Growing evidence challenges conservative transfusion dogma

The last few years have seen quite a push toward restrictive transfusion strategies with conservative hemoglobin (less than seven) triggers.  Not only did numerous research publications support such an approach but there are important theoretical concerns. For example banked blood is relatively ineffective in terms of oxygen delivery due to depletion of 2, 3 DPG levels. There's also a concern based on indirect evidence that blood transfusions may be immunosuppressive by poorly understand mechanisms. Guidelines support a conservative (hemoglobin seven) trigger in almost all situations (though allowing room for clinical judgment which might favor a trigger of 8 in some circumstances).
In recent years the discussion around transfusion restriction has morphed into a campaign of sorts with conservative triggers embedded into electronic medical records and institutional policies taking the form of dogma with little regard for clinical judgment or the unique attributes of certain patients.
A paper in Critical Care Medicine challenges this dogma in certain patients:

Patients: Adult cancer patients with septic shock in the first 6 hours of ICU admission.

Interventions: Patients were randomized to the liberal (hemoglobin threshold, less than 9g/dL) or to the restrictive strategy (hemoglobin threshold, less than 7g/dL) of RBC transfusion during ICU stay.

Measurements and Main Results: Patients were randomized to the liberal (n = 149) or to the restrictive transfusion strategy (n = 151) group. Patients in the liberal group received more RBC units than patients in the restrictive group (1 [0-3] vs 0 [0-2] unit; p less than 0.001). At 28 days after randomization, mortality rate in the liberal group (primary endpoint of the study) was 45% (67 patients) versus 56% (84 patients) in the restrictive group (hazard ratio, 0.74; 95% CI, 0.53-1.04; p = 0.08) with no differences in ICU and hospital length of stay. At 90 days after randomization, mortality rate in the liberal group was lower (59% vs 70%) than in the restrictive group (hazard ratio, 0.72; 95% CI, 0.53-0.97; p = 0.03).

Conclusions: We observed a survival trend favoring a liberal transfusion strategy in patients with septic shock when compared with the restrictive strategy. These results went in the opposite direction of the a priori hypothesis and of other trials in the field and need to be confirmed.
Although the survival advantage for more aggressive transfusion did not reach statistical significance 28 days it did at 90 days.

Early arterial ischemic events after VTE in cancer patients

From a recent report in AJM:

•Arterial events are a major cause of death in cancer patients with venous thrombosis.

•Arterial events occur early after venous thrombosis in cancer patients.

•The risk of arterial events should be considered in this clinical setting.

Abstract

Background

Venous thromboembolism is common in patients with malignancies, affecting up to 10% of this patient population. The association between arterial ischemic events and venous thromboembolism also has been established. However, the influence of arterial ischemic events on outcomes in cancer patients with venous thromboembolism has not been fully determined.

Methods

The current study analyzed clinical characteristics, time course, risk factors, incidence and severity of venous thromboembolism recurrences, arterial ischemic events and major bleeding in 5717 patients with active cancer and venous thromboembolism recruited into RIETE (multi-center prospective registry of patients with objectively confirmed venous thromboembolism).

Results

During the anticoagulation course (median 7.3 months), 499 (8.7%) patients developed venous thromboembolism recurrences, 63 (1.1%) developed arterial events, and 346 (6.1%) suffered from major bleeding. Overall, major bleeding and arterial events appeared earlier (median 35 and 36 days, respectively) than venous thromboembolism recurrences (median 97 days). Thirty-day mortality rates after each event were: 20% after recurrent pulmonary embolism, 13% after recurrent deep vein thrombosis, 41% after major bleeding, 40% after myocardial infarction, 64% after ischemic stroke, and 83% after lower limb amputation. Bleeding was the leading cause of death (67 fatal bleeds), whereas cumulative mortality due to arterial ischemic events (n = 27) was similar to that related to pulmonary embolism recurrences (n = 26).

Conclusions

In this study, arterial ischemic events and major bleeding appeared early after venous thromboembolism in patients with active cancer and were among frequent causes of their deaths. The risk and severity of arterial events need to be considered in this clinical setting.

Stress cardiomyopathy in cancer patients

From a recent study:

Takotsubo syndrome, also known as stress-induced cardiomyopathy (SC), is underrecognized in cancer patients. This study aims to investigate the incidence, natural history, and triggers of SC in cancer patients and its impact on cancer therapy and overall survival. A total of 30 subjects fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6-year period. Clinical presentation, electrocardiogram, laboratory data, and transthoracic echocardiogram results registered during the acute phase and follow-up were collected. All patients underwent coronary angiography. The most frequent presenting symptoms were chest pain in 63.3% of the patients and shortness of breath/dyspnea on exertion in 27% of the patients. T-wave inversion was a more common electrocardiographic presentation (60%) than ST elevation (13.3%). The median and interquartile range of peak creatine kinase MB fraction, troponin I, and brain natriuretic peptide were creatine kinase MB fraction 8.9, 4.6 to 21.1; troponin I 1.31, 0.7 to 3.3; and brain natriuretic peptide 1,124, 453.5 to 2,369.5. The most common complication of SC was cardiogenic shock requiring inotropic agents (20%). Of the 21 patients who required ongoing cancer treatment, 16 were able to resume chemotherapy, 5 underwent surgery, and 4 received radiation treatment. Median time to resume cancer treatment was 20 days after SC. None of the patients experienced recurrence of SC and other cardiac events. In conclusion, SC should be considered in the differential diagnosis of cancer patients who present with chest pain and ECG findings characteristic of acute coronary syndrome. Most of these patients normalize ejection fraction and may resume cancer therapy early.

The spectrum of pulmonary neuroendocrine tumors

Free full text article.

Obesity, body fat distribution and cancer risk

Form the British Journal of Cancer:

Background:

We evaluated the associations of anthropometric indicators of general obesity (body mass index, BMI), an established risk factor of various cancer, and body fat distribution (waist circumference, WC; hip circumference, HC; and waist-to-hip ratio, WHR), which may better reflect metabolic complications of obesity, with total obesity-related and site-specific (colorectal and postmenopausal breast) cancer incidence.

Methods:

This is a meta-analysis of seven prospective cohort studies participating in the CHANCES consortium including 18 668 men and 24 751 women with a mean age of 62 and 63 years, respectively. Harmonised individual participant data from all seven cohorts were analysed separately and alternatively for each anthropometric indicator using multivariable Cox proportional hazards models.

Results:

After a median follow-up period of 12 years, 1656 first-incident obesity-related cancers (defined as postmenopausal female breast, colorectum, lower oesophagus, cardia stomach, liver, gallbladder, pancreas, endometrium, ovary, and kidney) had occurred in men and women. In the meta-analysis of all studies, associations between indicators of adiposity, per s.d. increment, and risk for all obesity-related cancers combined yielded the following summary hazard ratios: 1.11 (95% CI 1.02–1.21) for BMI, 1.13 (95% CI 1.04–1.23) for WC, 1.09 (95% CI 0.98–1.21) for HC, and 1.15 (95% CI 1.00–1.32) for WHR. Increases in risk for colorectal cancer were 16%, 21%, 15%, and 20%, respectively per s.d. of BMI, WC, HC, and WHR…

Conclusions:

BMI, WC, HC, and WHR show comparable positive associations with obesity-related cancers combined and with colorectal cancer in older adults.

Pan CT scanning to look for occult malignancy after a diagnosis of unprovoked VTE

Not found to be helpful let alone cost effective.

Management of recurrent VTE in cancer patients

Here is a recent review. Form the review:

Venous thromboembolism (VTE) occurs in 10–20%% of patients with cancer and is associated with significant mortality and morbidity in these patients. The current standard of care recommended by international guidelines is to use low-molecular-weight heparin (LMWH) for 6 months for the management of cancer-associated thrombosis (CAT), which is based on evidence from randomized controlled trials demonstrating that LMWH significantly reduced the risk of recurrent VTE compared with vitamin K antagonists. However, patients with CAT have a high risk of VTE recurrence of up to 20% despite receiving anticoagulation. Reasons for recurrent VTE may include non-compliance, temporary cessation of therapy due to bleeding or for procedures, inadequate dosing, cancer progression, and the presence of heparin-induced thrombocytopenia. Management of patients with CAT and recurrent VTE is not well defined. Management strategies for recurrent VTE include switching to LMWH if an oral anticoagulant is employed, dose escalation of LMWH, or as a last resort option consider insertion of a vena cava filter. In this review, we discuss the acute, long-term, and extended management of CAT, risk factors for recurrent VTE, and management of recurrent VTE.

On line resources for cancer biology education

A compilation of resources can be found here.

Cancer associated thrombosis

Free review.

Is there a difference between IgM multiple myeloma and Waldenstrom’s macroglobulinemia? Is it important?

Yes and yes.

Here’s a case report that discusses these questions.

Hepatocellular carcinoma (HCC) with a focus on diagnosis and screening

Here is a free full text review.

Recommendations are that all patients with cirrhosis be screened as well as certain hepatitis B patients regardless of cirrhosis if certain risk factors are present. Some guidelines make similar recommendations for hepatitis C. The screening modality of choice is ultrasound. Imaging is favored over tumor markers.

Glioma and VTE

Glioma is associated with hypercoagulability to a greater extent than many other neoplasms. However, as noted in this paper, the CNS bleed rate of anticoagulated glioma patients is significant.

Pioglitazone and bladder cancer

This BMJ study adds strength to the association:

Design Population based cohort study.

Setting General practices contributing data to the United Kingdom Clinical Practice Research Datalink.

Participants A cohort of 145 806 patients newly treated with antidiabetic drugs between 1 January 2000 and 31 July 2013, with follow-up until 31 July 2014.

Main outcome measures The use of pioglitazone was treated as a time varying variable, with use lagged by one year for latency purposes. Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident bladder cancer associated with pioglitazone overall and by both cumulative duration of use and cumulative dose. Similar analyses were conducted for rosiglitazone, a thiazolidinedione not previously associated with an increased risk of bladder cancer.

Results The cohort generated 689 616 person years of follow-up, during which 622 patients were newly diagnosed as having bladder cancer (crude incidence 90.2 per 100 000 person years). Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100 000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, rosiglitazone was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100 000 person years; 1.10, 0.83 to 1.47). Duration-response and dose-response relations were observed for pioglitazone but not for rosiglitazone.

Conclusion The results of this large population based study indicate that pioglitazone is associated with an increased risk of bladder cancer. The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect.

This is unfortunate because pioglitazone was one of only two diabetes drugs (the other being metformin) associated with better macrovascular outcomes.

Carcinoids and other neuroendocrine tumors

This review in the Archives of Pathology and Laboratory Medicine helps clarify the sometimes confusing terminology around the diverse array of these tumors.

Evaluation and management of non-malignant pleural effusions

Free full text review.

Progress in the understanding and treatment of hairy cell leukemia

From a recent review:

Initially a uniformly fatal disease, new therapies in rapid succession transformed HCL into a chronic disease with a normal life expectancy in many cases. More recently, the identification of BRAFV600E mutations in the majority of patients with classic HCL have enabled targeted therapies as a therapeutic option. Additional discoveries into the biology of the disease have identified new subtypes of HCL. Modern approaches to the evaluation and treatment of HCL include detailed molecular analysis which informs therapeutic options, which may consist of traditional therapies such as purine nucleoside analogs, or targeted therapies with antibodies, BTK inhibitors, or BRAF inhibitors, or combination therapy.

Overview of hairy cell leukemia

From a recent review article:

Since the first clear description of HCL by Bouroncle in 1958 there has been a step change in the understanding of the biology of the disease and improvement in treatment. In the 1980s a review of cases reported a median survival of only 4 years. Life expectancy for patients now is the same, or very close to that of a normal age-matched population.

Diagnosis of HCL is usually straightforward with a typical clinical presentation and characteristic morphological and immunophenotypic profile of hairy cells. Once the possibility of HCL is entertained it is not difficult to confirm following careful examination of blood and bone marrow. Some of the more unusual clinical manifestations of the disease are discussed in this volume.

Despite the rarity of HCL and consequent difficulty in conducting large clinical trials, relatively early progress was made with the recognition that purine analogues could deliver a very high rate (80%) of durable remissions. The drugs pentostatin and cladribine have been the mainstay of treatment since the 1980s. However, about half of the patients will relapse and some will eventually become refractory to these agents. Until recently treatment options for patients with purine-analogue- refractory disease have been limited. The introduction of Monoclonal antibodies, given in combination or as an immunoconjugate, have been able to further prolong disease response and survival for patients.

One of the most exciting discoveries was the description, in 2011, of the V600E mutation of BRAF in virtually all cases of classical hairy cell leukaemia. This constitutively activates the MAPK pathway and appears to be the key genetic driver of the disease. Indeed, inhibition of BRAF in vitro reverses the classical morphological and genetic features of the hairy cell and induces hairy cell death. This translates into therapeutic activity in vivo , which has recently been confirmed by the publication of the successful results of a combined clinical trial of vemurafenib in relapsed HCL by Italian and US investigators.

Review of tumor lysis syndrome

Free full text.

Pioglitazone and cancer: the association remains unclear

There has been a signal for a link between pioglitazone use and bladder cancer. But now, from a recent report in JAMA, an association with prostate and pancreatic cancer is suggested:

Design, Setting, and Participants Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193 099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236 507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California.

Exposures Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent.

Main Outcomes and Measures Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma.

Results Among 193 099 persons in the bladder cancer cohort, 34 181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100 000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100 000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.

Conclusions and Relevance Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

Paraneoplastic neurologic disorders in small cell lung cancer are more common than appreciated

---in this study:

Methods: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies…

Results: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all less than 5%]).

Conclusions: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC.

Some background from the full text of the paper:

Currently almost half of all patients diagnosed with PNDs have associated SCLC,2 so this study is relevant to the broad epidemiology of these neurologic disorders. We found a higher frequency of PNDs (9.1% of SCLC) than previous SCLC surveys, perhaps because of the single-center prospective design with neurology input and high recruitment among the SCLC population. The findings suggest that PNDs in patients with SCLC may be underdiagnosed due to misattribution of symptoms; recognition of the disorders and their common antibody associations is important because the earlier the diagnosis is made, the better the oncologic and neurologic outcome.23,24

Via Clinical Correlations.