NEJM editorial Flashcards
hormone-receptor–positive, HER-2 negative metastatic breast cancer first line treatment
Post-menopausal women - 1st line:
- CDK 4/6 inhibitor + aromatase inhibitor
- fulvestrant and a CDK 4/6 inhibitor is an appropriate alternative
Pre-menopausal women - 1st line:
- Ovarian suppression or ablation + ET + a targeted agent (e.g. CDK4/6 inhibitor)
Background info:
- three agents (palbociclib, abemaciclib, and ribociclib, respectively all CDK4/6 inhibitors) significantly prolonged progression-free survival when administered in combination with endocrine therapy as first-line treatment in women with hormone-receptor–positive metastatic breast cancer. The MONALEESA-7 trial included pre-menopausal women showing positive results across the whole group. A premenopausal women in whom menopause is induced by ovarian suppression can be treated in the same way as a women with natural menopause PALOMA-2 (Palbociclib: Ongoing Trials in the Management of Breast Cancer–2), MONARCH-3, and MONALEESA-2 (Mammary Oncology Assessment of LEE011’s [Ribociclib’s] Efficacy and Safety–2)
- Only approved for post-menopausal women on the PBS
CDK4/6 inhibitors (3)
palbociclib, abemaciclib, and ribociclib
what is the mechanism of prostate cancer progression after androgen deprivation therapy with castration
androgens produced by the tumour
what drugs were developed to inhibit residual androgen stimulation of tumour tissue (in the case of castration-resistant prostate cancer)
abiraterone acetate and enzalutamide
what other drug is administered with abiraterone
low dose corticosteroids (10mg prednisolone)
Background:
- abiraterone leads to decreased cortisol production and increased build up of mineralcorticoids which causes hypokalaemia
MOA of abiraterone
inhibits the enzyme cytochrome P450 17A1 (CYP17A1), which is critical in the production of androgens
MOA of enzalutamide
binds the androgen receptor and inhibits its nuclear translocation, DNA binding, and transcription of androgen-dependent genes
first line treatment in metastatic, hormone-sensitive prostate cancer
- ADT with either medical or surgical orchiectomy as a component of the initial treatment to suppress serum testosterone levels for all patients requiring systemic therapy
- Surgical orchiectomy - bilateral orchiectomy
- Medical orchiectomy - most commonly continuous treatment with a gonadotropin-releasing hormone (GnRH) agonist, which suppresses luteinizing hormone production and, therefore, the synthesis of testicular androgens
- For men with high-risk disseminated prostate cancer: ADT with either docetaxel or abiraterone rather than using ADT alone (choice of agent based on SE profile)
- Enzalutamide has also been shown to prolong survival free progression in an interim analysis when encoporated into a ADT regimen. However, it has a much higher cost than abiraterone
Enzalutamide or abiraterone w androgen-deprivation therapy https://www.nejm.org.acs.hcn.com.au/doi/full/10.1056/NEJMe1906363
management of castration resistant metastatic carcinoma of the prostate
Clinical pathological features of aggressive variant prostate cancer:
- taxane + platinum based chemotherapy regimen
Assess for Lynch and BRCA genes
- Consider pembro/PARP inhibitor
Consider combination of docetaxel, antiadrogens if not used before
enzalutamide or abiraterone
pathogenesis of membranous nephropathy
IgG deposition in the subepithelial space of glomerular capillaries
membranous nephropathy with nephrotic range proteinuria treatment
currently cyclosporin or cyclophosphamide but MENTOR study showed superior efficacy of rituximab https://www.nejm.org.acs.hcn.com.au/doi/full/10.1056/NEJMe1906666
short-term effect of SGLT2 on eGFR
decreases eGFR due to vasoconstriction of the afferent arteriole due to increased sodium delivery to the distal renal tubule which is sensed by the juxtaglomerular apparatus
effect of SGLT2 on renal outcomes
improves progression of kidney disease and death from renal or cardiovascular outcome this is because the SGLT2 inhibition causing decreased glomerular perfusion and intraglomerular pressure. The level of angiotensin II decreases and atrial natriuretic peptide too alongside w inflammation and an increase in intrarenal oxygenation.
most commonly genetic abnormality in CLL
deletion of chromosome arm 13q –> leads to loss of microRNAs mir-15a and mir-16-1, which act as inhibitors of BCL2 expression
venetoclax MOA
BCL2 inhibitor
evidence for best agents in first line CLL
ibrutinib and venetoclax used in conjunction in the NEJM May 2019 paper to induce minimal residual disease remission in 60%. dual agent did not increase toxicity. ibrutinib was initiated first before venetoclax to reduce tumour burden to prevent TLS
Other options for 1st line therapy in symptomatic CLL:
- Ibrutinib alone
- Ibrutinib + ritux
- Venetoclax + obinutuzumab (another anti-CD 20 humanized monoclonal antibody)
- Venetoclax alone
https: //www.nejm.org.acs.hcn.com.au/doi/full/10.1056/NEJMe1904362
most commonly genetic abnormality in CLL
deletion of chromosome arm 13q –> leads to loss of microRNAs mir-15a and mir-16-1, which act as inhibitors of BCL2 expression
major initial AE of venetoclax
TLS - need for graduated dosing
first line in frail and elderly MM
Currently on UTD:
- bortezimib + len + dex OR dara + len + dex
- len + dex can be used in really frail patients
Background:
Lenalidomide and dexamethasone administered until disease progression resulted in superior progression-free and overall survival and had a more favorable safety profile than treatment with thalidomide plus melphalan and prednisone. The incorporation of daratumumab led to a substantially higher overall rate of response; an increased depth of response, including a significantly higher percentage of patients who were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as evaluated by next-generation sequencing; and significantly longer progression-free survival, with a higher percentage of patients having progression-free survival at 30 months (the primary end point) than lenalidomide and dexamethasone alone. However, the addition of dara leads to a higher incidence of neutropenia and infections, including pneumonia
Daratumumab MOA
IgGκ monoclonal antibody that targets CD38 and exhibits pleiotropic antitumor activity. Causes cells expressing CD38 to apoptose via ADCC and complement activity.
morphology of structural heart disease VT vs genetic VT
structural heart disease is usually monomorphic where as genetic causes are associated with channelopathies and usually polymorphic
Timing of coronary angiogram in out of hospital cardiac arrests
Immediate for STEMI patients
Unclear for everyone else.
Background (n engl j med 380;15):
- COACT trial showed no survival benefit in randomising to immediate coronary angio vs delayed
- Subgroup analysis showed possible benefit in: patients >70 yr, history of coronary artery disease
Anti-thrombotic therapy after PCI in atrial fibrillation patients
Still triple therapy with anticoagulant + aspirin + clopidogrel. NOACs appear superior to warfarin in patients who are eligible for it.
Aspirin has higher bleeding rates (mainly GI) but the study is not powered enough to see whether there is increased rate of coronary ischaemic events when aspirin is omitted.
It may be reasonable to have dual therapy (NOAC + clopidogrel) instead of triple therapy in patients with elective PCI with low angiographic and clinical risk.
Reference: NEJM editorial: Refining Antithrombotic Therapy for Atrial Fibrillation and Acute Coronary Syndromes or PCI
TAVR vs surgical valve replacement in severe aortic stenosis
2 NEJM RCTs in 2019 (Mack et al, Popma et al) found that TAVR was non inferior and even superior than surgical aortic valve replacement.
Other considerations:
- Patient <50 should have a mechanical valve unless there is a contraindication to anticoagulation
- The trials were predominantly men and noone had bicuspid valves (which make up 50% of aortic stenosis cases)
Most common mutation in hepatocellular carcinomas
Mutations in the TERT promoter (60% of cases); normally seen in the dysplastic nodule. Of note, TERT promoter is a recurrent insertion site for the HBV genome.
Reference:
n engl j med 380;15 nejm.org April 11, 2019
Supply of benign vs malignant liver nodules
Benign nodules are supplied by the portal system where as malignant nodules are supplied by the hepatic artery
HCC solitary nodule <2cm with preserved liver function
Ablation or resection
HCC solitary nodule >2cm or 2-3 nodules all <3cm with preserved liver function treatment
Resection and if not feasible, transplant.
If not a transplant candidate, ablation
Multinodular HCC with preserved liver function. 3 or more nodules or 2 or more nodules if 1 nodule >3cm.
No metastatic spread/macrovascular invasion.
Treatment?
Chemoembolization
Metastatic HCC treatment with preserved liver function
Sorafenib or lenvatinib
HCC criteria for liver transplantation
a single nodule ≤5 cm in diameter or up to three nodules, none larger than 3 cm in diameter
(The Milan criteria for liver transplantation)
Strongest independent risk for contrast-assocaited acute kidney injury
severe chronic kidney disease
what kind of contrast agent is recommended to prevent contrast associated AKI?
low-osmolality and iso-osmolality agents
Pathophysiology of contrast induced AKI
- Nephrotoxicity
- Tubular damange
- Increased in viscosity of tubular fluids -> tubular obstruction
- Disturbance in renal blood flow
- Arteriolar vasoconstriction
- Increased in blood osmolality and viscosity -> microvascular thrombosis
Ivacaftor
potentiator of residual CFTR function that has been approved for pa- tients with cystic fibrosis with gating and some splicing CFTR mutations
Metastatic renal cell carcinoma management
In 2018, the combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, were shown to have better efficacy than sunitinib.3 This combination, which was approved recently by the Food and Drug Administration and the European Medicines Agency, is the new standard of care, primarily in intermediate- and poor-risk patients.
In 2019 NEJM March 21st issue, the editorial discussed 2 new phase 3 trials that showed promising results for a PD-1 combined with axitinib and PD-L1 combined with axitinib
What is the most common organism found in aspiration pneumonia?
Community acquired: Strep, staph
Hospital acquired: gram negatives
Anaerobes are more rare now
Management of stage 1/2 HER-2 positive breast cancer who has residual disease found after surgery with previous neoadjuvant therapy
trastuzumab or Trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor
https://www.nejm.org.acs.hcn.com.au/doi/full/10.1056/NEJMoa1814017
omadacycline
new tetracycline
not on PBS
