The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

https://escholarship.org/content/qt7gf847t7/qt7gf847t7.pdf?t=qaejdd

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00222-3.pdf

Expanding global access to radiotherapy

http://static.guim.co.uk/ni/1432986420413/Ann-Oncol-2015.pdf

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

Global colorectal cancer burden in 2020 and projections to 2040

An ill wind

Fruquintinib for previously treated metastatic colorectal cancer.

NHS England statistics and long-term plan.

Pembrolizumab is signifi cantly better than ipilimumab in terms of progression-free survival, overall survival, and the proportion of patients achieving an overall response for treat ment of advanced melanoma, according to a new study. The randomised phase 3 trial compared ipilimumab with pembrolizumab given every 2 weeks or every 3 weeks. 834 patients with un resectable stage III or IV melanoma were evenly assigned to one of the three groups. Median estimates of progression-free survival were 5·5 months (95% CI 3·4–6·9) for patients receiving pembrolizumab every 2 weeks, 4·1 months (2·9–6·9) for those receiving pembrolizumab every 3 weeks, and 2·8 months (2·8–2·9) for those receiving ipilimumab. Hazard ratios for disease progression for pembrolizumab versus ipilimumab were 0·58 (95% CI 0·46–0·72; p<0·001) for the 2-week regimen and 0·58 (95% CI 0·47–0·72; p<0·001) for the 3-week regimen. Estimates of 1-year survival were 74·1% for the 2-week regimen, 68·4% for the 3-week regimen, and 58·2% for ipilimumab. Hazard ratios for death compared with ipilimumab were 0·63 (95% CI 0·47–0·83, p<0·0005) for the 2-week regimen, and 0·69 (95% CI 0·52–0·90, p=0·0036) for the 3-week regimen. The pembrolizumab regimens did not diff er in effi cacy. The independent data and safety monitoring committee were moved to allow patients from the ipilimumab group to instead be prescribed pembrolizumab.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)70193-2.pdf

Pembrolizumab for patients with advanced melanoma.

And how this book will influence you to do better future? It will relate to how the readers will get the lessons that are coming. As known, commonly many people will believe that reading can be an entrance to enter the new perception. The perception will influence how you step you life. Even that is difficult enough; people with high sprit may not feel bored or give up realizing that concept. It's what under the knife will give the thoughts for you.

Talha Khan Burki

Papers

An ill wind

Fruquintinib for previously treated metastatic colorectal cancer.

NHS England statistics and long-term plan.

Pembrolizumab for patients with advanced melanoma.

Under the knife.