When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Optimal timing of resumption of therapeutic anticoagulation (AC) in patients with hemorrhagic stroke or intracranial hemorrhage (ICH) is unclear because of lack of randomized controlled trials, but existing evidence suggests that 4-8 weeks may be reasonable in our patient (1). 

The American Heart Association/American Stroke Association 2015 guidelines recommend avoiding AC for at least 4 weeks in patients without mechanical heart valves (class IIB-very weak), while 1 study reported that prediction models of ICH in atrial fibrillation at high risk of thromboembolic event suggest that resumption of AC at 7-8 weeks may be the “sweet spot” when weighing safety against efficacy of AC in this patient population (1-3).

Two meta-analyses (1 involving patients with non-lobar ICH, another ICH in patients with nonvalvular atrial fibrillation) found that resumption of AC ranging from 10 to 44 days following ICH may be associated with decrease rates of thromboembolic events without significant change in the rate of repeat ICH (4,5).

There are many limitations to the published literature including their retrospective nature, unreported location and size of ICH in many studies, and use of warfarin (not DOACs) as an AC agent (1).

Clearly we need randomized controlled trials to answer this important question. In the meantime, a heavy dose of clinical judgement on a case-by-case basis seems appropriate.

Bonus Pearl: Did you know that lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) usually due to hypertensive vessel disease (1)? 

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1. Gibson D et al. When is it safe to resume anticoagulation in my patient with hemorrhagic stroke. The Hospitalist, February 5, 2019. https://www.the-hospitalist.org/hospitalist/article/193924/neurology/when-it-safe-resume-anticoagulation-my-patient-hemorrhagic/page/0/1
2. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60. https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000069
3. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20 https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.116.014643
4. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600. https://www.ahajournals.org/doi/full/10.1161/strokeaha.116.016327
5. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730065/

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

Short answer: Yes! Although we usually associate acute acalculous cholecystitis (AAC) with critically ill patients (eg, with sepsis, trauma, shock, major burns) in ICUs, AAC is not as rare as we might think in ambulatory patients. In fact, a 7 year study of AAC involving multiple centers reported that AAC among outpatients was increasing in prevalence and accounted for 77% of all cases (1)!

Although the pathophysiology of ACC is not fully understood, bile stasis and ischemia of the gallbladder either due to microvascular or macrovascular pathology have been implicated as potential causes (2). One study found that 72% of outpatients who developed ACC had atherosclerotic disease associated with hypertension, coronary, peripheral or cerebral vascular disease, diabetes or congestive heart failure (1). Interestingly, in contrast to calculous cholecystitis, “multiple arterial occlusions” have been observed on pathological examination of the gallbladder in at least some patients with ACC and accordingly a name change to “acute ischemic cholecystitis” has been proposed (3).

AAC can also complicate acute mesenteric ischemia and may herald critical ischemia and mesenteric infarction (3). The fact that cystic artery is a terminal branch artery probably doesn’t help and leaves the gallbladder more vulnerable to ischemia when arterial blood flow is compromised irrespective of the cause (4).

Of course, besides vascular ischemia there are numerous other causes of ACC, including infectious (eg, viral hepatitis, cytomegalovirus, Epstein-Barr virus, Salmonella, brucellosis, malaria, Rickettsia and enteroviruses), as well as many non-infectious causes such as vasculitides and, more recently, check-point inhibitor toxicity (1,5-8).

Bonus Pearl: Did you know that in contrast to cholecystitis associated with gallstones (where females and 4th and 5th decade age groups predominate), ACC in ambulatory patients is generally more common among males and older age groups (mean age 65 y) (1)?


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1. Savoca PE, Longo WE, Zucker KA, et al. The increasing prevalence of acalculous cholecystitis in outpatients: Result of a 7-year study. Ann Surg 1990;211: 433-37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358029/pdf/annsurg00170-0061.pdf
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22. https://www.cghjournal.org/article/S1542-3565(09)00880-5/pdf
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52. https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2168.1997.02775.x?sid=nlm%3Apubmed
4. Melo R, Pedro LM, Silvestre L, et al. Acute acalculous cholecystitis as a rare manifestation of chronic mesenteric ischemia. A case report. Int J Surg Case Rep 2016;25:207-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941110/
5. Aguilera-Alonso D, Median EVL, Del Rosal T, et al. Acalculous cholecystitis in a pediatric patient with Plasmodium falciparum infection: A case report and literature review. Ped Infect Dis J 2018;37: e43-e45. https://journals.lww.com/pidj/pages/articleviewer.aspx?year=2018&issue=02000&article=00020&type=Fulltext  
6. Kaya S, Eskazan AE, Ay N, et al. Acute acalculous cholecystitis due to viral hepatitis A. Case Rep Infect Dis 2013;Article ID 407182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784234/pdf/CRIM.ID2013-407182.pdf
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12. https://casereports.bmj.com/content/12/4/e228306
8. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J ImmunoTherapy of Cancer 2019;7:118. https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0604-2



Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

Absolutely! Although tracheobronchial calcification (TBC) is often found as part of normal aging process in the elderly, especially women, long-term warfarin use has also been implicated as a cause of TBC, even among those with less advanced age (1-4).

In a cohort of patients 60 years of age or older, radiographic evidence of trachea and bronchi calcification was found in 47% of patients on warfarin (mean age 64 years, mean duration of treatment 6 years) compared to 19% of controls (1). A positive correlation between the duration of warfarin therapy and increased levels of calcification was also found.  Fortunately, TBC is a benign finding and has no health consequences.

As for the mechanism for this rather intriguing phenomenon, the inhibition of a vitamin K-dependent protein that prevents calcification of cartilaginous tissue seems to be the most plausible (1). Although we often think of vitamin-K dependent factors in relation to the coagulation cascade, several vitamin K-dependent proteins also play an important role in the inhibition of calcification in soft tissues and blood vessels (eg, matrix Gla protein-MGP) (5,6).

In fact, rats maintained on warfarin undergo calcification of cartilage and elastic connective tissue, while exposure of the fetus to warfarin during pregnancy is associated with calcifications in and around joints, airway and nasal cartilages (4,7). These observations further support a causative role of warfarin in inducing TBC.


Bonus Pearl: Did you know that MGP deficiency in humans is known as the Keutel syndrome, a rare autosomal recessive disease characterized by several characteristic physical features, including severe cartilage calcifications and depressed nasal bridge?

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  1. Moncada RM, Venta LA, Venta ER, et al. Tracheal and bronchial cartilaginous rings: warfarin sodium-induced calcification. Radiology 1992;184:437-39. https://pubs.rsna.org/doi/10.1148/radiology.184.2.1620843
  2. Thoongsuwan N, Stern EJ. Warfarin-induced tracheobronchial calcification. J thoracic Imaging 2003;18:110-12. https://journals.lww.com/thoracicimaging/Abstract/2003/04000/Warfarin_Induced_Tracheobronchial_Calcification.12.aspx
  3. Nour SA, Nour HA, Mehta J, et al. Tracheobronchial calcification due to warfarin therapy. Am J Respir Crit Care Med 2014;189:e73. https://www.atsjournals.org/doi/full/10.1164/rccm.201305-0975IM
  4. Joshi A, Berdon WE, Ruzal-Shapiro C, et al. CT detection of the tracheobronchial calcification in an 18 year-old on maintenance warfarin sodium therapy. AJR Am J Roentgenol 2000;175:921-22. https://www.ajronline.org/doi/full/10.2214/ajr.175.3.1750921
  5. Wen L, Chen J, Duan L, et al. Vitamin K-dependent proteins involved in bone and cardiovascular health (review). Molecular Medicine Reports 2018;18:3-15. https://www.spandidos-publications.com/mmr/18/1/3/abstract \
  6. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr 2012; 3:166-173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648717/pdf/166.pdf

7.      Price PA, Williamson MK, Haba T, et al. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci  U.S.A 1982;79:7734-8. https://www.ncbi.nlm.nih.gov/pubmed/6984192

My 65 year old patient on chronic warfarin happens to have diffuse tracheobronchial calcification on her chest X-ray. Could warfarin be the culprit?

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?

Most likely!

We should routinely assess for poor sleep as a potential impediment to adequate pain control in our patients. Substantial research supports a bidirectional relationship between pain and sleep.  That is, not only can pain disrupt sleep but sleep quality can also adversely affect pain.1   In fact, even a short-term disturbance in a stable sleep pattern may lower the pain threshold 2 and the ability to tolerate previously controlled pain.3

These observations are thought to result from activated stress responses from poor sleep hygiene which in turn produce cellular oxidative stress and inflammation of tissues and the nervous system. 4 This process can result in a vicious cycle between increasing pain and persistent insomnia.4,5  Breaking this cycle can reduce pain and improve function, among other desired outcomes.

Ongoing insomnia may also be a sign of a variety of other conditions that should be treated, such as mood disorder and sleep apnea. For example, besides standard non-pharmaceutical measures to improve sleep hygiene, continuous positive air pressure (CPAP) can reduce pain and opioid use in the setting of sleep apnea .2,6

Remember also that controlling pain with opioids in hopes of improving sleep may be counterproductive as opioids can contribute to sleep apnea.7,8  Melatonin may be a better sleep aid in this setting. 9


  1. Wei Y, Blanken TF, Van Someren EJW. Insomnia really hurts: effect of a bad night’s sleep on pain increases with insomnia severity. Front Psychiatry 2018;9:377. doi: 10.3389/fpsyt.2018.00377. https://www.ncbi.nlm.nih.gov/pubmed/30210367
  2. Charokopos A, Card ME, Gunderson C, Steffens C, Bastian LA. The association of obstructive sleep apnea and pain outcomes in adults: a systematic review. Pain Med 2018;19(suppl_1):S69-S75. doi: 10.1093/pm/pny140. https://www.ncbi.nlm.nih.gov/pubmed/30203008
  3. Sivertsen B, Lallukka T, Petrie KJ, et al. Sleep and pain sensitivity in adults. Pain. 2015;156:1433-9. https://www.ncbi.nlm.nih.gov/pubmed/25915149
  4. Iacovides S, George K, Kamerman P, Baker FC. Sleep fragmentation hypersensitizes healthy young women to deep and superficial experimental pain. J Pain. 2017;18:844-854. doi: https://doi.org/10.1016/j.jpain.2017.02.436. https://www.ncbi.nlm.nih.gov/pubmed/28300651
  5. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008;137:202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  6. Edwards RR, Almeida DM, Klick B, Haythornthwaite JA, Smith MT. Duration of sleep contributes to next-day pain report in the general population. Pain. 2008 Jul;137(1):202-7. doi: 10.1016/j.pain.2008.01.025. https://www.ncbi.nlm.nih.gov/pubmed/18434020
  7. Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry 2018 20;87:234-244. https://www.ncbi.nlm.nih.gov/pubmed/28734941
  8. Jungquist CR, Flannery M, Perlis ML, Grace JT. Relationship of chronic pain and opioid use with respiratory disturbance during sleep. Pain Manag Nurs 2012;13:70-9. doi: 10.1016/j.pmn.2010.04.003. https://www.ncbi.nlm.nih.gov/pubmed/22652280
  9. Landis CA. Is melatonin the next “new” therapy to improve sleep and reduce pain? Sleep 2014; 37: 1405–1406. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153056/

Contributed by Paul Arnstein, PhD, RN, FAAN, Mass General Hospital, Boston, MA.

My patient with chronic pain complains of difficulty sleeping. Would improving her sleep hygiene impact her pain medication requirement?

Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

Conventional wisdom has been that in active tuberculosis (TB) patients harbor large numbers of replicating Mycobacterium tuberculosis (Mtb), requiring multiple antibiotics to prevent the emergence of resistant mutants. In contrast, Mtb under latent or “inactive” conditions is presumed to have little capacity for mutation due to reduced bacterial replication, thus generally requiring only one antibiotic for preventive therapy.1

However, the assumption that Mtb has a low capacity for mutation in latent TB due to slow bacterial replication has been challenged in recent years. An experimental study in macaque monkeys with latent Mtb infection using whole genome sequencing demonstrated that despite reduced replication, Mtb acquires a similar number of chromosomal mutations during latency as it does during active infection.1

This finding supports the more current and evolving concept of latent TB which assumes diverse mycobacterial growth states, ranging from complete absence of organisms to actively replicating bacterial populations.2 It also explains why, although effective, isoniazid monotherapy may be a risk factor for the emergence of INH resistance in latent TB. 1,3

 Bonus Pearl: Did you know that INH treatment of latent TB in adults is 60-80% protective when given for 6 months, and 90% protective when given for 9 months? 4

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  1. Ford CB, Lin PL, Chase M, et al . Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43:482-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101871/
  2. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res 2011;50:202-12. https://www.ncbi.nlm.nih.gov/pubmed/21717066
  3. Balcells ME, Thomas SL, Faussett PG, et al. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51. https://www.ncbi.nlm.nih.gov/pubmed/16704830
  4. Piccini P, Chiappini E, Tortoli E, et al. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014; 14 (Suppl 1):S4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015485/


Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

Is neurotoxicity caused by cefepime common?

The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1  Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.

Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.In addition,  several case reports of CIN have involved patients with normal renal function. 2  A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!

Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, and increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4



  1. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall. https://www.ncbi.nlm.nih.gov/pubmed/29071284
  2. Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120. https://academic.oup.com/omcr/article/2016/6/118/2362353
  3. Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7. https://www.ncbi.nlm.nih.gov/pubmed/21987544
  4. Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276. https://www.ncbi.nlm.nih.gov/pubmed/29137682


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Is neurotoxicity caused by cefepime common?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

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  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF



My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

Among antihypertensives, most commonly used angiotensin converting enzyme inhibitors (ACE-Is) such as captopril, enalapril, lisinopril, and benazepril are at least partially removed by hemodialysis; ramipril and fosinopril are not appreciably removed.1,2

In contrast, none of the commonly used angiotensin receptor blockers such as losartan, valsartan, and irbesartan are removed by hemodialysis.

Among β-blockers and combined α- and β-blockers, atenolol and metoprolol are removed by hemodialysis while carvedilol, bisoprolol, propranolol and labetalol are not.

Many other antihypertensives such as calcium channel blockers, α-blockers, clonidine, and hydralazine are not appreciably removed by hemodialysis, while isosorbide dinitrate appears to be.

Of interest, a 2015 retrospective cohort study found that initiation of high- dialyzability β-blockers (atenolol, acebutolol, or metoprolol) was associated with a higher risk of death in the following 180 days compared to that of low-dialyzability  β-blockers (bisoprolol or propranolol), suggesting that perhaps we should be more selective in our choice of β-blockers in this patient population.2 In contrast, no significant difference in all-cause mortality was noted among older patients receiving ACE-Is with high vs low dialyzability potential.3



  1. Inrig JK, Antihypertensive agents in hemodialysis patients: A current perspective. Semin dial 2010;23:290-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061334/pdf/nihms206964.pdf
  2. β-Blocker dialyzability and mortality in older patients receiving hemodialysis. J Am Soc Nephrol 2015;26:987-96. https://www.ncbi.nlm.nih.gov/pubmed/25359874
  3. Weir MA, Fleet JL, Dixon SN, et al. Angiotensin converting enzyme inhibitor dialyzability and outcomes in older patients receiving hemodialysis. Blood Purif 2015;40:232-42.  https://www.ncbi.nlm.nih.gov/pubmed/26382240   

Contributed in part by Andrew Lundquist, MD, PhD, Mass General Hospital, Boston, MA.

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My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

Can non-steroidal anti-inflammatory drugs (NSAIDs) suppress cancer metastasis?

A 2017 meta-analysis reported that NSAIDs are associated with lower risk of distant metastasis in patients with breast, prostate, lung, and colorectal cancer.1

The mechanism accounting for this observation is not fully understood. However, since inflammation has been implicated as a driving force for tumor metastasis 2, blunting the inflammatory microenvironment that surrounds tumors may explain NSAIDs’ reported beneficial effect.

NSAIDs may also have a direct effect on cancer cells. In-vitro studies demonstrate that NSAIDs induce the expression of a protein (p75 neurotrophic receptor, p75NTR) associated with suppression of tumor growth and metastasis in prostate cancer; this protein also suppresses growth of bladder cancer cells.3,4

Ibuprofen and indomethacin are among the commonly available NSAIDS shown to exhibit such anti-tumor effect. Interestingly, non-COX-inhibiting NSAIDS (eg, [R] flurbiprofen, an enantiomer of ibuprofen) may also be effective suggesting that inhibition of cell survival may not be COX-mediated.

Although these findings and observations are promising, randomized-controlled trials are clearly needed to better define the role of NSAIDs in the clinical management of cancer.



  1. Zhao X, Xu Z, Li H. NSAIDs use and reduced metastasis in cancer patients: Results from a meta-analysis. Sci Rep 2017; 7:1875. https://www.ncbi.nlm.nih.gov/pubmed/28500305
  2. Qian BZ. Inflammation fires up cancer metastasis. Semin Cancer Biol 2017; 47:170-176. https://www.ncbi.nlm.nih.gov/pubmed/28838845
  3. Khwaja F, Allen J, Lynch J, Andrews P, Djakiew D. Ibuprofen inhibits survival of bladder cancer cells by induced expression of the p75NTR tumor suppressor protein. Cancer Res 2004; 64:6207-6213. https://www.ncbi.nlm.nih.gov/pubmed/15342406
  4. Krygier S, Djakiew D. Neurotrophin receptor p75NTR suppresses growth and nerve growth factor-mediated metastasis of human prostate cancer cells. Int J Cancer 2002; 98:1-7. https://www.ncbi.nlm.nih.gov/pubmed/11857376

Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.

Can non-steroidal anti-inflammatory drugs (NSAIDs) suppress cancer metastasis?

Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?

It may be possible for patients with renal insufficiency, including those with end-stage kidney disease (ESKD), to undergo MRI using potentially safer preparations of gadolinium-based contrast agents (GBCAs) with “very low, if any” risk of the feared nephrogenic systemic sclerosis (NSF). 1

In contrast to the so called “linear” chelates of gadolinium (eg, gadodiamide, gadopentetate), “cyclic” GBCA’s (eg, gadoteridol) have not been clearly associated with NSF. 2 A Veterans Administration study involving gadoteridol identified no cases of NSF among the 141 patients on hemodialysis following 198 exposures. 2 In fact, the 2017 American College of Radiology (ACR) Manual on Contrast Media reports the risk of NSF with cyclic chelates as “very low, if any”. 1 Even when a cyclic GBCA is used in patients with ESKD, however, hemodialysis is recommended as soon as possible after MRI. 3

GBCAs are chelates with 2 major components: gadolinium and either a linear or cyclic ligand. Cyclic ligands bind to gadolinium more avidly, resulting in lower probability of circulating renally-cleared free gadolinium which when deposited in tissue is thought to potentially trigger NSF.2

Although NSF is characterized by progressive fibrosis of skin and soft tissue, it may involve multiple organs with an estimated 30% mortality rate. 4

 Bonus Pearl: Did you know NSF is really a new disease, with no evidence of its existence before 1997?


  1. “Nephrogenic Systemic Fibrosis”. In ACR Manual on Contrast Media; Version 10.3; May 31, 2017. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf
  2. Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008;3:747-51. https://www.ncbi.nlm.nih.gov/pubmed/18287249
  3. Wang Y, Alkasab TK, Nari O, et al. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 2011;260:105-111.  https://www.ncbi.nlm.nih.gov/pubmed/21586680
  4. Schlaudecker JD, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician 2009;80:711-14. https://www.aafp.org/afp/2009/1001/p711.pdf


Contributed by Richard Newcomb, MD, Mass General Hospital, Boston, MA.

Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?