Rare causes of abdominal pain: a primer for the admitting general surgeon.

The broad uptake of the acute surgical unit (ASU) model of surgical care in Australia has resulted in general surgeons becoming increasingly involved in the management of patients with acute abdominal pain (AAP), some of whom will be labelled as having non-specific abdominal pain (NSAP) (Kinnear N, Jolly S, Herath M, et al. The acute surgical unit: An updated systematic review and meta-analysis. review. Int. J. Surg. 2021;94:106109; Lehane CW, Jootun RN, Bennett M, Wong S, Truskett P. Does an acute care surgical model improve the management and outcome of acute cholecystitis? ANZ J. Surg. 2010;80:438-42). NSAP patients lack a clear diagnosis of surgical pathology based on standard clinical, laboratory and imaging work-up, although they may require ASU admission for pain control and assessment. This article provides a review of uncommon conditions, presenting as AAP, that could possibly be mis-labelled as NSAP, with a focus on aspects of the presentation that may aid diagnosis and management including specific demographic features, clinical findings, key investigations and initial treatment priorities for ASU clinicians. Ultimately, most of the conditions discussed will not require surgical intervention, however, they require a diagnosis to be made and initial treatment planning before on-referral to the appropriate specialty. For the on-call general surgeon, some knowledge of these conditions and an index of suspicion are invaluable for the prompt diagnosis and efficient management of these patients.

Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3- Cell-Mediated Modulation of CD103+ Dendritic Cells.

Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4+Foxp3- cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103+ dendritic cells (DC) and expansion of a myeloid subset that produces TNFα and iNOS (TIP-DCs). CD4+Foxp3- T cell-mediated activation of CD103+ DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4+Foxp3- cells in modulating this arm of the antitumor immune response. Cancer Immunol Res; 6(9); 1069-81. ©2018 AACR.

CD73: A potential biomarker for anti-PD-1 therapy.

In our recent study, we show that tumoral CD73 expression limits the efficacy of anti-PD-1 therapy, and this is rescued by concomitant A2A blockade. Since CD73 is known to be overexpressed in several human cancers and A2A antagonists have undergone clinical trials for Parkinson's Disease, this combination warrants further investigation.

Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses.

Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8(+) T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8(+) T cells and, accordingly, increased growth inhibition of CD73(+) tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti-PD-1 mAb in patients with cancer and that the efficacy of anti-PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti-PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer.

A2A blockade enhances anti-metastatic immune responses.

The specific targeting of tumor-elicited immunosuppression is a promising strategy for the treatment of cancer. We have recently demonstrated that targeting the immunosuppressive pathway mediated by CD73-derived adenosine through the blockade of A2A/A2B adenosine receptors significantly reduced the metastatic potential of CD73+ breast carcinomas and melanomas via both immunological and non-immunological mechanisms.