The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.

OBJECTIVE: The aim of the study was to develop recommended techniques and quality assurance metrics for the practice of Digital Anal Rectal Examination (DARE).
MATERIALS AND METHODS: The International Anal Neoplasia Society undertook a literature review and, using the AGREE II technique, developed guidelines for performing DARE.
RESULTS: A consensus was formed regarding the optimum conditions and characteristics of DARE. Several Quality Assurance metrics were developed.
CONCLUSIONS: Digital Anal Rectal Examination is a cheap and potentially universally available technique, which has the potential to facilitate the early diagnosis of anal cancers, when they are most amenable to treatment. These guidelines provide a basis for teaching the technique and may be used as for evaluation research.

INTRODUCTION: The major neoplastic and proliferative component of GCTB is the stromal tumor cells; that they have shown no evidence of bone destruction, instead the massive tissue destruction appears to be a result of tumor induced osteoclastogenesis. The discovery of receptor activator of nuclear factor kB (RANK) and RANK binding ligand (RANKL) uncovered the bone homeostasis and molecular mechanism by which multiple compounds (including vitamin D) regulated osteoclast differentiation; a function mediated by osteoblastic cells and osteoclast-precursor cells.
HYPOTHESIS: In a country burdened by vitamin D deficiency, causal relation between hypovitaminosis D and GCTB was hypothesized based on the vitamin D mediated RANKL expression and osteoclastogenesis, as India is also a population with higher incidence of GCTB as compared to Western populations described in the literature. The possibility of vitamin D regulated osteoclastogenesis in GCTB is postulated on the evidence from molecular research linking it to the RANK/RANKL/OPG pathway. The aim of this study was to analyse the prevalence of Vitamin D deficiency in patients with primary GCTB and to elucidate any difference in serum Vitamin 25(OD)D
MATERIALS AND RESULTS: 130 patients of primary GCTBs were matched to 310 controls from the general health check population and serum levels of 25(OH)D
DISCUSSION: The differential expression of RANKL and OPG in response to levels of vitamin D has been established. The stromal cells of osteolytic GCTB express high levels of RANKL, which is a key signal regulator in development of this disease and bone destruction typical of GCTBs. This has resulted in research targeting this pathway for therapeutic approach in GCTBs. As vitamin D supplementation is simple and safe, increased awareness to assess and if necessary correct vitamin D status of patients is warranted, however the question as to whether patients with low vitamin D levels are more prone to develop GCTB and thus would profit from vitamin D supplementation remains unanswered. To conclude, it is essential to assess vitamin D levels in patients with GCTB as deficiency is pronounced. Future research on this hypothesis might lead to an association between Vitamin D deficiency and the onset/natural history of GCTB that may in the future help us cure or prevent GCTBs.

The incidence of Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in the UK. Patients with HPV-positive OPSCC generally show superior clinical responses relative to HPV-negative patients. We hypothesised that these superior responses could be associated with defective repair of DNA double strand breaks (DSB). The study aimed to determine whether defective DNA repair could be associated with sensitivity to inhibition of DNA repair using the PARP inhibitor Olaparib. Sensitivity to Olaparib, and induction and repair of DNA damage, were assessed in a panel of 8 OPSCC cell-lines, including 2 novel HPV-positive lines. Effects on cell cycle distribution and levels of PARP1 and p53 were quantified. RNA-sequencing was used to assess differences in activity of DNA repair pathways. Two HPV-positive OPSCC lines were sensitive to Olaparib at potentially therapeutic doses (0.1-0.5 μM). Two HPV-negative lines were sensitive at an intermediate dose. Four other lines, derived from HPV-positive and HPV-negative tumours, were resistant to PARP inhibition. Only one cell-line, UPCISCC90, showed results consistent with the original hypothesis i.e. that in HPV-positive cells, treatment with Olaparib would cause accumulation of DSB, resulting in cell cycle arrest. There was no evidence that HPV-positive tumours exhibit defective repair of DSB. However, the data suggest that a subset of OPSCC may be susceptible to PARP-inhibitor based therapy.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAF

The erector spinae plane block is an interfascial plane block whereby local anesthetic is injected within the plane deep to the erector spinae muscle and superficial to the transverse process. To date, it has been used to provide analgesia in thoracic, abdominal, and lumbar regions. We present the first reported case of bilateral erector spinae plane block being used to provide surgical anesthesia in the cervical region.

BACKGROUND: The overall survival (OS) in non-small cell lung cancer (NSCLC) is poor, with median OS of advanced NSCLC with standard systemic chemotherapy being reported at 13.6 months and the 5-year survival rate at less than 15%. Therefore, the aim of this study was to evaluate Endostar combined with chemotherapy in patients with advanced NSCLC.
METHODS: Data on 116 cases of pathologically confirmed stage IIIB-IV NSCLC were retrospectively collected. The control group was treated with chemotherapy combined with intravenous infusion of Endostar while the test group received durative transfusion of Endostar. The short-term therapeutic effects including overall response rate (ORR), disease control rate (DCR), and safety were evaluated in both groups. In the follow-up, progression-free survival (PFS) and OS were also analysed.
RESULTS: In the test group, the ORR was 53.4%, which was similar to that in the control group (44.8%) (p > 0.05). However, the DCR in the test group (86.2%) was significantly higher than that in the control group (70.7%) (p < 0.01). The median time to progression in the test group (6 months) was also significantly longer than that in the control group (4 months). Importantly, the median OS in the test group (17.5 months) was improved compared to the control group (13.5 months). The 1-year survival rate in the test and control groups was 9.7 and 15.8%, respectively. There was no significant difference in side effects (including thrombocytopenia, leucopenia, nausea, and vomiting) between the two groups.
CONCLUSIONS: Endostar durative transfusion combined with chemotherapy showed a higher DCR, longer PFS and OS time, and was well tolerated in patients with advanced NSCLC.

BACKGROUND: Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain.
METHODS: We conducted an international, randomized, double-blind, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof) with a mutation in BRCA1, BRCA2, or both ( BRCA1/2) who had a complete or partial clinical response after platinum-based chemotherapy. The patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival.
RESULTS: Of the 391 patients who underwent randomization, 260 were assigned to receive olaparib and 131 to receive placebo. A total of 388 patients had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan-Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P<0.001). Adverse events were consistent with the known toxic effects of olaparib.
CONCLUSIONS: The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo. (Funded by AstraZeneca and Merck; SOLO1 ClinicalTrials.gov number, NCT01844986 .).

PURPOSE: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women.
METHODS: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing.
RESULTS: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case.
CONCLUSION: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.

BACKGROUND: Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer.
METHODS: Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted.
RESULTS: Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64-0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53-0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73-1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95).
CONCLUSION: Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers?

Prior studies on red and processed meat consumption with breast cancer risk have generated inconsistent results. We performed a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the relation of red meat and processed meat consumption with breast cancer incidence. We searched in MEDLINE and EMBASE databases through January 2018 for prospective studies that reported the association between red meat and processed meat consumption with incident breast cancer. The multivariable-adjusted relative risk (RR) was combined comparing the highest with the lowest category of red meat (unprocessed) and processed meat consumption using a random-effect meta-analysis. We identified 13 cohort, 3 nested case-control and two clinical trial studies. Comparing the highest to the lowest category, red meat (unprocessed) consumption was associated with a 6% higher breast cancer risk (pooled RR,1.06; 95% confidence intervals (95%CI):0.99-1.14; I

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15-30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10-30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10

Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). We show that rVAR2 efficiently captures CTCs from hepatic, lung, pancreatic, and prostate carcinoma patients with minimal contamination of peripheral blood mononuclear cells. Expression of ofCS is present on epithelial and mesenchymal cancer cells and is equally preserved during epithelial-mesenchymal transition of cancer cells. In 25 stage I-IV prostate cancer patient samples, CTC enumeration significantly correlates with disease stage. Lastly, rVAR2 targets a larger and more diverse population of CTCs compared to anti-EpCAM strategies.

Metastatic spine tumour surgeries (MSTS) are indicated for preservation or restoration of neurological function, to provide mechanical stability and pain alleviation. The goal of MSTS is to improve the quality of life of the patients with spinal metastases and rarely for oncological control which is usually achieved by adjuvant therapies. Hence outcome measures such as length of stay (LOS) and rate of complications after MSTS are important indicators of quality but there is limited literature evidence for the same. We carried out a retrospective study to determine the incidence and the factors influencing normal (nLOS) and extended length of stay (eLOS) after MSTS. Data of 220 consecutive patients who underwent MSTS between 2005 and 2015 were retrieved from hospital electronic records. The preoperative, intraoperative and postoperative variables, discharge destinations as well as socioeconomic factors were analyzed. eLOS defined as positive when the LOS exceeded the 75th percentile for this cohort, was the key outcome indicator. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of eLOS. The overall median LOS was 7 days (1-30 days) and 55 patients had eLOS (LOS ≥ 11 days). Multivariate analysis revealed that significant variables independently associated with eLOS were instrumentation >9 spinal segmental levels (OR 2.89, 95% CI 1.1-7.5, p = 0.032) and presence of postoperative complications (OR 3.68, 95% CI 1.85-7.30, p < 0.001). Metastatic tumours other than breast, prostate and lung have lesser risk of eLOS (OR 0.31, 95% CI 0.14-0.70, p = 0.004). Survival estimates show that patients with eLOS have shorter survival than patients with nLOS (Crude HR 1.81, 95% CI 1.13-2.89, p = 0.003).

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

PURPOSE: To test the hypothesis that increased acute toxicity, measured using subdomains reflective of epithelial cell damage, will be associated with reduced late biochemical failure, as a surrogate for tumor radiosensitivity.
METHODS AND MATERIALS: The study design was retrospective, with discovery and validation cohorts involving routinely collected data. Eligible patients had prostate cancer, underwent radiation therapy with curative intent, and had acute toxicity assessed prospectively. The discovery cohort was from a single institution. Genitourinary and gastrointestinal acute toxicity related to epithelial cell damage (hematuria, dysuria, proctitis, or mucus) were related to freedom from late biochemical failure (FFBF; nadir + 2). The validation cohort was from two separate institutions.
RESULTS: In all, 503 patients were included in the discovery cohort and 658 patients in the validation cohort. In the validation cohort, patients with acute radiation toxicity reflecting epithelial damage had a longer FFBF on both univariate (hazard ratio [HR] 0.37; P = .004) and multivariate (HR 0.45; P = .035) analysis. The impact of acute toxicity on late FFBF seemed to be greater in patients treated with androgen deprivation (HR 0.19) than in those without (HR 0.48).
CONCLUSION: Patients reporting acute radiation toxicity reflective of epithelial cell damage during definitive radiation therapy for prostate cancer have significantly longer FFBF, consistent with an underlying genetic link between normal tissue and tumor radiosensitivity.

BACKGROUND: Although ventricular fibromas are rare, they are the second most common type of cardiac tumor in children. While histologically benign, they have a propensity to cause malignant arrhythmias, with cardiac arrest often being the first presentation.
OBJECTIVE: The purpose of this study was to evaluate the arrhythmia risk and management strategies for pediatric ventricular fibromas.
METHODS: Fifteen centers in the British Paediatric Arrhythmia Group network were contacted to partake in the study to contribute cases. A detailed database search was performed at 2 hospitals for cases of ventricular fibromas.
RESULTS: A total of 19 patients were included in the study. Arrhythmias were common, with 5 patients presenting with cardiac arrest and 5 others having documented ventricular tachycardia. Nine patients have undergone surgical resection at various hospitals, and all these patients have survived with good long-term outcomes. One patient who did not have any treatment died, presumably of a ventricular arrhythmia; another died of metastatic disease. There were no recurrences of arrhythmia after surgery, and the need for a defibrillator was alleviated in all cases.
CONCLUSION: Ventricular fibromas have a high propensity to cause malignant arrhythmias, and if they are not managed appropriately, mortality is high. The outcomes of surgical resection are good, regardless of size, and this represents the best therapeutic option, with most patients being symptom free in the longer term.

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m

Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

BACKGROUND: Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed.
PROCEDURE: From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty-eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG).
RESULTS: Ten-year event-free (EFS) and overall survival (OS) were 74% (95% CI, 67-79%) and 92% (95% CI, 88-96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty-one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery.
CONCLUSIONS: About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (

BACKGROUND AND PURPOSE: Clinical challenges arise in the oligoprogressive (OP) state with little evidence to support the use of ablative strategies. Our aim is to report on outcomes and prognostic variables following stereotactic body radiotherapy (SBRT) for OP and oligometastases (OM).
MATERIAL AND METHODS: Overall (OS) and progression-free survivals (PFS) were calculated for 163 patients for 209 lesions (106 OM and 57 OP) treated with SBRT over 9 years. OS and PFS comparisons were calculated using the Kaplan-Meier actuarial survival and log rank methods. Uni, multi-variate analyses and cumulative incidences of local failure were performed using the Cox modelling and Gray's test respectively.
RESULTS: The median OS and PFS was 37 and 15 months versus 21.7 and 6.4 months in the OM and OP groups respectively (P = 0.02 and P = 0.01). Performance status (⩾2 HR 2.95) and number of metastases (1/2 vs ⩾3 HR 1.88) were independent prognosticators for survival. The 1/2-year PFS were 55%/25% versus 22%/6% in the OM and OP cohorts. Patterns of first relapse were four times higher outside the irradiated field and OP status (p = 0.03), ⩾3 metastasis (p = 0.002) and concurrent systemic therapy (p = 0.001) conferred a greater risk. Time to second-line treatment was 20 vs 11 months in the OM and OP groups (P = 0.001).
CONCLUSION: Survival and distant relapse following SBRT to OM/OP is determined by the extent of metastatic disease and performance status. Future research should address the benefit of integrating SBRT with systemic therapies to allow deferral or continuation of therapeutic agents.

Purpose Capturing patient-reported outcome data is important for evaluating the overall clinical benefits of new cancer therapeutics. We assessed self-reported symptoms of advanced non-small-cell lung cancer in patients treated with osimertinib or chemotherapy in the AURA3 phase III trial. Patients and Methods Patients completed the European Organisation for Research and Treatment of Cancer 13-item Quality of Life Questionnaire-Lung Cancer Module (EORTC QLQ-LC13) questionnaire on disease-specific symptoms and the EORTC 30-item Core Quality of Life Questionnaire (EORTC QLC-C30) on general cancer symptoms, functioning, global health status/quality of life. We assessed differences between treatments in time to deterioration of individual symptoms and odds of improvement (a deterioration or improvement was defined as a change in score from baseline of ≥ 10). Hazard ratios (HRs) were calculated using a log-rank test stratified by ethnicity; odds ratios (ORs) were assessed using logistic regression adjusted for ethnicity. Results At baseline, the questionnaires were completed by 82% to 88% of patients, and 30% to 70% had individual key symptoms. Time to deterioration was longer with osimertinib than with chemotherapy for cough (HR, 0.74; 95% CI, 0.53 to 1.05), chest pain (HR, 0.52; 95% CI, 0.37 to 0.73), and dyspnea (HR, 0.42; 95% CI, 0.31 to 0.58). The proportion of symptomatic patients with improvement in global health status/quality of life was higher with osimertinib (80 [37%] of 215) than with chemotherapy (23 [22%] of 105; OR, 2.11; 95% CI, 1.24 to 3.67; P = .007). Proportions were also higher for appetite loss (OR, 2.50; 95% CI, 1.31 to 4.84) and fatigue (OR, 1.96; 95% CI, 1.20 to 3.22). Conclusion Time to deterioration of key symptoms was longer with osimertinib than with chemotherapy, and a higher proportion of patients had improvement in global health status/quality of life, demonstrating improved patient outcomes with osimertinib.

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10

Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n = 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval; 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P = 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49;

The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified

The intravoxel incoherent motion (IVIM) model for diffusion-weighted imaging (DWI) MRI data bears much promise as a tool for visualizing tumours and monitoring treatment response. To improve the currently poor precision of IVIM, several fit algorithms have been suggested. In this work, we compared the performance of two Bayesian IVIM fit algorithms and four other IVIM fit algorithms for pancreatic cancer imaging. DWI data were acquired in 14 pancreatic cancer patients during two MRI examinations. Three different measures of performance of the fitting algorithms were assessed: (i) uniqueness of fit parameters (Spearman's rho); (ii) precision (within-subject coefficient of variation, wCV); and (iii) contrast between tumour and normal-appearing pancreatic tissue. For the diffusivity D and perfusion fraction f, a Bayesian fit (IVIM-Bayesian-lin) offered the best trade-off between tumour contrast and precision. With the exception for IVIM-Bayesian-lin, all algorithms resulted in a very poor precision of the pseudo-diffusion coefficient D* with a wCV of more than 50%. The pseudo-diffusion coefficient D* of the Bayesian approaches were, however, significantly correlated with D and f. Therefore, the added value of fitting D* was considered limited in pancreatic cancer patients. The easier implemented least squares fit with fixed D* (IVIM-fixed) performed similar to IVIM-Bayesian-lin for f and D. In conclusion, the best performing IVIM fit algorithm was IVM-Bayesian-lin, but an easier to implement least squares fit with fixed D* performs similarly in pancreatic cancer patients.

Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. Patients without high-risk factors, including Flt3 internal tandem duplication wt/- NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD-; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD-, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD- (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.