Analysis of a pre-2017 follicular variant papillary thyroid carcinoma cohort reclassified as noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP): an 11-year retrospective single institution experience.

INTRODUCTION: Noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP), represents a distinct class of thyroid neoplasms with very low risk of adverse outcome and a set of strict histologic criteria. Introduction of NIFTP as a non-cancer has had an appreciable decrease in risk of malignancy and body of literature on this entity continues to grow. In this study, we reviewed clinical, fine-needle aspiration cytology (FNAC), imaging, and molecular findings of histologically proven NIFTPs at our institution. MATERIALS AND METHODS: Thyroid resections during an 11-year period, with histologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC), were retrospectively reviewed to identify NIFTP. Ultrasonographic appearance, FNA findings, and molecular findings were also reviewed. RESULTS: Of 244 cases of FVPTC identified, 74 (30%) cases were reclassified as NIFTP. Mean tumor size was 2.5 cm. Of 33 patients with lymph node dissection, none had lymph node metastases. On imaging, 36 NIFTP (49%) showed vascularity, 25 (33%) were isoechoic to hypoechoic, there were calcifications in 14 cases (19%), and 7 cases (9%) showed a hypoechoic rim. Bethesda III/IV was the most common interpretation rendered on FNAC (31%). Seven cases had NRAS mutations and 1 case had BRAF V600E mutation. The remaining cases were either negative for BRAF V600E or had no identifiable molecular alterations. CONCLUSIONS: A significant percentage of tumors previously diagnosed as FVPTC were reclassified as NIFTP. This tumor cannot be reliably diagnosed preoperatively on FNAC, shows no characteristic features on ultrasound and has low suspicion of malignancy. BRAF V600E mutations are infrequent in NIFTP.

Evidence-based recommendations for induction and maintenance treatment of newly diagnosed transplant-ineligible multiple myeloma patients.

There is increasing evidence regarding the role of various maintenance therapy (MT) strategies after initial induction to treat newly diagnosed transplant-ineligible patients with MM. We reviewed the literature on available regimens for patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM). Lenalidomide (R)-based regimens are still the front-line therapy, but there is an increasing use of bortezomib-based regimens. The MT regimen is mainly based on the initial induction regimen. MT has shown survival benefits compared with patients without maintenance therapy. The most common adverse effects of MT include anemia, neutropenia, thrombocytopenia, infections, and peripheral neuropathy. In conclusion, induction followed by maintenance based on lenalidomide, bortezomib, ixazomib, or daratumumab-based regimens has shown promising results. Therefore, it is essential to conduct more clinical trials to better understand the role of MT in the treatment of NDMM patients who are not candidates for autologous stem cell transplantation.

Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature.

Multiple myeloma (MM) remains an incurable disease with the majority of patients experiencing disease relapse despite response to initial therapy. Antibody-drug conjugates (ADCs) and bispecific T-cell engagers are innovative immunotherapeutic approaches currently in development for the treatment of MM. This systematic review summarizes the efficacy and safety of ADCs and bispecific T-cell engagers in relapsed refractory (RR) MM patients from 2010 to date. Comprehensive literature search was conducted on PubMed, EMBASE, Wiley Cochrane Library, Web of Science, and Clinicaltrials.gov . A total of 13 studies (n = 529) met inclusion eligibility. All studies were prospective in nature investigating ADCs or bispecific T-cell engagers in RR MM; 10 trials were phase 1 and 3 were phase 2. The median age of patients ranged from 24 to 82 years. Among trials with ADC regimens, the overall response (OR) ranged from 34 to 60% and complete response (CR) ranged from 3 to 6%. The most common non-hematologic adverse event (AE) of ADCs was keratopathy, while anemia and thrombocytopenia were the most common hematological AEs. With bispecific T-cell engagers , ORR ranged from 31 to 83%, CR ranged from 7 to 22%, and partial response (PR) ranged from 5 to 16%. The most common non-hematologic AE of bispecific T-cell engagers was cytokine release syndrome (CRS) while the most common hematological AE was neutropenia. Initial data appears to show good clinical activity and tolerable safety profiles, making ADCs and bispecific T-cell engagers promising agents for RRMM. Future studies with newer combinations and a longer follow-up are needed to determine the precise role of these novel therapies in the evolving paradigm of MM treatment.

Systematic Review and Meta-analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes.

Acute lymphoblastic leukemia (ALL) typically responds better when treated with multiagent chemotherapy in the pediatric and young adolescent populations. Treatment of relapsed/refractory (RR) ALL remains a challenge. Even after stem-cell transplantation and intensive chemotherapy, the prognosis of RR-ALL remains grave. The advent of chimeric antigen receptors has demonstrated promising results in RR-ALL. Chimeric antigen receptor-modified T cells (CAR-T) and engineered T cells are used to target cancer cells. In 2017, the US Food and Drug Administration approved CD19-specific CAR-T (tisagenlecleucel) therapy for RR-B-cell ALL in patients under 25 years old. In this systematic review, we discuss the efficacy and safety of CD19-specific CAR-T therapy in RR-B-cell ALL in the pediatric and young adult population. We searched the PubMed, Embase, Web of Science, Cochrane Library, and clinical trials databases. A total of 448 patients received a CD19-specific CAR-T product, and 446 patients had evaluable data. The age range was 0 to 30 years. The incidence rate of complete remission was 82%. The cumulative incidence of relapse after CD19-specific CAR-T therapy is 36%. Similarly, the incidence rate of grade 3 or higher adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections, and cytokine release syndrome were 38%, 23%, 18%, 29%, and 19%, respectively. Our subgroup analysis shows the incidence rate of minimal residual negative complete remission was 69% with the CD28z costimulatory domain, 81% with the 4-1BB domain, and 77% with fourth-generation CD19-specific CAR-T therapy.

Febuxostat Modulates MAPK/NF-κBp65/TNF-α Signaling in Cardiac Ischemia-Reperfusion Injury.

Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR-control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-α, IL-6, and NF-κB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-κBp65/TNF-α pathway.

Galangin ameliorates cisplatin induced nephrotoxicity in vivo by modulation of oxidative stress, apoptosis and inflammation through interplay of MAPK signaling cascade.

BACKGROUND AND PURPOSE: Cisplatin is a widely used chemotherapeutic agent but now-a-days its usage is limited in clinical chemotherapy because of its severe nephrotoxic effect on renal tissues. Galangin, a flavonoid obtained from ginger family has been demonstrated to have antioxidant, anti-apoptotic and anti-inflammatory properties. This study is aimed to investigate the possible ameliorative effect of galangin in a rodent model of cisplatin-induced nephrotoxicity. MATERIAL AND METHODS: Adult male albino wistar rats were divided into six groups (n=6) viz normal, cisplatin-control, galangin (25, 50 and 100mg/kg p.o.) and per se (100mg/kg galangin, p.o.). Galangin was administrated orally to the rats for a period of 10 days. On the 7th day of the treatment, nephrotoxicity was induced in all the groups by a single dose of cisplatin (8mg/kg, i.p.) (except normal and per se group). On the 11th day, the rats were anaesthetized and blood was withdrawn via direct heart puncture for biochemical estimation. Rats were sacrificed and kidneys were isolated and preserved for evaluation of histopathological, ultra structural immunohistochemical studies and western blot analysis. RESULTS: Cisplatin significantly impaired renal function and increased oxidative stress and inflammation. It also increased expression of pro-apoptotic proteins Bax and caspase-3 and decreased the expression of the anti-apoptotic protein Bcl-2. Histological and ultrastructural findings were also supportive of renal tubular damage. Pretreatment with galangin (100mg/kg p.o.) preserved renal function, morphology, suppressed oxidative stress, inflammation and the activation of apoptotic pathways. TUNEL assay showed decreased DNA fragmentation on galangin pre-treatment. Furthermore, galangin (100mg/kg) pre-treatment also reduced the expression of NFκB along with proteins MAPK pathway i.e. p38, JNK and ERK1/2. CONCLUSION: In conclusion, Galangin (100mg/kg, p.o.) significantly ameliorated cisplatin induced nephrotoxicity by suppressing MAPK induced inflammation and apoptosis.

Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-ß1-MAPK-fibronectin pathways.

Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti-inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5-20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-ß1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-α, IL-6, and NF-κB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway.

Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol.

There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg/kg; i.p.), and rats with glucose level >250 mg/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL/kg; i.p.) and kaempferol (20 mg/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NF-κB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1/2 (ERK1/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated myocardial ischemia-reperfusion injury in diabetic rats by reducing AGE-RAGE/ mitogen activated protein kinase (MAPK) induced oxidative stress and inflammation.