Antimalarial activity of 2,6-dibenzylidenecyclohexanone derivatives.

Malaria remains one of the deadliest infectious diseases worldwide and continues to infect hundreds of millions of individuals each year. Here we report the discovery and derivatization of a series of 2,6-dibenzylidenecyclohexanones targeting the chloroquine-sensitive 3D7 strain of Plasmodium falciparum . While the initial lead compound displayed significant toxicity in a human cell proliferation assay, we were able to identify a derivative with no detectable toxicity and sub-micromolar potency.

Pembrolizumab-induced nephrotoxicity in a patient with breast cancer.

The introduction of immunotherapy has revolutionized the treatment and improved outcomes of multiple types of cancer. Although breast cancer is a less immune-responsive tumor type, the incorporation of pembrolizumab into chemotherapy regimens in the neoadjuvant and first-line metastatic setting for the triple-negative disease has improved outcomes. However, the use of this type of treatment is associated with a spectrum of adverse events. Although rarely affected, kidneys can be a target for immunotherapy, leading to irreversible injury if not recognized and addressed early. A 52-year-old woman presented with clinical stage II right breast cancer diagnosed at an outside facility. Neoadjuvant docetaxel/carboplatin/pembrolizumab every 3 weeks was started. Given the partial response on MRI after the 4th cycle, treatment was switched to doxorubicin/cyclophosphamide. However, pembrolizumab was held in cycle 2 due to the rash and then resumed in cycle 3 after the resolution of symptoms. Elevated creatinine was noted 3 weeks after the last dose of pembrolizumab without improvement despite adequate fluid resuscitation. Diagnostic workup was unremarkable except for pyuria and minimal albuminuria on urinalysis. In the absence of other risk factors and the temporal relationship between pembrolizumab administration and the onset of acute kidney injury (AKI), immune-related nephrotoxicity was the underlying diagnosis. After initiation of corticosteroids, creatinine decreased back to baseline without the need for kidney biopsy. An addendum to the original pathology report from the outside facility surfaced 5 months after starting treatment, revealing that the second breast lesion had a Fluorescence in situ hybridization (FISH) test performed that was positive. Given this fact, therapy was changed to two cycles of neoadjuvant paclitaxel/carboplatin/trastuzumab/pertuzumab, with approximately 8 weeks between the last pembrolizumab dose and the first dose of trastuzumab. Thereafter, she underwent a right breast mastectomy which showed residual invasive carcinoma with negative margins and lymph nodes. She completed 1 year of trastuzumab. Immune-related AKI is a rare, but potentially serious complication associated with an increase in mortality. Further research is needed in the development and early detection. There is promising research in the development of noninvasive biomarkers which has the added benefit of identifying patients who can be re-challenged with immunotherapy.

Oncotype DX Recurrence Score in premenopausal women.

In the past 20 years, clinicians have shifted away from relying solely on clinicopathologic indicators toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy for early-stage hormone receptor (HR)-positive, HER2-negative breast cancer. Oncotype DX Recurrence Score (RS) is one of the most widely used multigene assays when considering indications for adjuvant chemotherapy, and guidelines have recently incorporated its use in women with early HR-positive HER2-negative breast cancer and up to three positive lymph nodes. While multiple retrospective and prospective clinical studies have demonstrated that most women with a low- to mid-range RS (0-25) can safely forgo chemotherapy, premenopausal women remain an important subgroup for which recommendations based on RS are ill-defined. The majority of patients included in clinical trials and retrospective analyses validating the use of RS have been postmenopausal women. In the subgroup of premenopausal women with HR-positive HER2-negative breast cancer, studies indicate that traditional clinicopathologic methods for assessing risk continue to be powerful tools when combined with RS to predict benefit from chemotherapy. This suggests that there is an element of uncaptured risk inherent to the premenopausal state that evades characterization by RS alone. This review describes the evidence that has supported the recommendation of RS in clinical guidelines, specifically focusing on data for its current use in premenopausal women. We review available data regarding the impact of the menstrual cycle on hormonally regulated gene expression, which may drive variations in the RS. Further research on the reliability and interpretation of the RS in the premenopausal subgroup is necessary and represents a gap in knowledge of how the RS should be applied in premenopausal women.