The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over ...90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.
The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy ...for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.
Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of several genes including protooncogene cellular myelocytomatosis ...(c-Myc). c-Myc is difficult to target directly by agents due to its disordered alpha helical protein structure and predominant nuclear localization. The epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. MT-1 is a bivalent BD inhibitor that is 100-fold more potent than the first-in-class BD inhibitor JQ1. MT-1 decreased cell viability and causes cell cycle arrest in G0/G1 phase in castration-sensitive and resistant PC cell lines in a dose-dependent fashion. The inhibition of c-Myc function by MT-1 was molecularly corroborated by the de-repression of Protein Kinase D1 (PrKD) and increased phosphorylation of PrKD substrate proteins: threonine 120, serine 11, and serine 216 amino acid residues in β-Catenin, snail, and cell division cycle 25c (CDC25c) proteins, respectively. The treatment of 3D cell cultures derived from three unique clinically annotated heavily pretreated patient-derived PC xenografts (PDX) mice models with increasing doses of MT-1 demonstrated the lowest IC
in tumors with c-Myc amplification and clinically resistant to Docetaxel, Cabazitaxel, Abiraterone, and Enzalutamide. An intraperitoneal injection of either MT-1 or in combination with 3jc48-3, an inhibitor of obligate heterodimerization with MYC-associated protein X (MAX), in mice implanted with orthotopic PC PDX, decreased tumor growth. This is the first pre-clinical study demonstrating potential utility of MT-1 in the treatment of PC with c-Myc dysregulation.
We report the development of filterless deep ultraviolet photoconductive detectors using cerium fluoride (CeF3) thin films fabricated by pulsed laser deposition (PLD). By varying the PLD laser power ...during thin film growth, we observed that CeF3 breaks down to CeF2 at PLD laser powers greater than 100 mW. This consequently leads to the formation of fluorine defects that effectively narrowed the optical bandgap of the thin films, resulting in the decreased resistivity of the photoconductive detector. Under ultraviolet irradiation, the detector using a thin film grown at 5 mW PLD laser power exhibited close to four orders of magnitude increase in photocurrent compared to the dark current. The spectral response of the photoconductive detectors can be tuned from 300 nm to 400 nm when PLD laser powers ranging from 5 mW to 400 mW are used to fabricate the thin films. The filterless nature of the detectors simplifies their production, and their tunability can extend their use to a wider range of applications.
Background
The objective of this study was to evaluate the efficacy of gemcitabine plus nab‐paclitaxel in patients with recurrent ovarian cancer.
Methods
We performed a single institution ...retrospective review of patients with recurrent ovarian cancer who were treated with gemcitabine plus nab‐paclitaxel from 2012 to 2018 at the Mayo Clinic in Florida.
Results
Twenty patients were identified and the median PFS for patients treated with gemcitabine plus nab‐paclitaxel was 9 months (95% CI, 5.7–20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3 months 25%). For platinum‐sensitive disease and platinum‐resistant disease, the median OS were 38.7 months (95% CI, 5.8–63.1) and 31.2 months (95% CI, 12.8–51.8), respectively (p = 0.4306).
Conclusion
This well‐tolerated regimen shows promising activity in recurrent ovarian cancer and is a viable option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.
In this retrospective review, 20 patients were treated with gemcitabine plus nab‐paclitaxel and the median PFS was 9 months (95% CI, 5.7–20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3 months 25%). For platinum‐sensitive disease and platinum‐resistant disease, the median OS were 38.7 months (95% CI, 5.8–63.1) and 31.2 months (95% CI, 12.8–51.8), respectively (p = 0.4306). This regimen is a viable and well tolerated option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.
Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET-CT has ...proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET-CT and negative conventional imaging to positive PSMA PET-CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET-CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.
•Immune checkpoint inhibitors can be safely administered to patients with dermatomyositis.•Immunosuppressants did not impact the efficacy of treatment with an immune check point inhibitor.•Patients ...with autoimmune disorders who require immune check point inhibitors should be monitored by a rheumatologist.
The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have ...improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.
Patients with relapsed follicular lymphoma who do not respond to CAR‐T have a poor outcome. We present a case of refractory follicular lymphoma who relapsed after two CAR‐T infusions and achieved a ...complete remission after treatment with obinutuzumab and lenalidomide. This represents a promising treatment option in the post‐CAR‐T setting.
Lenalidomide plus obinutuzumab should be considered in patients with refractory follicular lymphoma who progress after CAR‐T.
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