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ObjectiveEpidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFRcopy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).DesignEGFRCN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.ResultsEGFRamplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFRCN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA.ConclusionEGFRCN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.

Radical concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C (MMC) remains the standard of care for squamous cell carcinoma of the anus. Phase III trials over 2 decades have used combined radiation doses of 50 to 60 Gy with concurrent fluoropyrimidines, MMC, or cisplatin in various doses and schedules. Modern radiotherapy techniques allow the production of highly conformal plans, decreasing radiation doses to the organs at risk and ensuring a shorter overall treatment time without the need for treatment breaks. These techniques offer the potential to improve compliance and even escalate doses of radiation.

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RASmutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RASmutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RASmutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Childhood poverty is unacceptably common in the US and threatens the health, development, and lifelong well-being of millions of children. Health care providers should be prepared through medical curricula to directly address the health harms of poverty. In this article, authors from The Child Poverty Education Subcommittee (CPES) of the Academic Pediatric Association Task Force on Child Poverty describe the development of the first such child poverty curriculum for teachers and learners across the medical education continuum.

About one-fourth of all toddlers and preschool children in the United States are overweight or at risk of being overweight. Child care providers have the opportunity to influence children’s nutrition early in their development, given the amount of time providers spend with them, particularly during meals. The Academy of Nutrition and Dietetics and the American Academy of Pediatrics have addressed the importance of increasing nutrition education. Implementing policy change to promote training among child care providers is one method to address childhood obesity. AB 290, a bill on child care licensing, was signed into law. This will require incoming child care providers to take 1 hour of early childhood nutrition, as part of the licensing process. The bill will require nutrition training to include information on age-appropriate meal patterns and on participation in the federal Child and Adult Care Food Program. The passage of AB 290 will help to increase nutrition training among providers, as nutrition education is currently not required. Other states should consider amending child care licensing laws related to nutrition training. Effective childhood obesity prevention legislation addressing the importance of nutrition is one small step that can be taken to combat the obesity epidemic.

Oesophageal and gastric cancers are common tumors that represent a number of challenges for oncologists, gastroenterologists and surgeons. The prognosis remains poor with the majority of patients presenting with advanced disease. Combined chemotherapy and radiotherapy has demonstrated a survival benefit in patients with loco-regional oesophageal cancer compared to radiotherapy alone. In an interim analysis we have observed a 62% response rate using a chemoradiation regimen based on protracted venous infusion of 5-fluorouracil and cisplatin combined with radiotherapy in patients with inoperable oesophageal cancer. Improved outcomes with loco-regional disease has rekindled interest in preoperative therapy. In a trial comparing preoperative chemoradiation to surgery alone in patients with operable oesophageal adenocarcinoma, survival was improved with multimodality treatment In addition, a study including both adeno- and squamous carcinomas demonstrated a trend towards improved survival. A complete pathological response to chemoradiation was associated with significantly improved survival. Gastric cancer is one of the most chemosensitive solid tumors of the gastrointestinal tract with the majority of patients being suitable for palliative chemotherapy. The ECF (epirubicin, cisplatin, protracted venous infusion 5-fluorouracil) regimen was developed in the Gastrointestinal unit of the Royal Marsden Hospital and first reported in 1991. In a prospective randomised trial including 274 patients ECF has been compared with the standard combination of 5-fluorouracil, adriamycin and methotrexate (FAMTX) in patients with previously untreated gastric cancer. Overall response rate, failure-free and overall survival were significantly improved with ECF. ECF also demonstrated improved quality of life and cost effectiveness when compared to the FAMTX regimen. ECF should now be regarded as the standard treatment for advanced oesophago-gastric cancer against which new therapies should be compared. In addition the Medical Research Council are conducting a trial randomising patients between surgery alone and perioperative chemotherapy using the ECF regimen in operable gastric cancer.

The electronic structure of octaalkylporphine bearing different meso-substituents (chloro, formyl, hydroxymethyl, nitro and amino groups) has been studied using AM1 and MMX methods. The electronic effect induced by the substituents at meso position considerably alters the optical transition energies, one-electron electrochemical redox potentials of the porphine ring and the pKvalues of the porphines. The experimentally determined values correlate well with the theoretical predictions. The small puckering of the porphine plane induced by the meso-substituent as revealed by MMX calculations plays a minor role in the observed physical properties.

There is currently no standard salvage chemotherapy regimen in patients with relapsed/ refractory DLBCL. We have previously shown that GEM-P is an effective salvage regimen in patients with relapsed/refractory lymphoma; 10 patients in this study had DLBCL (Br J Cancer2005;92:1352–7). The aim of this study was to evaluate the combination of GEM-P in a larger subset of DLBCL patients. This has not been reported before. Between 1/01 and 3/05, 39 (10 patients had transformed lymphoma) heavily pre-treated relapsed and refractory DLBCL patients received GEM-P; 24 (61%) of these patients also received Rituximab (R). The median age was 49 y (range, 18–68); 28 males; 64% patients had Stage III/IV disease; 69% had IPI ≥2. The median time from diagnosis to start of GEM-P ± R was 17 mo (range, 2mo-7 yrs). All patients had previously received an anthracycline-based regimen. The disease status at start of GEM-P ± R was: 24 patients were in 1st relapse, 7 had primary refractory disease, 5 were in 2nd relapse and 3 in 3rd relapse. Median number of cycles of GEM-P ± R received were 2 (range, 1–4). The overall response rate (RR) was 59% (95% CI 42.1–74.4). 11 (28%) patients attained complete response, 12 partial response and 15 patients did not respond; 1 patient died of progressive disease. The median response duration to GEM-P ± R in 23 responding patients was 332 days (range, 36–1530) compared to 170 days (range, 26–2264) in 32 responding patients to 1st-line chemotherapy. Of the 24 patients who received R (not randomised; given when available via NHS funding network) with GEM-P, the overall RR was 67% (95% CI 45–84) compared to 47% (95% CI 21–73) in those who did not receive R (P=0.2). Eight patients were consolidated with high-dose therapy which was an autologous stem cell transplant (ASCT) in 7 (all are alive and well except one who relapsed 4 mo later and died of progressive disease) and a reduced intensity conditioning matched unrelated donor transplant in 1 patient who died of transplant-related complications. The remaining patients did not undergo an ASCT due to treatment failure (n=16), cardiac insufficiency (n=2) and subclavian vein thrombosis (n=1). ASCT was not planned in the other 12 patients because of indolent histology (n=2), inadequate stem cell collection (n=1), lost-to follow-up (n=1), previous high-dose therapy (n=3) and stage 1 disease (n=1), physicians decision (n=1), patients choice (n=1) multiply relapsed disease (n=2). Progression-free survival (PFS) and overall surveival (OS) are shown in the Table. 23 patients are alive at a median follow-up of 543 days (range, 76–1598). In conclusion, GEM-P is an effective salvage regimen with long response duration in patients with relapsed or refrcatory DLBCL. The additional benefit with Rituximab on outcome warrants further studies in new and relapsed patients with DLBCL in a prospective, randomised trial. Survival OS PFS GEM-P (n=15) 3-y 40%(95%CI 16–63) 1-y 27%(95%CI 8–49) GEM-P +R (n=24) 3-y 65%(95%CI 40–82) 1-y 51% (95%CI 28–69) GEM-P ±R (n=39) 3-y 53.4% (95% CI 35–69) Median 157d (95% CI 42–271) PFS by rituximab use PFS by rituximab use

There is currently no standard salvage chemotherapy regimen in patients with relapsed/ refractory DLBCL. We have previously shown that GEM-P is an effective salvage regimen in patients with relapsed/refractory lymphoma; 10 patients in this study had DLBCL (Br J Cancer 2005; 92:1352–7). The aim of this study was to evaluate the combination of GEM-P in a larger subset of DLBCL patients. This has not been reported before. Between 1/01 and 3/05, 39 (10 patients had transformed lymphoma) heavily pre-treated relapsed and refractory DLBCL patients received GEM-P; 24 (61%) of these patients also received Rituximab (R). The median age was 49 y (range, 18–68); 28 males; 64% patients had Stage III/IV disease; 69% had IPI ≥2. The median time from diagnosis to start of GEM-P ± R was 17 mo (range, 2mo-7 yrs). All patients had previously received an anthracycline-based regimen. The disease status at start of GEM-P ± R was: 24 patients were in 1st relapse, 7 had primary refractory disease, 5 were in 2ndrelapse and 3 in 3rdrelapse. Median number of cycles of GEM-P ± R received were 2 (range, 1–4). The overall response rate (RR) was 59% (95% CI 42.1–74.4). 11 (28%) patients attained complete response, 12 partial response and 15 patients did not respond; 1 patient died of progressive disease. The median response duration to GEM-P ± R in 23 responding patients was 332 days (range, 36–1530) compared to 170 days (range, 26–2264) in 32 responding patients to 1st-line chemotherapy. Of the 24 patients who received R (not randomised; given when available via NHS funding network) with GEM-P, the overall RR was 67% (95% CI 45–84) compared to 47% (95% CI 21–73) in those who did not receive R (P=0.2). Eight patients were consolidated with high-dose therapy which was an autologous stem cell transplant (ASCT) in 7 (all are alive and well except one who relapsed 4 mo later and died of progressive disease) and a reduced intensity conditioning matched unrelated donor transplant in 1 patient who died of transplant-related complications. The remaining patients did not undergo an ASCT due to treatment failure (n=16), cardiac insufficiency (n=2) and subclavian vein thrombosis (n=1). ASCT was not planned in the other 12 patients because of indolent histology (n=2), inadequate stem cell collection (n=1), lost-to follow-up (n=1), previous high-dose therapy (n=3) and stage 1 disease (n=1), physicians decision (n=1), patients choice (n=1) multiply relapsed disease (n=2). Progression-free survival (PFS) and overall surveival (OS) are shown in the Table. 23 patients are alive at a median follow-up of 543 days (range, 76–1598). In conclusion, GEM-P is an effective salvage regimen with long response duration in patients with relapsed or refrcatory DLBCL. The additional benefit with Rituximab on outcome warrants further studies in new and relapsed patients with DLBCL in a prospective, randomised trial.

A personal narrative is presented which explores the author's experience of moving to New York from Zambia when she was seven years old.