To report a case of stage IIIB juvenile granulosa cell tumor (JGCT) complicating pregnancy in a 33 year-old (y.o.) woman. Retrospective review of the clinical data, imaging studies, and pathology reports of a case of JGCT diagnosed during pregnancy. Patient consent was obtained for review and presentation of the case. A literature review was conducted. A 33 y.o., gravida 3, para 1 was incidentally found to have an 8 cm left ovarian mass on an anatomy scan at 22 weeks gestation. Four days later, she presented to labor and delivery triage with abdominal pain. An ultrasound revealed an 11 cm heterogeneous, solid mass in the left adnexa and free fluid at this level. The diagnosis of degenerating fibroid was made based on her clinical presentation and she was discharged. A follow up outpatient MRI revealed a 15 cm left ovarian mass consistent with a primary malignant ovarian neoplasm with moderate ascites and omental, left cul de sac, and probable paracolic gutter implantation. She re-presented 2 weeks later with an acute abdomen and was admitted for a gynecologic oncology consult. Pre-op tumor markers showed an elevated inhibin B. She underwent an exploratory laparotomy, left salpingo-oophorectomy, omental biopsy, and small bowel resection at 25 weeks gestation. Intra-op findings included a ruptured tumor and metastases. Tumor reductive surgery was completed to R0. Pathology revealed a JGCT, FIGO stage IIIB. The pathology and management were reviewed in collaboration with an outside institution. Chemotherapy was delayed until after delivery with monthly MRI surveillance. She underwent induction of labor at 37 weeks followed by an uncomplicated vaginal delivery. She received 3 cycles of bleomycin, etoposide, and cisplatin starting six weeks postpartum. Last known contact was over five years after the initial diagnosis with no evidence of recurrent disease. JGCTs account for 5% of granulosa cell tumors and 3% are diagnosed after age 30. JGCT is an uncommon neoplasm in pregnancy. 90% are stage I at diagnosis, but advanced stage tumors are aggressive often resulting in recurrence or death within 3 years of diagnosis. We present a surgically treated case with delay in chemotherapy until after delivery with a good outcome after 5 years of follow up.

Dihydronicotinamide rioside (NRH), the reduced form of nicotinamide riboside (NR), is a recently identified, naturally occurring precursor of arguably the most crucial cofactor for cellular function, nicotinamide adenine dinucleotide (NAD+). Recent investigation suggests that NRH is more adept at increasing NAD+ stores than traditional NAD+ precursors, and such extreme NAD+ boosting via NRH supplementation induces cytotoxicity in certain cellular contexts. It has also been shown that the lack of functional BRCA protein in epithelial ovarian cancer (EOC) directly impacts intracellular NAD+ levels. Given that altered cellular metabolism and DNA repair mechanisms are central alterations in EOC, and these processes are functionally dependent on NAD+, we sought to assess whether NRH supplementation in EOC cell lines enhanced cellular cytotoxicity alone and in combination with standard therapeutic agents. Significant cytotoxicity was noted in NRH treated cells (~40%) with minimal cell death in the nicotinic acid (NA)-treated lines. Levels of NAD(P)H were confirmed to have increased with NRH supplementation, albeit at different levels among the different cell lines. Overall, the cytotoxicity associated with NRH supplementation appears to be independent of ROS generation. Strikingly, NRH supplementation enhanced cytotoxicity of carboplatin in OVCAR8, but not ES2 or SKOV3. Paclitaxel cytotoxicity was also enhanced by the addition of NRH in OVCAR8, but not ES2 or SKOV3 cell lines. NA supplementation had no effect on baseline treatment-induced cytotoxicity. PARP inhibition by olaparib requires NAD+. Interestingly, NRH supplementation enhanced olaparib cytotoxicity in SKOV3 and OVCAR8, but not ES2 cells. NRH in combination with olaparib completely altered mitochondrial respiration, thereby shutting down energy consumption, which would lead to cell death. Coupled together with expression data of key enzymes required for NRH/NAD metabolism, this could be key in understanding mechanisms of cell death with NRH supplementation. Here, we showed that in the context of EOC, exploitation of the NAD+ bioenergetic phenotype through NRH supplementation is a biologically feasible strategy to enhance the response of traditional therapy with potentially minimal toxicity. These data suggest several potential mechanisms by which cellular NAD+ availability impacts treatment efficacy and resistance and highlights the potential utility of NAD+ metabolomics as a biomarker to guide treatment decisions.