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Background: Oxaliplatin has become one of the major cytotoxic agents for the treatment of gastrointestinal tumors. As a result, several cases of the so-called oxaliplatin-associated hypersensitivity reaction have been documented. Patients and Methods: We have retrospectively evaluated and characterized these reactions in our patient group by reviewing the files of 1,224 patients exposed to an oxaliplatin-containing regimen in order to provide useful clinical information for diagnosis and management. Results: Three hundred and eight (308) patients who have never been exposed to platinum compounds developed symptoms compatible with a reaction to oxaliplatin that was verified by manifestation of at least similar symptoms on rechallenging. The reactions occurred after the first 5 courses, with a median course number of 9 (range 1–24). These reactions could be distinguished as (1) mild reactions occurring in 195 (63%) patients manifesting with itching and small area erythema either during treatment or within the next hours, and (2) severe reactions occurring in 113 (37%) patients within minutes of drug infusion manifesting with diffuse erythroderma, facial swelling, chest tightness, bronchospasm and changes in blood pressure. Oxaliplatin withdrawal was not required in patients with a mild reaction. Forty-eight (42%) patients having a severe reaction with appropriate premedication and prolongation of the infusion duration could tolerate 2–4 subsequent courses. For the remaining 65 (58%) patients, oxaliplatin withdrawal was inevitable because of the very severe reactions occurring on rechallenging. In addition, 3 patients presented with thrombocytopenia and 3 others with hemolytic anemia, all reversible upon oxaliplatin discontinuation. Conclusions: Hypersensitivity reactions to oxaliplatin are underestimated. Although the reactions are not frequent during first courses, in extensively pretreated patients, they may become a serious problem. In the majority of patients, drug discontinuation might not be necessary. In patients manifesting a severe reaction, re-exposure to oxaliplatin should be considered only if the patient can tolerate the reaction and there has been clinical benefit from this therapy. Physicians and nursing staff should be aware of the risk and be well prepared.

Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor-infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M-MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific CD4+ T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity.

Disseminated malignancy is the major cause of prostate cancer-related mortality. Circulating tumor cells (CTCs) are essential for the establishment of metastasis. Various contemporary and molecular methods using prostate-specific biomarkers have been applied to detect extraprostatic disease that is undetectable by conventional imaging techniques, assessing the risk for disease recurrence after therapy of curative intent. However, the clinical relevance of CTC detection is still controversial. We review current literature regarding molecular methods used for the detection of CTCs in the peripheral blood and bone marrow biopsies of patients with prostate cancer, and we discuss the methodological pitfalls that influence the clinical significance of molecular staging.

SUMMARY Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48 / Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN’s beneficial functions in cognition and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein, mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss.