Cancer by Sfakianakis Alexandros: 09/26/17

Τρίτη 26 Σεπτεμβρίου 2017

Overcoming barriers to integrating patient-reported outcomes in clinical practice and electronic health records

There is burgeoning interest in integrating electronic patient-reported outcomes (PROs) into the workflow of routine cancer care. In general, this involves offering patients an interface for self-reporting their symptoms, distress, physical functioning, and other clinically oriented information through online or telephone systems, with this information conveyed to clinicians through real-time alerts and longitudinal graphic reports.

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Secondary CNS lymphoma: the poisoned needle in the haystack

The term secondary central nervous system (CNS) lymphoma (SCNSL) defines the involvement of the CNS at presentation or relapse in patients with systemic lymphoma. In the 1990s, most reported studies on SCNSL were focused on pediatric series and/or highly aggressive lymphomas. Subsequently, some retrospective studies of adult patients with 'high-grade' lymphomas aimed to identify factors predicting CNS dissemination and several series of rare extranodal lymphomas with varied risk of CNS involvement were reported. More recently, studies on the effect of rituximab on CNS recurrence rate, some proposals of risk scores and the first prospective trials focused on CNS prophylaxis or treatment of SCNSL were published. Despite all these efforts, the level of evidence remains low, and some criticisms of reported studies keep many questions open. In this issue of Annals of Oncology, Gleeson et al. [1] on behalf of the UK NCRI, add new knowledge to this challenging field. The authors analyzed CNS events in 1080 patients with diffuse large B-cell lymphomas (DLBCL) registered in the NCRI R-CHOP14vs21 trial, and, as the main findings, they report a CNS recurrence rate of 1.9% for the whole series and 2.8% for patients selected to receive CNS prophylaxis [1]. Unfortunately, the authors did not identify risk factors, probably due to the small number of events, but they documented CNS relapse sites and confirmed that prognosis of SCNSL patients is poor. The authors should be commended for the collection of a huge mass of data and for the good-sense analysis performed.

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Of mice and men: patient-derived xenografts in cancer medicine

A large proportion of oncological care is directed towards patients in whom the fraction of responders is low and the duration of response short with minimal clinical benefit. As acerbically observed by Roy Porter, 'What an ignominious destiny if the future of medicine turns into bestowing meagre increments of unenjoyed life?' [1]. Thus, it is a priority in cancer research to radically shift from therapies which are used indiscriminately across specific tumour types, to personalized therapies which can both improve efficacy and reduce unnecessary toxicities and futile treatments [2].

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ESMO-Magnitude of Clinical Benefit Scale version 1.1

Abstract

Background

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review.

Methods

The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board.

Results

Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1).

Conclusions

ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies.

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Annals of Oncology: un bon travail

It is now almost 4 years since I was appointed Editor-in-Chief of the journal Annals of Oncology by the leadership of ESMO and JSMO. I would like here to pause and reflect on what has been achieved.

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Midostaurin: a magic bullet that blocks mast cell expansion and activation

Abstract

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

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Including Lynch syndrome in personalized prognostication and follow-up of stage II and III colon cancer

We read with interest the paper by Dienstmann et al. [1], in which the authors found that incorporating microsatellite instability (MSI), BRAF and KRAS mutational status to overall survival models with TNM staging increases prognostic accuracy in stage II and III colorectal cancer (CRC) patients.

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Treatment of squamous cell carcinoma of the anal canal (SCCA): a new era?

There are no therapies available after progression on cisplatin and 5-FU that can improve survival for patients with squamous cell carcinoma of the anal canal (SCCA). Recently, two studies have been published [1, 2] that open the era of checkpoint inhibitors in SCCA.

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Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors

Abstract

Background

While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.

Patients and methods

Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.

Results

We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.

Conclusions

Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

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First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study

Abstract

Background

Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.

Patients and methods

Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.

Results

Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43–0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.

Conclusions

First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.

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Right–left or midgut–hindgut?

In their recent article in Annals of Oncology, Arnold et al. suggest that primary tumour side may play a role as a predictive clinical marker for efficacy of systemic antineoplastic treatment in patients with advanced colorectal cancer [1]. We would like to make a few comments and questions to the authors.

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Blood- and tissue-based tumor genomics: a battle royale or match made in heaven?

Barata et al. [1] provided the first analysis of genomic alterations (GAs) identified by matched circulating tumor DNA (ctDNA) and tumor tissue next-generation sequencing (NGS) platforms in patients with advanced urothelial carcinoma (UC). When controlling for GAs screened by both platforms, the authors reported low concordance between ctDNA and tissue NGS (16.4%). The discordance observed, between ctDNA and tissue NGS, may reflect their potential complementarity leading to improved detection of GAs and revealing the dynamics of tumor genomic heterogeneity.

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Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Abstract

Background

Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient.

Methods

Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)].

Results

The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0–767), after a median number of 0 (0–3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%–50%), and 17.1% (0%–50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%–100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001).

Conclusions

This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

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Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review

Abstract

Background

Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class.

Methods

Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ² tests and multivariable regression models were used to analyse for effect size and associations.

Results

We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.

Discussion

CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.

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Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies

Abstract

Background

Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease.

Patients and methods

From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously.

Results

The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial–myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen.

Conclusions

Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.

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Changes in the use of end points in clinical trials for elderly cancer patients over time

Abstract

Background

Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s.

Patients and methods

All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials.

Results

Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period.Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported.

Conclusion

During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.

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‘Thursday’s child has far to go’—interpreting subgroups and the STAMPEDE trial

STAMPEDE is a multi-arm multi-stage randomised controlled trial protocol, recruiting men with locally advanced or metastatic prostate cancer who are commencing long-term androgen deprivation therapy. Opening to recruitment with five research questions in 2005 and adding in a further five questions over the past 6 years, it has reported survival data on 6 of these 10 RCT questions over the past 2 years [1–3]. Some of these results have been of practice-changing magnitude [4, 5], but, in conversation, we have noticed some misinterpretation, both over-interpretation and under-interpretation, of subgroup analyses by the wider clinical community which could impact negatively on practice. We suspect, therefore, that such problems in interpretation may be common. Our intention here is to provide comment on interpretation of subgroup analysis in general using examples from STAMPEDE. Specifically, we would like to highlight some possible implications from the misinterpretation of subgroups and how these might be avoided, particularly where these contravene the very design of the research question. In this, we would hope to contribute to the conversation on subgroup analyses [6–11].

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Vemurafenib in patients with BRAF V600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study

Abstract

Background

The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAF^V600 mutation–positive metastatic melanoma. We present final OS data from BRIM-3.

Patients and methods

Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m² every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.

Results

Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0–15.4] versus 9.7 months [95% CI 7.9–12.8; hazard ratio (HR) 0.81 [95% CI 0.67–0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0–15.4) versus 10.3 months (95% CI 9.1–12.8); HR 0.81 (95% CI 0.68–0.96); P = 0.01]. Kaplan–Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.

Conclusions

Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.

ClinicalTrials.gov

NCT01006980.

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Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation

Abstract

Background

Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required.

Patients and methods

We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).

Results

NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRD^NGS(−)] (defined as <10⁻⁶) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRD^NGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRD^NGS(−) (n = 24) showed a significantly better PFS than those that were MRD^NGS(+) (n = 15) (P =0.02). Moreover, MRD^NGS(−) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRD^NGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10⁻⁷) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33).

Conclusions

Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.

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Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study

Abstract

Background

Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD.

Patients and methods

Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999–2010 period. The study PC cohort comprised 22 084 patients aged ≥18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling.

Results

The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12–1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41–0.76).

Conclusion

PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy.

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Peritoneum as the sole distant metastatic site of lung adenosquamous cell carcinoma: a case report

Peritoneum metastasis of lung cancer is a rare event which, in addition to the peritoneum, usually involves multiple metastatic tissues. Here we report a case of a patient with lung adenosquamous cell carcinom...

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Deep cerebral venous thrombosis mimicking influenza-associated acute necrotizing encephalopathy: a case report

Acute necrotizing encephalopathy is one of the most devastating neurological complications of influenza virus infection. Acute necrotizing encephalopathy preferentially affects the thalamus bilaterally, as doe...

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Voluntary wheel running reduces the acute inflammatory response to liver carcinogen in a sex-specific manner

Inflammation contributes to the development of cancer, yet acute inflammatory responses are also needed to eradicate tumorigenic cells and activate adaptive immune responses to combat cancer. Physical exercise has direct immunomodulatory effects, and in line with this exercise has been demonstrated to inhibit tumor growth, including diethylnitrosamine-(DEN)-induced hepatocarcinoma. Having observed a sex-dependent development of DEN-induced hepatocarcinoma, we aimed to evaluate the effect of exercise and sex on the acute inflammatory response to DEN. Thus, we randomized male and female mice to cages with or without running wheels for 6 weeks, whereafter DEN was administered and the inflammatory response was evaluated for up to 96 hours. DEN administration caused marked acute inflammatory responses in female mice with weight loss, reduced food intake, release of liver enzymes and increased systemic levels of IL-6. Moreover, DEN caused increased hepatic expression of cytokines, immune cell-markers, and components of the TLR (toll-like receptor) signaling pathway. In male mice, DEN administration provoked similar physiological effects with weight loss and reduced food intake, but less systemic and hepatic acute inflammation, which was associated with a higher baseline expression of the detoxifying enzyme glutathione S-transferase and lower expression of ERα in male mice. Voluntary wheel running attenuated systemic and hepatic inflammation, in particular in the female mice, and shifted the peak time of the inflammatory response. In conclusion, DEN elicited an acute inflammatory response in particular in female mice, and this response was attenuated by prior exercise.

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Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab

Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early stage non-small cell lung cancer (NSCLC) patients. Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab Phase II study of 24 treatment-naïve patients with Stage IB-IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28 dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated TILs than those observed in PBMCs. Surprisingly, we found 4 cases of pre-existing tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating Tregs and MDSCs. Conclusions: This study did not meet the primary endpoint of detecting an increase in blood based tumor associated antigen T cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunological data from combined immune checkpoint blockade immunotherapies.

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Degalactotigonin, a natural compound from Solanum nigrum L., inhibits growth and metastasis of osteosarcoma through GSK3{beta} inactivation-mediated repression of the Hedgehog/Gli1 pathway

Purpose: Agents extracted from natural sources with anti-tumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma. Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array. Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of OS patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation. Conclusions: DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation-mediated repression of the Hedgehog/Gli1 pathway.

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Degalactotigonin, a natural compound from Solanum nigrum L., inhibits growth and metastasis of osteosarcoma through GSK3{beta} inactivation-mediated repression of the Hedgehog/Gli1 pathway

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Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab

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Head and neck squamous cell carcinomas are characterized by a stable immune signature within the primary tumor over time

Purpose: Genetic and morphological heterogeneity is well-documented in solid cancers. Immune cells are also variably distributed within the tumor; this heterogeneity is difficult to assess in small biopsies, and may confound our understanding of the determinants of successful immunotherapy. We examined the transcriptomic variability of the immunological signature in head and neck squamous cell carcinoma (HNSCC) within individual tumors using transcriptomic and immunohistochemical assessments. Experimental design: Forty-four tumor biopsies from 16 HNSCC patients, taken at diagnosis and later at resection, were analyzed using RNA-sequencing. Variance filtering was used to identify the top 4000 most variable genes. Principal component analysis, hierarchical clustering and correlation analysis were performed. Gene expression of CD8A was correlated to immunohistochemical analysis. Results: Analysis of immunological gene expression was highly consistent in replicates from the same cancer. Across the cohort, samples from the same patient were most similar to each other, both spatially (at diagnosis) and notably, over time (diagnostic biopsy compared to resection); comparison of global gene expression by hierarchical clustering [p=<0.0001] and correlation analysis [median intrapatient r=0.82; median interpatient r=0.63]. CD8A gene transcript counts were highly correlated with CD8 T-cell counts by immunohistochemistry (r=0.82). Conclusion: Our data demonstrate that in HNSCC the global tumor and adaptive immune signatures are stable between discrete parts of the same tumor and also at different timepoints. This suggests that immunological heterogeneity may not be a key reason for failure of immunotherapy and underpins the use of transcriptomics for immunological evaluation of novel agents in HNSCC patients.

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Head and neck squamous cell carcinomas are characterized by a stable immune signature within the primary tumor over time

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History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

British Journal of Cancer 117, 1063 (26 September 2017). doi:10.1038/bjc.2017.267

Authors: Albina N Minlikeeva, Jo L Freudenheim, Rikki A Cannioto, Kevin H Eng, J Brian Szender, Paul Mayor, John L Etter, Daniel W Cramer, Brenda Diergaarde, Jennifer A Doherty, Thilo Dörk, Robert Edwards, Anna deFazio, Grace Friel, Marc T Goodman, Peter Hillemanns, Estrid Høgdall, Allan Jensen, Susan J Jordan, Beth Y Karlan, Susanne K Kjær, Rüdiger Klapdor, Keitaro Matsuo, Mika Mizuno, Christina M Nagle, Kunle Odunsi, Lisa Paddock, Mary Anne Rossing, Joellen M Schildkraut, Barbara Schmalfeldt, Brahm H Segal, Kristen Starbuck, Kathryn L Terry, Penelope M Webb, Emese Zsiros, Roberta B Ness, Francesmary Modugno, Elisa V Bandera, Jenny Chang-Claude & Kirsten B Moysich

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Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

British Journal of Cancer 117, 913 (26 September 2017). doi:10.1038/bjc.2017.274

Authors: Ashley M Hopkins, Andrew Rowland, Ganessan Kichenadasse, Michael D Wiese, Howard Gurney, Ross A McKinnon, Chris S Karapetis & Michael J Sorich

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Comprehensive geriatric assessment in 326 older women with early breast cancer

Comprehensive geriatric assessment in 326 older women with early breast cancer

British Journal of Cancer 117, 925 (26 September 2017). doi:10.1038/bjc.2017.257

Authors: D O Okonji, R Sinha, I Phillips, D Fatz & A Ring

http://ift.tt/2utrJBv

Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

British Journal of Cancer 117, 913 (26 September 2017). doi:10.1038/bjc.2017.274

Authors: Ashley M Hopkins, Andrew Rowland, Ganessan Kichenadasse, Michael D Wiese, Howard Gurney, Ross A McKinnon, Chris S Karapetis & Michael J Sorich

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Influence of dietary insulin scores on survival in colorectal cancer patients

Influence of dietary insulin scores on survival in colorectal cancer patients

British Journal of Cancer 117, 1079 (26 September 2017). doi:10.1038/bjc.2017.272

Authors: Chen Yuan, Ying Bao, Kaori Sato, Katharina Nimptsch, Mingyang Song, Jennie C Brand-Miller, Vicente Morales-Oyarvide, Emilie S Zoltick, NaNa Keum, Brian M Wolpin, Jeffrey A Meyerhardt, Andrew T Chan, Walter C Willett, Meir J Stampfer, Kana Wu, Edward L Giovannucci, Charles S Fuchs & Kimmie Ng

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History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

British Journal of Cancer 117, 1063 (26 September 2017). doi:10.1038/bjc.2017.267

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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

British Journal of Cancer 117, 984 (26 September 2017). doi:10.1038/bjc.2017.243

Authors: Nicola Cirillo, David J Morgan, Maria Carmela Pedicillo, Antonio Celentano, Lorenzo Lo Muzio, Michael J McCullough & Stephen S Prime

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Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

British Journal of Cancer 117, 1048 (26 September 2017). doi:10.1038/bjc.2017.286

Authors: Javier Gayarre, Paloma Martín-Gimeno, Ana Osorio, Beatriz Paumard, Alicia Barroso, Victoria Fernández, Miguel de la Hoya, Alejandro Rojo, Trinidad Caldés, José Palacios, Miguel Urioste, Javier Benítez & María J García

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Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

British Journal of Cancer 117, 1048 (26 September 2017). doi:10.1038/bjc.2017.286

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Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

British Journal of Cancer 117, 921 (26 September 2017). doi:10.1038/bjc.2017.253

Authors: Rebecca Y Tay, Elizabeth Blackley, Catriona McLean, Maggie Moore, Peter Bergin, Sanjeev Gill & Andrew Haydon

http://ift.tt/2uti9OO

Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

British Journal of Cancer 117, 921 (26 September 2017). doi:10.1038/bjc.2017.253

Authors: Rebecca Y Tay, Elizabeth Blackley, Catriona McLean, Maggie Moore, Peter Bergin, Sanjeev Gill & Andrew Haydon

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The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

British Journal of Cancer 117, 1007 (26 September 2017). doi:10.1038/bjc.2017.249

Authors: Pirjo Åström, Krista Juurikka, Elin S Hadler-Olsen, Gunbjørg Svineng, Nilva K Cervigne, Ricardo D Coletta, Juha Risteli, Joonas H Kauppila, Sini Skarp, Samuel Kuttner, Ana Oteiza, Meeri Sutinen & Tuula Salo

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The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

British Journal of Cancer 117, 1007 (26 September 2017). doi:10.1038/bjc.2017.249

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Comprehensive geriatric assessment in 326 older women with early breast cancer

Comprehensive geriatric assessment in 326 older women with early breast cancer

British Journal of Cancer 117, 925 (26 September 2017). doi:10.1038/bjc.2017.257

Authors: D O Okonji, R Sinha, I Phillips, D Fatz & A Ring

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Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

British Journal of Cancer 117, 932 (26 September 2017). doi:10.1038/bjc.2017.264

Authors: Wen-Ying Lin, Chih-Peng Lin, Chih-Hung Hsu, Ying-Hui Lee, Yi-Ting Lin, Meng-Chi Hsu & Yu-Yun Shao

http://ift.tt/2vBGkue

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

British Journal of Cancer 117, 1026 (26 September 2017). doi:10.1038/bjc.2017.254

Authors: Nikki R Adler, Rory Wolfe, John W Kelly, Andrew Haydon, Grant A McArthur, Catriona A McLean & Victoria J Mar

http://ift.tt/2vjFkZ0

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

British Journal of Cancer 117, 932 (26 September 2017). doi:10.1038/bjc.2017.264

Authors: Wen-Ying Lin, Chih-Peng Lin, Chih-Hung Hsu, Ying-Hui Lee, Yi-Ting Lin, Meng-Chi Hsu & Yu-Yun Shao

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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

British Journal of Cancer 117, 938 (26 September 2017). doi:10.1038/bjc.2017.271

Authors: Alastair Greystoke, Nicola Steele, Hendrik-Tobias Arkenau, Fiona Blackhall, Noor Md Haris, Colin R Lindsay, Raffaele Califano, Mark Voskoboynik, Yvonne Summers, Karen So, Dana Ghiorghiu, Angela W Dymond, Stuart Hossack, Ruth Plummer & Emma Dean

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Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

British Journal of Cancer 117, 1026 (26 September 2017). doi:10.1038/bjc.2017.254

Authors: Nikki R Adler, Rory Wolfe, John W Kelly, Andrew Haydon, Grant A McArthur, Catriona A McLean & Victoria J Mar

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Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study

British Journal of Cancer 117, 1070 (26 September 2017). doi:10.1038/bjc.2017.268

Authors: Hannah Oh, Hannah Arem, Charles E Matthews, Nicolas Wentzensen, Kerryn W Reding, Louise A Brinton, Garnet L Anderson, Sally B Coburn, Jane A Cauley, Chu Chen, Deborah Goodman, Ruth M Pfeiffer, Roni T Falk, Xia Xu & Britton Trabert

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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

British Journal of Cancer 117, 938 (26 September 2017). doi:10.1038/bjc.2017.271

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CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

British Journal of Cancer 117, 947 (26 September 2017). doi:10.1038/bjc.2017.276

Authors: Maeva Dufies, Sandy Giuliano, Julien Viotti, Delphine Borchiellini, Linsay S Cooley, Damien Ambrosetti, Mélanie Guyot, Papa Diogop Ndiaye, Julien Parola, Audrey Claren, Renaud Schiappa, Jocelyn Gal, Antoine Frangeul, Arnaud Jacquel, Ophélie Cassuto, Renaud Grépin, Patrick Auberger, Andréas Bikfalvi, Gérard Milano, Bernard Escudier, Nathalie Rioux-Leclercq, Camillo Porta, Sylvie Negrier, Emmanuel Chamorey, Jean-Marc Ferrero & Gilles Pagès

http://ift.tt/2iHkdNM

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study

British Journal of Cancer 117, 1070 (26 September 2017). doi:10.1038/bjc.2017.268

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Non-conventional role of haemoglobin beta in breast malignancy

Non-conventional role of haemoglobin beta in breast malignancy

British Journal of Cancer 117, 994 (26 September 2017). doi:10.1038/bjc.2017.247

Authors: Marco Ponzetti, Mattia Capulli, Adriano Angelucci, Luca Ventura, Simona Delle Monache, Cinzia Mercurio, Alessia Calgani, Patrizia Sanità, Anna Teti & Nadia Rucci

http://ift.tt/2u9pP8H

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

British Journal of Cancer 117, 947 (26 September 2017). doi:10.1038/bjc.2017.276

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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

British Journal of Cancer 117, 954 (26 September 2017). doi:10.1038/bjc.2017.277

Authors: Saoirse O Dolly, Mark D Gurden, Konstantinos Drosopoulos, Paul Clarke, Johann de Bono, Stan Kaye, Paul Workman & Spiros Linardopoulos

http://ift.tt/2xav2ez

Non-conventional role of haemoglobin beta in breast malignancy

Non-conventional role of haemoglobin beta in breast malignancy

British Journal of Cancer 117, 994 (26 September 2017). doi:10.1038/bjc.2017.247

Authors: Marco Ponzetti, Mattia Capulli, Adriano Angelucci, Luca Ventura, Simona Delle Monache, Cinzia Mercurio, Alessia Calgani, Patrizia Sanità, Anna Teti & Nadia Rucci

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Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

British Journal of Cancer 117, 1017 (26 September 2017). doi:10.1038/bjc.2017.250

Authors: David Sefrioui, France Blanchard, Emmanuel Toure, Paul Basile, Ludivine Beaussire, Claire Dolfus, Anne Perdrix, Marianne Paresy, Michel Antonietti, Isabelle Iwanicki-Caron, Raied Alhameedi, Stephane Lecleire, Alice Gangloff, Lilian Schwarz, Florian Clatot, Jean-Jacques Tuech, Thierry Frébourg, Fabrice Jardin, Jean-Christophe Sabourin, Nasrin Sarafan-Vasseur, Pierre Michel & Frédéric Di Fiore

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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

British Journal of Cancer 117, 954 (26 September 2017). doi:10.1038/bjc.2017.277

Authors: Saoirse O Dolly, Mark D Gurden, Konstantinos Drosopoulos, Paul Clarke, Johann de Bono, Stan Kaye, Paul Workman & Spiros Linardopoulos

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Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

British Journal of Cancer 117, 965 (26 September 2017). doi:10.1038/bjc.2017.278

Authors: Francis Lévi, Abdoulaye Karaboué, Raphaël Saffroy, Christophe Desterke, Valerie Boige, Denis Smith, Mohamed Hebbar, Pasquale Innominato, Julien Taieb, Carlos Carvalho, Rosine Guimbaud, Christian Focan, Mohamed Bouchahda, René Adam, Michel Ducreux, Gérard Milano & Antoinette Lemoine

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Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

British Journal of Cancer 117, 1017 (26 September 2017). doi:10.1038/bjc.2017.250

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miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

British Journal of Cancer 117, 1036 (26 September 2017). doi:10.1038/bjc.2017.255

Authors: Cuijuan Shi, Linlin Ren, Cuiyun Sun, Lin Yu, Xiuwu Bian, Xuexia Zhou, Yanjun Wen, Dan Hua, Shujun Zhao, Wenjun Luo, Run Wang, Chun Rao, Qian Wang & Shizhu Yu

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Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

British Journal of Cancer 117, 965 (26 September 2017). doi:10.1038/bjc.2017.278

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Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

British Journal of Cancer 117, 974 (26 September 2017). doi:10.1038/bjc.2017.292

Authors: Meng Li, Jingyu Yang, Wenlong Zhou, Yong Ren, Xiaoxuan Wang, Huiping Chen, Jingyuan Zhang, Junli Chen, Yuhong Sun, Lijuan Cui, Xing Liu, Lihui Wang & Chunfu Wu

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miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

British Journal of Cancer 117, 1036 (26 September 2017). doi:10.1038/bjc.2017.255

Authors: Cuijuan Shi, Linlin Ren, Cuiyun Sun, Lin Yu, Xiuwu Bian, Xuexia Zhou, Yanjun Wen, Dan Hua, Shujun Zhao, Wenjun Luo, Run Wang, Chun Rao, Qian Wang & Shizhu Yu

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Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

British Journal of Cancer 117, 974 (26 September 2017). doi:10.1038/bjc.2017.292

Authors: Meng Li, Jingyu Yang, Wenlong Zhou, Yong Ren, Xiaoxuan Wang, Huiping Chen, Jingyuan Zhang, Junli Chen, Yuhong Sun, Lijuan Cui, Xing Liu, Lihui Wang & Chunfu Wu

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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

British Journal of Cancer 117, 984 (26 September 2017). doi:10.1038/bjc.2017.243

Authors: Nicola Cirillo, David J Morgan, Maria Carmela Pedicillo, Antonio Celentano, Lorenzo Lo Muzio, Michael J McCullough & Stephen S Prime

http://ift.tt/2uL9suE

Influence of dietary insulin scores on survival in colorectal cancer patients

Influence of dietary insulin scores on survival in colorectal cancer patients

British Journal of Cancer 117, 1079 (26 September 2017). doi:10.1038/bjc.2017.272

http://ift.tt/2wUKA60

Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced anti-neoplastic activities both in vitro and vivo. An integrative analysis using both whole-transcriptome sequencing (RNA-Seq) and chromatin-immunoprecipitation sequencing (ChIP-Seq) pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2 and the long non-coding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease.

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Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma

Proliferating EpCAM-positive ductal cells in the inflamed liver give rise to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here we demonstrate that PDC expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDC were specifically labeled in newly developed EpcamCreERT2 mice and traced in a chemically-induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis.

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Modeling cytostatic and cytotoxic responses to new treatment regimens for ovarian cancer

The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analysed a 12 treatment groups trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two- and three-drug schemes of cisplatin (DDP), bevacizumab (BEV) and paclitaxel (PTX) with conventional and two levels ("equi" and "high") of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight in the differences between treatment options. Individual drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme both cell death and regrowth impairment were intensified enough to achieve complete remission and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy.

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Multiscale modeling of inflammation-induced tumorigenesis reveals competing oncogenic and onco-protective roles for inflammation

Chronic inflammation is a serious risk factor for cancer; however, the routes from inflammation to cancer are poorly understood. Based on the processes implicated by frequently mutated genes associated with inflammation and cancer in three organs (stomach, colon and liver) extracted from the GEO, TCGA and GO databases, we present a multiscale model of the long-term evolutionary dynamics leading from inflammation to tumorigenesis. The model incorporates crosstalk among interactions on several scales, including responses to DNA damage, gene mutation, cell cycle behavior, population dynamics, inflammation, and metabolism-immune balance. Model simulations revealed two stages of inflammation-induced tumorigenesis: a precancerous state and tumorigenesis. The precancerous state was mainly caused by mutations in the cell proliferation pathway; the transition from the precancerous to tumorigenic states was induced by mutations in pathways associated with apoptosis, differentiation, and metabolism-immune balance. We identified opposing effects of inflammation on tumorigenesis: mild inflammation removed cells with DNA damage through DNA damage-induced cell death, whereas severe inflammation accelerated accumulation of mutations and hence promoted tumorigenesis. These results provide insight into the evolutionary dynamics of inflammation-induced tumorigenesis and highlight the combinatorial effects of inflammation and metabolism-immune balance. This approach establishes methods for quantifying cancer risk, for the discovery of driver pathways in inflammation-induced tumorigenesis, and have direct relevance for early detection and prevention and development of new treatment regimes.

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Inflammatory monocytes promote perineural invasion via CCL2-mediated recruitment and cathepsin B expression

Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI but the contributing conditions within the tumor microenvironment are not well understood. Here we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B-mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2-CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI.

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Calcium promotes human gastric cancer via a novel coupling of calcium-sensing receptor and TRPV4 channel

Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer (GC) development. CaSR expression was enhanced in GC specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in GC patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were co-localized in GC cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of GC cells through a Ca2+/AKT/β-catenin relay which occurred only in GC cells or normal cells overexpressing CaSR. Tumor growth and metastasis of GC depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote GC, and that targeting the novel CaSR/TRPV4/ Ca2+ pathway might serve as preventive or therapeutic strategies for GC.

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SMYD5 controls heterochromatin and chromosome integrity during embryonic stem cell differentiation

Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications such as trimethylated histone lysine 20 (H4K20me3) in development and genome stability are largely unknown. Here we show that depletion of SET and MYND domain-containing protein 5 (SMYD5), which mediates H4K20me3, leads to genome-wide decreases in H4K20me3 and H3K9me3 levels and derepression of endogenous LTR and LINE repetitive DNA elements during differentiation of mouse embryonic stem (ES) cells. SMYD5 depletion resulted in chromosomal aberrations and the formation of transformed cells that exhibited decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells was associated with LTR and endogenous retrovirus (ERV) elements and decreased H4K20me3. In addition, depletion of SMYD5 in human colon and lung cancer cells results in increased tumor growth and upregulation of genes overexpressed in colon and lung cancers, respectively. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation.

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PHGDH as a key enzyme for serine biosynthesis in HIF2{alpha} targeting therapy for renal cell carcinoma

Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to anti-angiogenic multi-kinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a Phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the multi-kinase inhibitor sunitinib. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists.

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MYC Inhibition depletes cancer stem-like cells in triple-negative breast cancer

There is mounting evidence that cancer stem-like cells (CSCs) are selectively enriched in residual tumors after anticancer therapies which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here we report that Triptolide (C1572), a small molecule natural product selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that ex vivo treatment of TNBC cells with C1572 reduced CSC levels by 28-fold. In mouse xenograft models of human TNBC, administration of C1572 suppressed tumor growth and depleted CSCs in a manner correlated with diminished MYC expression in residual tumor tissues. Together, these new findings provide a preclinical proof of concept defining C1572 as a promising therapeutic agent to eradicate CSCs for drug-resistant TNBC treatment.

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Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition

BRAF V600E colorectal cancers (CRC) are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that CRC progression specimens invariably harbored lesions in elements of the RAS-RAF-MEK-ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in CRC patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in CRC than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant CRC.

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FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3{beta}-Nrf2 signaling

The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4-GSK3β-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management.

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Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD and normal tissues. Somatic BRAF variants were found in 5/22 (23%) of AAH patients, 4/5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in all ever-smoker cases in the cohort (18%) exclusive of the cases with BRAF mutations. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF- mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed anti-tumor (Th1; IL12A, GZMB) and elevated pro-tumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways of AAH and immune dysregulation in the pathogenesis of this pre-malignant lung lesion.

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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

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The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

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Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

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Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

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The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

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Comprehensive geriatric assessment in 326 older women with early breast cancer

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Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

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Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

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Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

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Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes

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Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

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Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy

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CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

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Comprehensive geriatric assessment in 326 older women with early breast cancer

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Non-conventional role of haemoglobin beta in breast malignancy

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Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers

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RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

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Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

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Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

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Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

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Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

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miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

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Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study

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Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

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CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas

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History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

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Non-conventional role of haemoglobin beta in breast malignancy

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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

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Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours

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Influence of dietary insulin scores on survival in colorectal cancer patients

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Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)

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miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

http://ift.tt/2jYVmp8

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

http://ift.tt/2y8jvQk

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

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Characterisation of the cancer-associated glucocorticoid system: key role of 11β-hydroxysteroid dehydrogenase type 2

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Influence of dietary insulin scores on survival in colorectal cancer patients

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Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway

Extranodal NK/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with poor prognosis. Resveratrol (RSV, 3,5,4′-trihydroxystilbene), a natural nontoxic phenolic compound found in the skin of gr...

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A genomic screen for angiosuppressor genes in the tumor endothelium identifies a multifaceted angiostatic role for bromodomain containing 7 (BRD7)

Abstract

Tumor angiogenesis is characterized by deregulated gene expression in endothelial cells (EC). While studies until now have mainly focused on overexpressed genes in tumor endothelium, we here describe the identification of transcripts that are repressed in tumor endothelium and thus have potential suppressive effects on angiogenesis. We identified nineteen putative angiosuppressor genes, one of them being bromodomain containing 7 (BRD7), a gene that has been assigned tumor suppressor properties. BRD7 was studied in more detail, and we demonstrate that BRD7 expression is inversely related to EC activation. Ectopic expression of BRD7 resulted in a dramatic reduction of EC proliferation and viability. Furthermore, overexpression of BRD7 resulted in a bromodomain-dependent induction of NFκB-activity and NFκB-dependent gene expression, including ICAM1, enabling leukocyte–endothelial interactions. In silico functional annotation analysis of genome-wide expression data on BRD7 knockdown and overexpression revealed that the transcriptional signature of low BRD7 expressing cells is associated with increased angiogenesis (a.o. upregulation of angiopoietin-2, VEGF receptor-1 and neuropilin-1), cytokine activity (a.o. upregulation of CXCL1 and CXCL6), and a reduction of immune surveillance (TNF-α, NFκB, ICAM1). Thus, combining in silico and in vitro data reveals multiple pathways of angiosuppressor and anti-tumor activities of BRD7.

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A genomic screen for angiosuppressor genes in the tumor endothelium identifies a multifaceted angiostatic role for bromodomain containing 7 (BRD7)

Abstract

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Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017. © 2017 American Cancer Society.

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Human papillomavirus 16 E6 antibodies are sensitive for human papillomavirus–driven oropharyngeal cancer and are associated with recurrence

BACKGROUND

Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus–driven oropharyngeal cancer (HPV-OPC).

METHODS

This study identified 161 incident oropharyngeal cancer (OPC) cases diagnosed at the University of Pittsburgh (2003-2013) with pretreatment serum. One hundred twelve had preexisting clinical HPV testing with p16 immunohistochemistry and HPV in situ hybridization (87 were dual-positive [HPV-OPC], and 25 were dual-negative [HPV-negative]); 62 had at least 1 posttreatment serum sample. Eighty-six of the 161 tumors were available for additional HPV16 DNA/RNA testing (45 were dual-positive [HPV16–OPC], and 19 were dual-negative [HPV16–negative). HPV16 E6 antibody testing was conducted with multiplex serology. The following were evaluated: 1) the sensitivity and specificity of HPV16 E6 serology for distinguishing HPV-OPC and HPV16–OPC from HPV-negative OPC, 2) HPV16 E6 antibody decay after treatment with linear models accommodating correlations in variance estimates, and 3) pre- and posttreatment HPV16 E6 levels and the risk of recurrence with Cox proportional hazards models.

RESULTS

Seventy-eight of 87 HPV-OPCs were HPV16 E6–seropositive (sensitivity, 89.7%; 95% confidence interval [CI], 81.3%-95.2%), and 24 of 25 HPV-negative OPCs were HPV16 E6–seronegative (specificity, 96.0%; 95% CI, 79.6%-99.9%). Forty-two of 45 HPV16–OPCs were HPV16 E6–seropositive (sensitivity, 93.3%; 95% CI, 81.7%-98.6%), and 18 of 19 HPV16–negative OPCs were HPV16 E6–seronegative (specificity, 94.7%; 95% CI, 74.0%-99.9%). Posttreatment HPV16 E6 antibody levels did not decrease significantly from the baseline (P = .575; median follow-up, 307 days) and were not associated with the risk of recurrence. However, pretreatment HPV16 E6 seropositivity was associated with an 86% reduced risk of local/regional recurrence (hazard ratio, 0.14; 95% CI, 0.03-0.68; P = .015).

CONCLUSIONS

HPV16 E6 antibodies may have potential clinical utility for the diagnosis and/or prognosis of HPV-OPC. Cancer 2017. © 2017 American Cancer Society.

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Serum antibodies open the door to prediction and prognostication in human papillomavirus–related head and neck cancer

In human papillomavirus–related head and neck cancer, who can be de-escalated, and who requires more intensive therapy to achieve similar oncologic efficacy? The answers may very well be circulating in saliva and serum. See also pages 000-000.

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Diagnosis and management of primary central nervous system lymphoma

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