Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe ...immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
Distinguishing neoplastic from nonneoplastic intracerebral hematoma has great clinical relevance for the appropriate management of patients. Imaging is not always able to clearly identify a ...tumor-related intraparenchymal cerebral hemorrhage (ICH), especially in the acute phase, the diagnosis being frequently based on evolution patterns. The aim of this study was to test the value of (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SPECT as a noninvasive diagnostic tool in early diagnosis of hemorrhagic brain neoplasm.
We prospectively studied 29 patients harboring a nontraumatic acute onset of clinical deterioration caused by ICH with atypical clinical or neuroradiologic features. All patients underwent (99m)Tc-MIBI SPECT within 48 h from the clinical onset. Early and delayed images were obtained. Both visual and semiquantitative analyses were performed. The (99m)Tc-MIBI index was obtained from both early and delayed images and the retention index was calculated.
In 19 patients (65.5%), a nonneoplastic hemorrhage (15 vascular degenerative diseases, 2 cavernous angiomas, 1 thrombosed middle cerebral artery giant aneurysm, and 1 sinus rectus thrombosis) was diagnosed by clinical and neuroradiologic follow-up or open surgery. In 10 patients (34.5%), a neoplastic hemorrhage (6 metastases, 2 glioblastomas multiforme, 1 ependymoma, and 1 intracranial angioblastic meningioma) was diagnosed by direct histologic typing (open surgery or stereotactic biopsy). In all neoplasm-related hemorrhages, a focal increased tracer uptake was observed in the area of the lesion, whereas no focal increased tracer uptake was noted in all nonneoplastic hematomas. A wide cutoff in the early ratio between neoplastic and nonneoplastic hemorrhages was found. Moreover, a statistically significant difference was found in the delayed ratio (P < 0.01) and the retention index (P < 0.05) between the 2 groups.
Our data suggest that (99m)Tc-MIBI SPECT could play a role in the early noninvasive diagnostic work-up of hemorrhagic brain lesions, allowing a clear differentiation between neoplastic and nonneoplastic ICHs. The high availability and low cost of this nuclear medicine technique can be considered additional advantages.
A 45-year-old female patient was referred for peptide receptor radionuclide therapy of liver metastases of neuroendocrine origin; the patient had undergone 2 years earlier surgical resection of a ...grade 2 neuroendocrine neoplasm of ampulla of Vater infiltrating the duodenal submucosa and muscular layers and the neighboring pancreatic tissue. Post-therapy whole-body scan performed to evaluate in vivo radiopharmaceutical distribution confirmed high accumulation in liver lesions and revealed increased uptake in the hip bone. Bone scan and corresponding CT images demonstrated changes of Paget disease in the same district.
Distinguishing neoplastic from nonneoplastic intracerebral hematoma has great clinical relevance for the appropriate management of patients. Imaging is not always able to clearly identify a ...tumor-related intraparenchymal cerebral hemorrhage (ICH), especially in the acute phase, the diagnosis being frequently based on evolution patterns. The aim of this study was to test the value of (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SPECT as a noninvasive diagnostic tool in early diagnosis of hemorrhagic brain neoplasm. We prospectively studied 29 patients harboring a nontraumatic acute onset of clinical deterioration caused by ICH with atypical clinical or neuroradiologic features. All patients underwent (99m)Tc-MIBI SPECT within 48 h from the clinical onset. Early and delayed images were obtained. Both visual and semiquantitative analyses were performed. The (99m)Tc-MIBI index was obtained from both early and delayed images and the retention index was calculated. In 19 patients (65.5%), a nonneoplastic hemorrhage (15 vascular degenerative diseases, 2 cavernous angiomas, 1 thrombosed middle cerebral artery giant aneurysm, and 1 sinus rectus thrombosis) was diagnosed by clinical and neuroradiologic follow-up or open surgery. In 10 patients (34.5%), a neoplastic hemorrhage (6 metastases, 2 glioblastomas multiforme, 1 ependymoma, and 1 intracranial angioblastic meningioma) was diagnosed by direct histologic typing (open surgery or stereotactic biopsy). In all neoplasm-related hemorrhages, a focal increased tracer uptake was observed in the area of the lesion, whereas no focal increased tracer uptake was noted in all nonneoplastic hematomas. A wide cutoff in the early ratio between neoplastic and nonneoplastic hemorrhages was found. Moreover, a statistically significant difference was found in the delayed ratio (P < 0.01) and the retention index (P < 0.05) between the 2 groups. Our data suggest that (99m)Tc-MIBI SPECT could play a role in the early noninvasive diagnostic work-up of hemorrhagic brain lesions, allowing a clear differentiation between neoplastic and nonneoplastic ICHs. The high availability and low cost of this nuclear medicine technique can be considered additional advantages.
Hepatobiliary scintigraphy (HBS) was performed in a patient in whom pyogenic liver abscess developed approximately 1 month after he underwent an interventional radiology procedure to relieve ...obstructive jaundice caused by an ampullary tumor. HBS, apart from detecting the abscess cavity as a “cold” space-occupying lesion, well demonstrated biliary flow impairment and dilatation of bile ducts, the communication between the abscess cavity and the biliary tree, and the presence of a bile leak. All these findings were disclosed by a single imaging procedure and appeared to be useful for patient management.
Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of ...myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-γ. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors.
T-cell-based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers ( approximately 20 million) of tumor-specific T ...cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that approximately 10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12-engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8(+) T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4(+) Foxp3(+) T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells.
Myeloid cells represent a major component of the tumor microenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, ...tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy.
Whereas preclinical investigations and clinical studies have established that CD8
+
T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the ...prevalent view that the beneficial effect of CD8
+
T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8
+
T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8
+
T cell immunity, leading to the emergence of dysfunctional CD8
+
T cells. The existence of different types of CD8
+
T cells in cancer calls for a more precise definition of the CD8
+
T cell immune phenotypes in cancer and the abandonment of the generic terms "pro-tumor" and "antitumor." Based on recent studies investigating the functions of CD8
+
T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8
+
T cells in cancer.
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