Chondrosarcoma is a cartilage forming neoplasm, which is the second most common primary malignancy of bone. Clinicians who treat chondrosarcoma patients must determine the grade of the tumor, and must ascertain the likelihood of metastasis. Acral lesions are unlikely to metastasize, regardless of grade, whereas axial, or more proximal lesions are much more likely to metastasize than tumors found in the distal extremities with equivalent histology. Chondrosarcoma is resistant to both chemotherapy and radiation, making wide local excision the only treatment. Local recurrence is frequently seen after intralesional excision, thus wide local excision is sometimes employed despite significant morbidity, even in low-grade lesions. Chondrosarcoma is difficult to treat. The surgeon must balance the risk of significant morbidity with the ability to minimize the chance of local recurrence and maximize the likelihood of long-term survival.

Tumor antigen-specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor-antigen-specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T cell-intrinsic energy consumption was the process of oxidative protein folding and disulfide-bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α. To test this hypothesis, we created TCR transgenic mice with a T cell-specific PERK gene deletion (OT1 + Lckcre + PERK f/f , PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T cell groups displayed superior tumor control compared to T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1 + tumor antigen-specific CD8 + TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1 + CD8 + TILs and bolstered CD8 + TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.

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Gastrocnemius flaps have been used for decades to reconstruct defects of the proximal tibia and knee. They have proven to be useful in the soft-tissue reconstruction of defects caused by trauma, tumors, and infections about the knee, and the reconstruction of extensor mechanism discontinuity with and without total joint arthroplasty. The flaps have low failure rates and a distinct proximally based blood supply that allows them to be elevated and rotated up to 15 cm above the level of the knee joint. The vascular anatomy is reproducible because rotational flaps do not require microvascular anastomosis. An understanding of the applied surgical anatomy, approaches, and utility of the gastrocnemius flap makes the technique a useful tool for the orthopaedic surgeon when plastic surgery assistance is not readily available.