Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Palbociclib Plus Fulvestrant in Korean Patients from PALOMA-3 With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1-not estimable] vs. 5.4 months [95% CI, 1.9-9.2]; hazard ratio, 0.40 [95% CI, 0.19-0.83]; one-sided p =0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24-24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2- ABC, regardless of menopausal status.

The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats.

BACKGROUND: The use of calcineurin inhibitors is a well-known risk factor for hyperuricemia in kidney transplant recipients. We evaluated the effect of febuxostat (Fx), a new uric acid-lowering drug, on hyperuricemia and renal injury in an experimental model of chronic tacrolimus (Tac)-induced nephropathy. METHODS: Chronic Tac nephropathy was induced by administering Tac (1.5 mg/kg/day) to rats on a low-salt diet (0.05%) with oxonic acid (OA, 2%, 0.2 g/kg/day) for 28 days. Two doses of Fx (5 and 10 mg/kg) were concomitantly administered with Tac or vehicle (Vh). We evaluated the effect of Fx on hyperuricemia by measuring serum uric acid (SUA) levels, fractional excretion of uric acid (FEUA), and urate transporters in Tac-induced nephropathy. The effects of Fx on Tac-induced renal injury were evaluated in terms of renal function and arteriolopathy, tubulointerstitial fibrosis, inflammation, and apoptosis. We evaluated oxidative stress as a protective mechanism via xanthine oxidase (XO) activity, and as a marker of oxidative stress (via evaluation of levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-hexenal (4-HHE)). RESULTS: The Tac group showed higher SUA levels and lower FEUA than did the Vh group, but Fx treatment significantly decreased SUA levels in a dose-dependent manner, with an increase of FEUA at a high dose (10 mg/kg). Tac treatment increased urate-anion exchanger 1 and decreased organic anion transporter type 1 expression in renal tubular cells, but Fx treatment reversed the effects on those transporters. Impaired renal function and histological injury (interstitial fibrosis, inflammation, and arteriolopathy) in the Tac group were markedly improved by Fx administration. Increases in apoptotic cell death and activation of proapoptotic caspase-3 by Tac were remarkably decreased by Fx treatment. Tac administration increased the activity of XO in kidney tissue and serum, and the levels of 8-OHdG in urine and 8-OHdG and 4-HHE of kidney tissue, but combined treatment with Fx decreased the levels of these parameters. CONCLUSIONS: Fx is effective in controlling hyperuricemia and in preventing Tac-induced renal injury, via a reduction of oxidative stress. Therefore, a targeted therapy aimed at inhibiting uric acid by Fx may be a useful approach in the management of the progression of nephropathy in renal transplant patients treated with Tac.

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats.

BACKGROUND/AIMS: Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL). METHODS: DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS). The effects of MET on the expression of adenosine monophosphate-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets. RESULTS: IPGTT showed that both TAC and SRL induced hyperglycemia and reduced plasma insulin concentration compared with vehicle. These changes were reversed by addition of MET to SRL but not to TAC. Pancreatic islet cell size was decreased by TAC but not by SRL, but addition of MET did not affect pancreatic islet cell size in either group. MET significantly increased GSIS in SRL- but not in TAC-treated rats. AMPK expression was not affected by TAC but was significantly decreased in SRL-treated islets. Addition of MET restored AMPK expression in SRL-treated islets but not in TAC-treated islets. CONCLUSIONS: MET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.

Clinical Significance of Pre-Transplant Arterial Stiffness and the Impact of Kidney Transplantation on Arterial Stiffness.

BACKGROUND: Arterial stiffness is closely associated with cardiovascular disease (CVD) in end stage renal disease (ESRD) patients. However, the clinical significance of pre-transplant arterial stiffness and the impact of kidney transplantation (KT) on arterial stiffness have not yet been determined. METHOD: We measured the brachial-ankle pulse wave velocity (baPWV) before KT and one year after KT. We evaluated the potential utility of pre-transplant baPWV as a screening test to predict CVD. The impact of KT on progression of arterial stiffness was evaluated according to changes in baPWV after KT. The factors that influence the change of baPWV after KT were also examined. RESULT: The mean value of pre-transplant baPWV was 1508 ± 300 cm/s in ESRD patients; 93.4% had a higher baPWV value than healthy controls. Pre-transplant baPWV was higher in patients with CVD than in those without CVD (1800 ± 440 vs. 1491 ± 265 cm/s, p<0.05), and was a strong predictive factor of CVD (OR 1.003, p<0.05). The optimal cut-off value of baPWV for the detection of CVD was 1591 cm/s, and this value was an independent predictor of CVD in KT recipients (OR 6.3, p<0.05). The post-transplant baPWV was significantly decreased compared to that of pre-transplant rates (1418 ± 235 vs. 1517 ± 293 cm/s, p<0.05), and progression of arterial stiffness was not observed in 86.9% patients. Logistic regression analysis revealed that higher body mass index and the degree of increase in calcium levels were independent risk factors that affected baPWV after KT. CONCLUSIONS: Evaluation of arterial stiffness with baPWV is a useful screening test for predicting CVD after KT, and KT is effective in preventing the progression of arterial stiffness in ESRD patients.

Immunologic and non-immunologic complications of a third kidney transplantation.

BACKGROUND/AIMS: Patients who undergo repeat kidney transplantations (KTs) are considered at high risk for experiencing immunologic and non-immunologic complications. In this study, we investigated the clinical outcomes, including medical and surgical complications, of patients who underwent a third KT at our center. METHODS: Between March 1969 and December 2012, a total of 2,110 KTs were performed at the Seoul St. Mary's Hospital. Of them, we examined 11 patients who underwent a third KT, and investigated the allograft outcomes and complication rates. RESULTS: The mean follow-up duration after KT was 72.4 ± 78.3 months. The mean age at KT was 38.2 ± 8.0 years, and seven patients (63.6%) were males. Nine patients (81.8%) underwent living-donor KT. A cross-match test yielded positive results in four of the nine patients, and all underwent pretransplant desensitization therapy. After KT, three patients (27.2%) showed delayed graft function. Acute rejection developed in four patients (36.4%), and surgical complications that required surgical correction occurred in three patients. Allograft failure developed due to acute rejection (n = 3) or chronic rejection (n = 1) in four patients. Allograft survival rates at 1, 5, and 10 years were 81.8%, 42.9%, and 42.9%, respectively; however, the allograft survival rate at 5 years was > 80% in patients who underwent KT only after results of the panel reactive antibody test became available. CONCLUSIONS: Thus, a third KT procedure may be acceptable, although aggressive pretransplant immune monitoring and patient selection may be required to reduce the risks of acute rejection and surgical complications.

Fatal Breakthrough Mucormycosis in an Acute Myelogenous Leukemia Patient while on Posaconazole Prophylaxis.

Posaconazole is a new oral triazole with broad-spectrum antifungal activity. Posaconazole has also shown a significant advantage of preventing invasive fungal infection compared to fluconazole or itraconazole in patients with prolonged neutropenia. Indeed, posaconazole has been commonly used for antifungal prophylaxis in patients undergoing remission induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. We experienced a case of fatal mucormycosis despite posaconazole prophylaxis. To our knowledge, this is the first reported case of fatal breakthrough mucormycosis in a patient receiving posaconazole prophylaxis during remission induction chemotherapy in Korea. This case demonstrated that breakthrough fungal infection can occurs in patients receiving posaconazole prophylaxis because of its limited activity against some mucorales.

Experience of advance directives in a hospice center.

To protect patient autonomy when confronting death, the importance of advance directives (ADs) has recently became an issue and gradually accepted in Korea. However, in real practice, ADs were not completed by patients but their families in most cases. To analyze the current situation of performing ADs, we reviewed medical charts of 214 terminal cancer patients admitted to the hospice center from October 2012 to September 2013. Seventy-six (35.5%) patients completed ADs. All ADs were completed by patients themselves. The most common reason for not completing ADs was poor physical and/or mental condition. As a proxy, the majority of patients preferred their spouses (55.3%). Few patients wanted life sustaining treatment (1.3%), however palliative sedation was accepted in 89.5%. The median timing of ADs after admission was three (0-90) days, and duration of survival since ADs was 22 (1-340) days. In conclusion, approximately one third of terminal cancer patients completed ADs by themselves. Considering that patient's poor condition is the main reason for not completing ADs, earlier discussion regarding ADs is necessary to enhance patients' participation.

Pancreatic adenocarcinosarcoma of monoclonal origin: a case report.

Adenocarcinosarcoma, a neoplasm containing both carcinomatous and sarcomatous components, is a rare form of a cancer and the pathophysiology is currently poorly understood. Moreover, definitive treatment guidelines for this disease have not yet been established. Pancreatic adenocarcinosarcoma is even more rare and the prognosis is fatal. Here, we report a case of a 77-year-old male with pancreatic adenocarcinosarcoma and metastasis to the liver. The patient presented at our hospital with uncontrolled glucose levels and diabetes mellitus. The patient's laboratory findings were unremarkable with the exception of elevated carbohydrate antigen 19-9 levels. Biopsies of the tumors in the pancreas and the liver revealed two types of tumors: pancreatic adenocarcinoma and a poorly differentiated sarcoma. To determine if KRAS mutations were present, we performed a peptide nucleic acid (PNA) clamp PCR-based assay. DNA sequencing by PNA clamp PCR identified a point mutation in codon 12 of exon 2 within KRAS from both tumor types. Because the KRAS mutation is observed in both tumor components, our findings support a monoclonal tumor origin followed by subsequent divergent differentiation into the sarcomatous and carcinomatous tumor populations. After we considered the patient's status and the late stage of tumor detection, gemcitabine chemotherapy was administered.

Trichinosis caused by ingestion of raw soft-shelled turtle meat in Korea.

Reptiles, unlike mammals, have been considered to be unsuitable hosts of Trichinella spp., though larvae have been detected in their muscles and human outbreaks related to their consumption have, in fact, occurred. Herein we report 2 Korean cases of trichinosis, possibly transmitted via consumption of reptile meat. Both patients suffered from myalgia, headache, and facial edema. Laboratory examinations revealed leukocytosis with eosinophilia (54% and 39%, respectively) and elevated creatinine phosphokinase. ELISA was performed under the suspicion of trichinosis, showing positivity at the 29th and 60th day post-infection. Since they had consumed raw soft-shelled turtle meat, turtle was strongly suggested to be an infection source of trichinosis in Korea next to the wild boar and badger.

Pulmonary cryptococcosis mimicking primary lung cancer with multiple lung metastases.

Cryptococcosis is an invasive fungal infection, which is more common in immunocompromised patients. However, pulmonary cryptococcosis can occur in immunocompetent patients and should be considered on a differential diagnosis for nodular or mass-like lesions in chest radiograph. Recently, we experienced a patient with pulmonary cryptococcosis, successfully treated with oral fluconazole therapy. A 74-year-old female patient was referred for an evaluation of abnormal images, a large consolidative mass with multiple nodular consolidations and small nodules that mimics primary lung cancer with multiple lung to lung metastases. Computed tomography-guided lung biopsy confirmed the diagnosis of pulmonary cryptococcosis. The follow-up image taken after 4 months with oral fluconazole treatment showed marked improvement.