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Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T‐cell–engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.

Investigation of PI3K-AKT signalling in FGFR amplified cell lines.

Supplementary Table 1. Expression of estrogen receptor regulated genes in patient 207 was determined using Nanostring. Data was normalized as described in the Online Methods and is presented as the Log2 ratio. Supplementary Table 2. A list of cell lines including FGFR status. Supplementary Table 3. Copy Number Variation and Gene Expression Assays.

Results of parallel siRNA screens in FGFR driven cell lines with analysis of ERK and AKT phosphorylation in and panel of FGFR driven cancer cell lines.

Clinical activity of FGFR inhibitor AZD4547 in FGFR amplified breast and gastric cancer.

High-level FGFR2 amplified cell lines are highly sensitive to FGFR inhibition.

Models of PI3 kinase-AKT signalling in FGFR driven cell lines.

Background Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection commonly affecting immunocompromised people. Diagnosis usually requires invasive techniques to obtain respiratory specimens. Minimally invasive detection tests have been proposed, but their operating characteristics are poorly described. Objectives To systematically review and meta-analyse the performance of minimally invasive PCP detection tests to inform diagnostic algorithms. Data sources Medline, Embase, Cochrane Library (inception to 15 October 2020). Study eligibility criteria Studies of minimally invasive PCP detection tests were included if they contained a minimum of ten PCP cases. Participants Adults at risk of PCP. Tests Non-invasive PCP detection tests. Reference standard Diagnosis using the combination of clinical and radiographical features with invasive sampling. Assessment of risk bias Using the QUADAS-2 tool. Methods We used bivariate and, when necessary, univariate analysis models to estimate diagnostic test sensitivity and specificity. Results Fifty-two studies were included; most studies (40) comprised exclusively human immunodeficiency virus (HIV) -infected individuals; nine were mixed (HIV and non-HIV), two were non-HIV and one study did not report HIV status. Sampling sites included induced sputum, nasopharyngeal aspirate, oral wash and blood. The four testing modalities evaluated were cytological staining, fluorescent antibody, PCR and lactate dehydrogenase. Induced sputum had the most data available; this modality was both highly sensitive at 99% (95% CI 51%–100%) and specific at 96% (95% CI 88%–99%). Induced sputum cytological staining had moderate sensitivity at 50% (95% CI 39%–61%) and high specificity at 100% (95% CI 100%–100%), as did fluorescent antibody testing with sensitivity 74% (95% CI 62%–87%) and specificity 100% (95% CI 91%–100%). Conclusion There are several promising minimally invasive PCP diagnostic tests available, some of which may reduce the need for invasive respiratory sampling. Understanding the operating characteristics of these tests can augment current diagnostic strategies and help establish a more confident clinical diagnosis of PCP. Further studies in non-HIV infected populations are needed.

Association between genotype and toxicity Grade 3 or greater

Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathologic response rates, survival, and toxicity for patients randomized to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial.Experimental Design: DNA was extracted from nontumor resection formalin-fixed paraffin-embedded (FFPE) blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion, and TYMS (TS) 5′ 2R/3R using multiplex PCR. Post PCR amplification, TS 2R/3R and GSTT1 samples underwent gel electrophoresis.Results: Polymorphism data were available for 289 of 456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathologic response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years, respectively (log rank P value = 0.0053). The P value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs. 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity.Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted. Clin Cancer Res; 23(24); 7543–9. ©2017 AACR.

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Gastric cancer; Metastasectomy; Oligometastasis Cáncer gástrico; Metastasectomía; Oligometástasis Càncer gàstric; Metastasectomia; Oligometàstasi Background Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. Methods In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). Conclusion The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Background The prognostic benefits of primary tumour and lymph node (LN) downstaging after neoadjuvant chemotherapy for oesophageal adenocarcinoma are well described. Pathological primary tumour regression grading (TRG) is widely used in the assessment of response to chemotherapy and has been shown to have prognostic value in this patient group. However, there is a lack of robust evidence regarding the prognostic effect of pathological response in LN despite emerging evidence of a discrepancy, up to 25% of patients in some studies, between TRG in the primary tumour and response in regional LNs. Although primary tumour regression is routinely documented as part of the standard pathological reporting of oesophagectomy specimens, LN regression is generally overlooked despite it's potential prognostic value. The aim of this study was to investigate the relationship between pathological response in LN, tumour recurrence and survival. Methods Multicentre cohort study including 763 patients with oesophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgery at Guy's and St Thomas’ NHS Foundation Trust (NHS-FT), The Royal Marsden NHS-FT, University Hospitals Birmingham NHS-FT, University Hospital Southampton NHS-FT and Belfast Health and Social Care Trust. Tumour regression was assessed in the primary tumour (as described by Mandard) and, retrospectively, in LNs retrieved from oesophagectomy specimens. LN were graded according to the proportion of fibrosis and residual tumour providing a LN regression score (LNRS). LNRS 1, complete response; LNRS 2, < 10% remaining tumour; LNRS 3, 10–50% remaining tumour; LNRS 4, > 50% viable tumour; LNRS 5, no evidence of response. Regression was defined as a LNRS of 1–3. Patients were classified as LN negative (no evidence of tumour or regression in any LN), complete LN-responders (evidence of regression ≥1 LN, no residual tumour in any LN), partial LN-responders (evidence of regression ≥1 LN with residual tumour ≥1 LN) and LN non-responders (no or minimal regression in any LN). Survival analysis was performed using multivariable Cox regression providing hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, gender, chemotherapy regimen, clinical stage, tumour grade, lympho-vascular invasion and primary tumour response. Results Mean age was 63 years with the majority male (86.2%). In total, 17,930 LN from 763 patients were analysed for evidence of response to chemotherapy. Overall, 243 (31.8%) patients were classified as LN negative, 62 (8.1%) as complete LN-responders, 155 (20.3%) as partial LN-responders and 303 (39.7%) as LN non-responders. Less than half (322/763, 42.2%) of patients demonstrated a pathological response in the primary tumour (Mandard score 1–3). Some patients had a LN response in the absence of a response in the primary tumour (97/431, 22.5%). Multivariable Cox regression survival analysis demonstrated improved overall survival in complete LN-responders (HR 0.37 95% CI 0.24–0.58), partial LN-responders (HR 0.70 95% CI 0.55–0.89) and LN negative patients (HR 0.34 95% CI 0.26–0.44) compared to LN non-responders. Similar results were observed for disease-free survival (complete LN-responders, HR 0.34 95% CI 0.22–0.53; partial LN-responders, HR 0.74 95% CI 0.58–0.93; LN negative, HR 0.33 95% CI 0.25–0.42). Rates of tumour recurrence were lower in patients who demonstrated a LN response or had negative LN (LN negative 23.0% vs complete LN-responders 19.4% vs partial LN-responders 50.3% vs LN non-responders 66.7%, p Conclusions In this cohort of patients with oeosphageal adenocarcinoma treated with neoadjuvant chemotherapy prior to surgical resection, LN regression was a strong predictive factor for better survival. This relationship was independent of primary tumour response, which was discordant in a significant number of patients. Complete LN-responders had equivalent survival to those with negative LN. Complete and partial LN-responders had better survival than LN non-responders. Evaluation and documentation of LN regression should be considered during the standard pathological reporting of oesophagectomy specimens.

Contemporary farming often involves more machines, access to information, and public pressure to protect or regenerate non-human nature than in the past. However, this is scarcely reflected in the farm novel, which is largely bound to an historical era. Australian farm novels include Benjamin Cozens’ Princess of the Mallee (1903), John Naish’s The Cruel Field (1962), Randolph Stow’s The Merry-Go-Round in the Sea (1965), and Carrie Tiffany’s Everyman’s Rules for Scientific Living (2005). Each feature realism and pre-1960s settings. In this article, I propose a major revision of the farm novel by employing magic realism to challenge Australia’s realist representations of farming as a rational, money-making enterprise. Magic realism allows me to position Australia’s dominant profit-driven approach to agriculture as fantasy and hopefully to stimulate new notions of farming and the farmer. By casting sugarcane and machines as a colonial farming alliance and humans as their marginalized subjects, I draw attention to a gradual depopulation of rural lands, subvert a persistent anthropocentric element of the settler-colonial ideology, and challenge notions of humans controlling the farm. This article is also a case study in a performance of John Kinsella’s international regionalism (He, 2021; Kinsella, 2001), in which Australia’s Wet Tropics connects with creative writing discourse.

The prognostic benefit of primary tumour and lymph node (LN) downstaging after neoadjuvant chemotherapy for oesophageal adenocarcinoma (OAC) is well described. However, there is no robust evidence regarding the prognostic effect of pathological LN regression despite emerging evidence of a discrepancy, in some patients, between tumour regression grade in the primary tumour and response in regional LNs. The aim of this study was to investigate the relationship between pathological LN regression, tumour recurrence and survival. Retrospective, multicentre cohort study including 763 patients with OAC treated with neoadjuvant chemotherapy followed by surgery at 5 high-volume tertiary referral centres in the United Kingdom. Tumour regression was assessed in the primary tumour (Mandard) and LNs retrieved from oesophagectomy specimens. Patients were classified as LN negative (no evidence of tumour or regression in any LN), complete LN-responders (evidence of regression ≥1 LN, no residual tumour in any LN), partial LN-responders (evidence of regression ≥1 LN with residual tumour ≥1 LN) and LN non-responders (no or minimal regression in any LN). Survival analysis was performed using Kaplan-Meier and Cox regression. Overall, 243 (31.8%) patients were classified as LN negative, 62 (8.1%) as complete LN-responders, 155 (20.3%) as partial LN-responders and 303 (39.7%) as LN non-responders. Some patients had a LN response in the absence of a response in the primary tumour (97/431, 22.5%). Multivariable Cox regression survival analysis (adjusting for age, gender, chemotherapy regimen, clinical stage, tumour grade, lympho-vascular invasion and primary tumour response) demonstrated improved overall survival in complete LN-responders (Hazard ratio (HR) 0.37 95% confidence interval (CI) 0.24-0.58), partial LN-responders (HR 0.70 95% CI 0.55-0.89) and LN negative patients (HR 0.34 95% CI 0.26-0.44) compared to LN non-responders. In this cohort of patients with OAC treated with neoadjuvant chemotherapy prior to surgical resection, LN regression was a strong prognostic factor independent of primary tumour response, which was discordant in a significant number of patients. Complete LN-responders had equivalent survival to those with negative LN. Complete and partial LN-responders had better survival than LN non-responders. Evaluation and documentation of LN regression should be considered during the standard pathological reporting of oesophagectomy specimens.

The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status.