SummaryBackgroundIncomplete surgical resection of medulloblastoma is controversially considered a marker of high-risk disease; driving aggressive surgical resections, “second-look” surgeries, and/or intensified chemoradiotherapy. All prior publications evaluating the clinical importance of extent of resection (EOR) failed to account for molecular subgroup. We analysed the prognostic value of EOR across 787 medulloblastoma samples in a subgroup-specific manner.MethodsWe retrospectively identified patients from Medulloblastoma Advanced Genomics International Consortium (MAGIC) centres with a histological diagnosis of medulloblastoma and complete extent of resection and survival data. Specimens were collected from 35 international institutions. Medulloblastoma subgroup affiliation was determined using nanoString gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. Extent of resection (EOR) based on post-operative imaging was classified as gross total (GTR), near total (NTR, <1·5cm2), or subtotal (STR, ≥ 1·5cm2). Overall survival (OS) and progression-free survival (PFS) multivariable analyses including subgroup, age, metastatic status, geographical location of therapy (North America/Australia vs world), and adjuvant therapy regimen were performed. The primary endpoint was the impact of surgical EOR by molecular subgroup and other clinical variables on OS and PFS.Findings787 medulloblastoma patients (86 WNT, 242 SHH, 163 Group 3, and 296 Group 4) were included in a multivariable Cox model of PFS and OS. The marked benefit of EOR in the overall cohort was greatly attenuated after including molecular subgroup in the multivariable analysis. There was an observed PFS benefit of GTR over STR (hazard ration [HR] 1·45, 95% CI; 1·07–1·96, p=0·02) but there was no observed PFS or OS benefit of GTR over NTR (HR 1·05, 0·71–1·53, p=0·82 and HR 1·14, 0·75–1·72, p=0.55). There was no statistically significant survival benefit to greater EOR for patients with WNT, SHH, or Group 3 patients (HR 1·03, 0·67–1·58, p=0·9 for STR vs. GTR). There was a PFS benefit for GTR over STR in patients with Group 4 medulloblastoma (HR1·97, 1·22–3·17, p=0·01), particularly those with metastatic disease (HR 2·22, 1–4·93, p=0·05). A nomogram based on this multivariable cox proportional hazards model shows the comparably smaller impact of EOR on relative risk for PFS and OS than subgroup affiliation, metastatic status, radiation dose, and adjuvant chemotherapy.InterpretationThe prognostic benefit of EOR for patients with medulloblastoma is attenuated after accounting for molecular subgroup affiliation. Although maximal safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high as there is no definitive benefit to GTR over NTR. Our results suggest a re-evaluation of the long-term implications of intensified craniospinal irradiation (36 Gy) in children with small residual portions of medullobla...

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognise homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at two weeks postnatal compared to wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

At present, several modalities exist for the preoperative staging of rectal lesions, including computed tomography (CT), body coil or endorectal coil magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) done by rigid or flexible probes, and positron emission tomography (PET). Staging accuracy for CT ranges from 53% to 94% for T-stage accuracy and from 54% to 70% for N-stage accuracy. Improved CT accuracy is observed at higher disease stages. Body coil MRI has shownT-and N-stage accuracy ranging from 59% to 95% and 39% to 95 %, respectively. Endorectal coil MRI has shown improved T-and N-stage accuracy, with rates of 66% to 91% and 72% to 79%, respectively. The development of phased-array MRI, combining high spatial resolution with a larger field of view, offers promise to improve on these rates. EUS, considered the current gold standard, has shown T-stage accuracy ranging from 75% to 95%, with N-stage accuracy ranging from 65% to 80%. Flexible EUS probes have the advantage of being able to access and sample iliac nodes. Recent studies also suggest that three-dimensional EUS may provide greater accuracy than conventional two-dimensional EUS. Limited studies exist on the use of PET in primary tumor staging. PET may upstage disease in 8% to 24% of patients and has also been used in posttreatment restaging and surveillance. Postradiation edema, necrosis, and fibrosis seem to decrease restaging accuracy in all modalities. This article reviews the current literature about the staging accuracy of the various modalities and suggests a staging algorithm for rectal cancer.Accurate staging of rectal cancer is necessary to provide the optimal treatment strategy. Staging information includes extent of tumor involvement of the rectal wall and adjacent structures, presence or absence of adjacent lymphadenopathy, and determination of distant metastasis. Preoperative radiation therapy and total mesorectal excision (TME) are increasingly used in the treatment of locally advanced rectal cancer to reduce tumor recurrence. Recent data have shown that preoperative radiation therapy can reduce tumor recurrence from 27% to 11% (1). In addition, TME (a surgical technique that removes the rectum and surrounding mesorectal fat and perirectal lymph nodes and surrounding mesorectal fascia) has been shown to reduce postoperative recurrence to 10% without radiation therapy (2). A recent randomized controlled trial has shown that the combination of these techniques may reduce recurrence to 2.4% at 2 years compared with 8.2% with TME alone (3). Thus, accurate local staging information is paramount for stratifying patients who would benefit from neoadjuvant therapy as well as for predicting the surgical approach. Figure 1 illustrates major decision points that should be addressed in the staging process.At present, several modalities exist for the preoperative staging of rectal cancer: computed tomography (CT); magnetic resonance imaging (MRI) with traditional body, endorectal, or phased-array coils; endorectal ultrasonogra...