A short 🧵 on its history and pivotal moments, covering key trials to show realignment of #hematology#rheumatology, disciplines that belong to each other♥️
In the early 1940s, folic acid was isolated and found to cure some patients with megaloblastic anemia, not responding to vitamin B 12.
Also, patients with acute leukemia were treated with folic acid or folate conjugates (polyglutamated forms of folic acid)
👉proved ineffective:(
The subsequent demonstration by Heinle and Welch that a diet-induced deficiency of folic acid caused a decrease in the leukemia cell count, stimulated efforts, primarily by the Lederle group, to synthesize analogs of folic acid.
Overview of isolation and synthesis of folates👇
Era of chemotherapy:
-Aminopterin (4-aminopterolylglutamic acid),
proved to be a powerful antagonist, shown by Farber et al in a landmark paper, to produce remissions in children with acute lymphocytic leukemia (ALL)
-nitrogen mustard caused regressions in patients with lymphoma
Aminopterin interfered with proliferation of connective tissue. This led to a study in 1951 by Gubner et al. in several patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis👉rapid improvement in RA signs and symptoms 6/7 seven patients
In 1956, studies of leukemia-bearing mice showed that methotrexate, another folate analog, had a therapeutic index superior to that of´aminopterin; based on these studies, methotrexate supplanted
aminopterin in the clinic.
Lessons learnt early:
-drug resistance occurs rapidly if cure is not achieved (for most tumors within 4-6 months)👉treatment failure
-curable diseases with drugs: Hodgkin's, DLBCL, certain childhood solid tumors
-treatment with MTX not associated with long term
side effects
Other drugs were also found to be useful in the treatment of ALL, in particular 6-mercaptopurine (6MP), prednisone, and vincristine.
A very important study by the Acute Leukemia B cooperative group showed that 6MP-MTX was better than either drug used alone.
The next major advance (1971, 1978) that led to cures in 50% of the patients was the use of intrathecal methotrexate with adequate central nervous system (CNS) irradiation, for prophylaxis of sanctuary disease.
In 1972, Rex Hoffmeister, reported positive effects with intramuscular MTX (10-15 mg per week) in 29 patients with RA. 11/2929 patients had “major” clinical improvements and 14 had “moderate” improvements in RA activity. These patients underwent treatment for up to 25 months.
In 1983, a RCT crossover study of 35 patients with refractory RA was done.
Initial MTX dose: 7.5 mg per week with an increase at 6 weeks to 15 mg/w.
- 3 weeks after MTX initiation: >50% with >50% improved joint tenderness index
- 39% with improvement in the joint swelling index
The other pivotal study was an NIH-funded study network of 189 patients with active RA. Patients initially received MTX at 7.5 mg per week with dose escalation to 15 mg per week.
-32% had >50% decrease in the joint tenderness index
-21% with reduction in joint swelling index
Graft-versus-host disease:
In 1986, Storb and colleagues reported that the combination of MTX with cyclosporine A was superior to CSA alone in a series of prospective randomized phase 3 trials. This remains one of the most widely used regimen today as prophylaxis regimen in BMT.
If we go back in time 75 years and tell Dr Farber, that 21st-century medicine would utilize MTX more in rheumatology but also show the widespread use in oncology and hematology, he might scratch his head...that's a lovely thought, showing the beauty of medical research!
Rule 1: Lead by example
As a mentor, your actions speak louder than words. Demonstrate the ethics, dedication, and passion you wish to instill in your mentees.
Practice what you preach🙏
Rule 2: Listen actively
Effective mentoring starts with listening. Understand your mentee's needs, fears, and aspirations. This builds trust and opens up more honest communication.
Short intro to sickle cell disease (SCD):
-group of inherited red blood cell disorders
-affects ~ 1 in 500 African American and 1 in 36,000 Hispanic American children
-results in anemia
-main clinical feature is acute painful crisis
👉 often requires hospitalization
2/15
Acute pain:
-one of the most common types of vaso-occlusive events in SCD
BUT
-not all patients are in true crisis
BUT
-pain shouldnt be allowed to progress to crisis
AND
-most patients grow with pain, so ask them how severe it is❗️
-do not to delay analgesia
3/15
Intro:
-rare but underestimated bleeding disorder
-lab and clinic similar to inherited form
-usually occurs more frequently in adults with no history of bleeding
-renewed interest
👉association with 🫀disorders (eg aortic stenosis), cancer, autoimmune disease...
2/14
History I - (inherited) VWS:
-1924
-5-year-old girl from 🇫🇮 brought to hospital in Helsinki, seen by physician Erik Adolf von Willebrand
-assessed 66 members of her family
-reported in a 1926 a previously undescribed bleeding disorder, called "Hereditary pseudohemophilia"
3/14
😱Gastrointestinal (GI) manifestations in hematology😱
A short visual 🧵with diagnosis
1/19
Intro:
-lympho-/myeloproliferative disorders
-nodal and/or extranodal
-GI tract one of the most common extranodal sites
-diagnosis of GI hematologic malignancy challenging
👉esp in absence of documented nodal/extranodal disease
👉due to higher incidence of other pathologies
2/19
Importance of imaging:
-although tissue biopsy is often required to reach the definitive diagnosis, imaging plays a crucial role in raising suspicion of underlying hematologic malignancy
-imaging also guides biopsies, staging, and evaluating response to treatment
3/19
History part I:
-1928, Maurice Richter reported generalized swelling of lymph nodes, liver + spleen in a patient with chronic lymphocytic leukemia (CLL)
-due to infiltration by rapidly growing cells
👉termed it generalized reticular cell sarcoma
-patient died after 22 days
2/20
History part II:
-1964, Lortholary described case series of 14 patients with CLL developing malignant reticulopath
👉occurrence of diffuse large B cell lymphoma (DLBCL)
👉named it Richter's transformation (RT)
-DLBCL most common
-also Hodgkin lymphoma, T cell lymphoma
3/20
When I started med school, I subscribed to the New England Journal of Medicine. Apart from published trials, case records are the world's treasure for education & help navigate clinical courses & differentials better than any class.
A visual 🧵of selected cases #MedTwitter #MedX
50-year-old man with back pain, fatigue, weight loss, and knee swelling
Final diagnosis: Ankylosing spondylitis
-affects 0.5% of population
-strongly associated with HLA-B27 allele
-90% of patients with ankylosing spondylitis are positive for HLA-B27 nejm.org/doi/full/10.10…
60-year-old man with bone pain and skeletal lesions on imaging
Final diagnosis: epithelioid hemangioendothelioma
-affects <300 patients per year in US, ~1% of all vascular neoplasms nejm.org/doi/full/10.10…