Can my patient with cirrhosis and hepatocellular carcinoma still qualify for a liver transplant?

 

Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related deaths1. Liver transplant removes the HCC tumor and addresses the underlying cirrhosis. Unfortunately, the demand for liver transplants exceeds the supply of available livers, making it necessary to select patients with the best recurrent-free survival following transplantation. .

Mazzaferro2 found that patients who had one lesion <5 cm, no more than 3 lesions each <3 cm, and no extrahepatic involvement or vascular invasion had significantly higher rates of recurrent-free survival following liver transplant than patients with tumors exceeding this criteria (92% vs 59% at 4 years, respectively, P = .002). This criteria, also known as the Milan criteria, has been substantiated by numerous studies3 and widely adopted. Other more inclusive criteria has also been proposed, including the UCSF criteria4 (one tumor <6.5 cm, no more than 3 tumors, all <4.5 cm and cumulative size <8cm) which have good survival rates, but have not been adopted due to limited supply of available livers.

Interestingly, patients with HCC not initially meeting the Milan criteria but who receive treatment to meet the criteria have similar post-transplantation recurrence-free survival rates as those who meet the criteria without downstaging4,5.

 

References

  1. El–Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007 Jun 30;132(7):2557-76.
  2. Mazzaferro V, Regalia E, Doci R, et al. L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.
  3. Mazzaferro V, Bhoori S, Sposito C, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence‐based analysis of 15 years of experience. Liver Transplantation 2011;17(S2): S44-S57.
  4. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver transplantation. 2002 Sep 1;8(9):765-74.
  5. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–2557.
  6. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology. 2008;48:819–827.

Contributed by Marissa Shoji, Medical Student, Harvard Medical School

Can my patient with cirrhosis and hepatocellular carcinoma still qualify for a liver transplant?

What complications should I look for in my hospitalized patient suspected of having check-point inhibitor toxicity?

Targeting the host immune system via monoclonal antibodies known as checkpoint inhibitors (CPIs) is an exciting new strategy aimed at interfering with the ability of cancer cells to evade the patient’s existing antitumor immune response. CPIs have been shown to be effective in a wide variety of cancers and are likely to be the next major breakthrough for solid tumors1-3. Unfortunately, serious—at times fatal— immune-related Adverse Events (irAEs) have also been associated with their use4,5.

IrAEs occur in the majority of patients treated with nivolumab (a programmed death 1 [PD-1] CPI] or ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] CPI)1. The severity of irAEs may range from mild (grade 1) to very severe (grade 4). Grading system categories discussed in more detail at link below:

https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

Although fatigue, diarrhea, pruritis, rash and nausea are not uncommon, more severe grade (3 or 4) irAEs may also occur (Figure). The most frequent grade 3 or 4 irAEs are diarrhea and colitis; elevated ALT or AST are also reported, particularly when CPIs are used in combination. Hypophysitis, thyroiditis, adrenal insufficiency, pneumonitis, enteritis sparing the colon with small bowel obstruction, and hematologic and neurologic toxicities may also occur.

Generally, skin and GI toxicities appear first, within a few weeks of therapy, followed by hepatitis and endocrinopathies which usually present between weeks 12 and 245. High suspicion and early diagnosis is key to successful management of irAEs.

Figure. Selected irAEs associated with nivolumab and ipilimumab (adapted from reference 1).

chceky2

References

  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
  2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-1639.
  3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373:123-135.
  4. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol 2015;33:2092-2099.
  5. Weber JS. Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. Am Soc Clin Oncol Educ Book. 2012:174-177.

Contributed by Kerry Reynolds, MD, Mass General Hospital, Boston.

 

 

 

 

What complications should I look for in my hospitalized patient suspected of having check-point inhibitor toxicity?

How should I interpret high serum vitamin B12 levels in my patient with anemia?

High serum B12 levels, aka hypercobalaminemia (HC),  is not rare among hospitalized patients with 1 study reporting “high” (813-1355 pg/ml) and “very high” (>1355 pg/ml) serum B12 levels in 13 and 7% of patients, respectively1.

Common causes include excess B12 intake, solid neoplasms (particularly, hepatocellular carcinoma and metastatic neoplastic liver disease), blood disorders (eg, myelodysplastic syndrome, CML, and acute leukemias, particularly AML3), and other liver diseases, including alcohol-related diseases as well as acute and chronic hepatitis.  Other inflammatory states and renal failure have also been reported2.  

Paradoxically, even in the presence of HC, a functional B12 deficiency may still exist. This may be related to poor B12 delivery to cells due to its high binding by transport proteins transcobalamin I and III in HC which may in turn cause a decrease in the binding of B12 to transcobalamin II, a key player in B12 transport to tissues2.  In this setting, elevated serum methylmalonic acid and homocysteine levels may be helpful.

References:

  1. Arendt JFB, Nexo E. Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. PLoS ONE 2012;9:e45979. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045979
  2. Andres E, Serraj K, Zhu J. et al. The pathophysiology of elevated vitamin B12 in clinical practice. Q J Med 2013;106:505-515.https://www.ncbi.nlm.nih.gov/pubmed/23447660
How should I interpret high serum vitamin B12 levels in my patient with anemia?

What is the significance of smudge cells on peripheral blood smear?

Smudge cells (SCs)  also known as “basket cells”, are remnants of B lymphocytes ruptured during slide preparation (photo below). Although at low numbers (~0-5% of lymphocytes) SCs may be observed in healthy individuals, when found at higher numbers (>10%) they are associated with chronic lymphocytic leukemia (CLL) and other lymphoproliferative diseases1; the percentage of SCs may not discriminate between these malignancies, however2.

For nearly a century, SCs were thought to be just an artifact of slide preparation resulting from the fragility of CLL cells3. Although the mechanism accounting for the appearance of SCs is still unclear, their formation is inversely correlated with B cell content of vimentin, a cytoskeletal protein essential for rigidity and integrity of lymphocytes 3-5.

High vimentin expression is associated with an aggressive variant of CLL and shorter survival times3-5. Therefore, higher number of SCs at the time of CLL diagnosis (>20% or >30%) may actually indicate a better prognosis4-6!

smudgecellsarrow

Photo courtesy of U.S. National Library of Medicine

 

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References

  1. Petrakis NL, Lieberman E, Fullerton J. The dead leukocyte content of the blood in normal and leukemic patients. Blood. 1957 Apr;12:367-72. https://www.ncbi.nlm.nih.gov/pubmed/13412765
  2. Matos DM, Perini G, Kruzich C, Rego EM, Falcao RP. Smudge cells in peripheral blood smears did not differentiate chronic lymphocytic leukemia from other B-cell chronic lymphoprolipherative diseases. Rev Bras Hematol Hemoter. 2009;31:333–6. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-84842009000500010
  3. Nowakowski GS1, Hoyer JD, Shanafelt TD, et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J Clin Oncol. 2009;27:1844-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668708/
  4. Nowakowski GS, Hoyer JD, Shanafelt TD, et al. Using smudge cells on routine blood smears to predict clinical outcome in chronic lymphocytic leukemia: a universally available prognostic test. Mayo Clin Proc. 2007;82:449-53. https://www.mayoclinicproceedings.org/article/S0025-6196(11)61073-2/fulltext
  5. Johansson P, Eisele L, Klein-Hitpass L, et al. Percentage of smudge cells determined on routine blood smears is a novel prognostic factor in chronic lymphocytic leukemia. Leuk Res. 2010;34:892-8. https://reference.medscape.com/medline/abstract/20353875
  6. Gogia A, Raina V, Gupta R, et al. Prognostic and predictive significance of smudge cell percentage on routine blood smear in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2014;14(6):514-7. https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(14)00049-4/abstract

 

 

Contributed by Khin-Kyemon Aung, medical student, Harvard Medical School, Boston.

 

 

 

 

 

 

 

 

 

What is the significance of smudge cells on peripheral blood smear?

When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?

The most significant risk factor for PCP prophylaxis is defect in cell-mediated immunity including high-dose glucocorticoid (HDGC, ≥20 mg of prednisone daily) treatment1.  A systematic review concluded that at a PCP rate of 6.2% in control groups, PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) is highly effective (85% risk reduction) in non-HIV patients with acute leukemia or solid organ/autologous bone marrow  transplantation (number needed to treat 19)2.

Other Indications for PCP prophylaxis include1:

  1. HDGC treatment for ≥1month plus another cause of immunocompromise.
  2. Combination of immunosuppressive drugs, such as tumor-necrosing factor- α inhibitors plus HDGC or other immunosuppression.
  3. Polymyositis/dermatomyositis with interstitial pulmonary fibrosis on glucocorticoids.
  4. Certain primary immunodeficiencies (eg idiopathic CD4-lymphopenia, hyper-IgM syndrome).
  5. Granulomatosis with polyangiitis (Wegener’s) on methotrexate and HDGC
  6. Rheumatologic diseases on HDGC and a second immunosuppressive drug
  7. T-cell depleting agents (eg, fludarabine)
  8. Severe malnutrition

TMP/STX may be given either as double-strength 3x/week or single-strength daily1,2.

 

References

  1. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.
  2. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. 
When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?

Why has my hospitalized patient with head and neck cancer developed thrombocytosis few days following surgery?

Thrombocytosis or elevated platelet count is not uncommon among hospitalized patients and may be related to several factors, including “tissue damage” from a surgical procedure, infection, acute blood loss, iron deficiency, and less well known, enoxaparin.1-4 

Postoperative thrombocytosis is thought to be related to increased platelet production as well as redistribution of platelets from the splenic platelet pool to the general circulation.1  Increased levels of megakaryocytic growth factors such as thrombopoietin, and pro-or anti-inflammatory cytokines such as interleukin (IL)-1, 3, 6, or 11 may also stimulate megakaryopoeisis in the setting of inflammation.2 The mechanism of iron deficiency causing thrombocytosis is unknown.4

Enoxaparin-related thrombocytosis usually develops within the first 2 weeks of therapy and resolves 2 weeks following its discontinuation.3

In our patient, although malignancy is also associated with secondary thrombocytosis, given its acute nature in our patient, it is less likely to be playing a role.

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References

  1. Griesshammer M, Bangerter M, Sauer T, et al. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999;245:295-300. https://www.ncbi.nlm.nih.gov/pubmed/10205592
  2. Kulnigg-Dabsch S, Schmid W, Howaldt S, et al. Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial. Inflamm Bowel Dis 2013;published online, DOI10.1097/MIB.0b013e318281f4db. https://www.ncbi.nlm.nih.gov/pubmed/23644823
  3. Hummel MC, Morse BC, Hayes LE. Reactive thrombocytosis associated with enoxaparin. Pharmacotherapy 2006;26:1667-1670. https://www.ncbi.nlm.nih.gov/pubmed/17064215
  4. Dan K. Thrombocytosis in iron deficiency anemia. Intern Med 2005;44: 1025-6. https://www.jstage.jst.go.jp/article/internalmedicine/44/10/44_10_1025/_pdf

 

Why has my hospitalized patient with head and neck cancer developed thrombocytosis few days following surgery?

My patient with metastatic lung cancer has a WBC count >20,000 without an obvious cause. Can it be related to the cancer?

Absolutely! Although tumor necrosis may be associated with mild to moderate leukocytosis, another explanation for a rise in WBC count (particularly when “leukemoid” like) in patients with cancer may be related to granulocyte colony-stimulating factor (G-CSF) production by the neoplasm itself.  

In vivo production of G-CSF by bladder cancer was reported over 25 years ago in a patient with marked leukocytosis (>100,000)1.  Subsequently, numerous G-CSF-producing tumors have been reported, including those associated with the genitourinary  tract (eg, bladder, ureter, prostate), lung, gynecological organs, gallbladder, stomach, esophagus, small intestine, pancreas, mesothelioma, thyroid, and myeloma2.

 In most cases, G-CSF-producing tumors are advanced with very poor prognosis 2.  Although the mechanism underlying a link between G-CSF production and tumor progression is unclear, a direct action on GCSF receptors of tumor cells, formation of more aggressive cancer cells,  and changes in  the function of T-cells and endothelial cells that may enhance tumor growth have been postulated2.

 

References

  1. Ito N, Matsuda T, Kakehi Y, et al. Bladder cancer producing granulocyte colony-stimulating factor. N Engl J Med 1990;323:1709-10. http://www.nejm.org/doi/pdf/10.1056/NEJM199012133232418
  2. Yamano T, Moril E, Ikeda J-I, Aozasa K. Granulocyte colony-stimulating factor production and rapid progression of gastric cancer after histological change in the tumor. Jpn J Clin Oncol 2007;37:793-796. https://academic.oup.com/jjco/article/37/10/793/831502
My patient with metastatic lung cancer has a WBC count >20,000 without an obvious cause. Can it be related to the cancer?

Is aspirin effective in reducing the risk of cancer?

Yes, at least for certain types of cancer! A recent report based on 2 ongoing prospective studies (Nurses’ Health Study and Health Professionals Follow-up Study) assessed the risk of cancer in non-regular and regular users of aspirin at a dose of at least 0.5-1.5 standard tablets (325 mg) per week or a low daily dose of 81 mg.  It involved nearly 136,000 subjects while taking into account many potential confounders, including age and cancer screening1.

Compared to non-regular use, aspirin use for at least 6 years was associated with a 3% lower risk of overall cancer, and 15% lower incidence of gastrointestinal cancers, especially colorectal cancers (19% risk reduction); the incidence of breast, advanced prostate or lung cancer was not affected. The irreversible inhibition of cyclooxygenase-2 (COX-2), the principle enzyme that produces pro-inflammatory prostaglandins such as prostaglandin E2 (PGE2) found in human colorectal adenomas and carcinomas2, may explain aspirin’s protective effect1.

 

References

  1. Cao Y, Nishihara R, Wu K, et al. The population impact of long-term use of aspirin and risk of cancer. JAMA Oncol 2016;2:762-769
  2. Greenhough A, Smartt HJM, Moore, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009;30:377-386.

 

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny

Is aspirin effective in reducing the risk of cancer?