagnosed patients decreased following restrictions and population immobilisation. Additionally, there was a higher proportion of advanced disease (37% vs. 17% before and after COVID‐9, p < 0.001) and larger median tumour volume (559 cm3 vs. 328 and 434 cm3 before and after, p < 0.0001). Also in Brazil, the proportion of advanced disease was higher during the national decrease in mobilisation and start of restrictions (50% and 24% vs. 11% and 18% before and after, p < 0.01). Tumour volume in Brazil was also higher during the first months of COVID‐19 (599 cm3 vs. 459 and 514 cm3), although not significant (p = 0.17). We did not observe any delays in referral time nor in time to start treatment, even though COVID‐19 restrictions may have caused children to reach care later.
Conclusion
The COVID‐19 pandemic briefly changed the tumour characteristics of children presenting with renal tumours. The longer‐term impact on clinical outcomes will be kept under review.
The COVID‐19 pandemic briefly changed the tumour characteristics of children presenting with renal tumours. During the first peak of COVID‐19, more children presented with metastatic disease and median tumour volume was higher. Further analyses after longer follow‐up is needed to study the influence on clinical outcomes.
Objective
To evaluate the value of radiotherapy boost omission in patients with intermediate‐risk, stage III Wilms tumours (WT) with positive lymph nodes (LN).
Methods and materials
All patients with ...intermediate‐risk, stage III (LN positive) WT consecutively registered in the SIOP‐WT‐2001 study were included in this analysis. Endpoints were 5‐year event‐free survival (EFS), loco‐regional control (LRC) and overall survival (OS).
Results
Between June 2001 and May 2015, 2,569 patients with stage I to III WT after preoperative chemotherapy were registered in the SIOP‐WT‐2001 study. Five hundred and twenty‐three (20%) had stage III disease, of which 113 patients had stage III due to positive LN only. Of those, 101 (89%) received radiotherapy, 36 of which (36%) received, apart from flank irradiation, a boost dose to the LN positive area. Four patients (4%) did not receive any adjuvant radiotherapy. In eight patients information on radiotherapy was not available.
With a median follow‐up of 71 months, no difference in 5‐year EFS (84% vs. 83%, P = 0.77) and LRC (96% vs. 97%, P = 0.91) was observed between patients receiving a radiotherapy boost and those without boost, respectively. Five‐year OS, including salvage therapy, was excellent (boost vs. no boost: 97% vs. 95%, P = 0.58).
Conclusions
Outcome data demonstrate that omission of the radiotherapy boost to the loco‐regional positive lymph nodes in patients with intermediate‐risk, stage III WT who receive preoperative chemotherapy and postoperative flank irradiation (14.4 Gy) can be considered a safe approach for future SIOP protocols.
Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed ...to compare the currently most active induction regimens.
In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0–1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete.
Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 62% male and 203 38% female; median age 62 years IQR 54–69) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7–53·1) in groups A and B and 49·9 months (44·5–52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7–10·5) in group A versus 10·6 months (9·9–12·1) in group B (stratified hazard ratio HR 0·76 95% CI 0·60–0·98; p=0·032), and 10·8 months (95% CI 9·9–12·6) in group C versus 10·4 months (9·8–13·0) in group D (stratified HR 1·11 95% CI 0·84–1·48; p=0·46). The most frequent grade 3–4 events in groups A and B were neutropenia (19 13% patients in group A vs 57 40% in group B; p<0·0001), hypertension (21 14% vs 20 14%; p=1·00), and diarrhoea (five 3% vs 28 19%; p<0·0001), and in groups C and D were neutropenia (29 25% vs 24 21%; p=0·44), skin toxicity (one 1% vs 29 25%; p<0·0001), hypertension (20 18% vs eight 7%; p=0·016), and diarrhoea (five 4% vs 18 16%; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis).
In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity.
Roche and Amgen.
Abstract Background and purpose The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16 Gy boost dose significantly improved local control, but ...increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology. Materials and methods A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5 years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate >4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram. Results Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p = 0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade ( p < 0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68. Conclusions The nomogram for predicting IBR 10 years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients.
Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with ...poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact.
One-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based "BRCA1-like" test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner.
In the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087).
This validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum-based chemotherapy regimens. Moreover, frequent PARP1 upregulation in BRCA1-like tumors may also point to susceptibility to treatment with PARP inhibitors. Limitations are the requirement of high tumor content and high-quality DNA.
PDF
