Mysterious disease in Kazakhstan – A new von Economo encephalitis, post-vaccine, or mass hysteria?

Perhaps of note, Kalachi was one of the USSR’s “secret cities” (an uranium mine).

Mysterious disease in Kazakhstan resembles plot of X-Files series

10 SEPTEMBER 2014, 10:49 (GMT+05:00)
Photo: Mysterious disease in Kazakhstan resembles plot of X-Files series / Kazakhstan

Baku, Azerbaijan, Sept. 10

By Elena Kosolapova – Trend: The story developing in a small settlement in northern Kazakhstan is worthy of a plot for popular American science fiction television drama series, “The X-Files.”

The residents of the Kazakh village of Kalachi are racking with a mysterious disease that could not be explained by a wide range of specialists in medicine and many other specialized fields.

The villagers complain of severe fatigue and constant desire to sleep. They can suddenly fall asleep in the most unexpected places – at work, at school, in the street – and sleep for several days. Nobody and nothing can wake them up. And after waking up some of them lose memory, have hallucinations, and behave like in a dream.

The first case of the manifestation of this sleeping disease occurred in Kalachi in March 2013. And the disease breaks out once every few months. Ten percent of the village population exceeding 600 people has been infected with this disease.

The strangest thing that despite the authorities’ investigation with the involvement of local and invited specialists, the cause of the sickness remains a mystery. The scientists conducted thousands of experiments on soil, air and water in the village and the diseased patients, but the only thing they could say the people are quite healthy and the symptoms they experience do not fit into any of the known diseases.

Some kind of sleeping sickness, which also called “human African trypanosomiasis,” is a widespread tropical disease. But besides permanent desire to sleep the symptoms of this disease are different. Moreover African disease is spread by a bite of an infected tsetse fly living dozens of thousands kilometers far from Kazakhstan. And bacteriological and viral tests on Kalachi’s villagers have proved negative.
Local people are in despair. They think the authorities are hiding the truth about the disease and invent a number of fantastic explanations of its reasons from biology experiments conducted by western laboratories to aliens and God’s punishment.

However there are some versions which are more real at first glance. Kalachi is located in the vicinity of former Soviet secret uranium mining town Krasnogorsk, which was closed after Soviet Union’s collapse about 20 years ago. Some people associate abnormal sleep with the abandoned uranium mine. But scientists working at the scene say that the radiation level is normal across the village. Moreover the unfortunate Kalachi is the only village affected by this strange sickness and the dwellers of other settlements located nearby and even those who worked in the uranium mine for all their life are safe and sound.

Local nuclear specialists also assure that radiation sickness does not produce sleeping effects. Western experts share their opinion on this issue.
“In my work so far I have never heard of radiation causing any sleeping disease,” Britt-Marie Drottz Sjoberg, psychology professor at the Norwegian University of Science and Technology who has lead and participated in a number of researches and projects relation to public reactions to radiation, radioactive waste and environmental issues told Trend by e-mail.

“I doubt that uranium is the cause of the sleeping sickness… There is no such thing as “normal” for radiation levels… they should be published and compared to places without uranium mining operations,” Janette Sherman, M.D. specializing in internal medicine and toxicology with an emphasis on chemicals and nuclear radiation who earlier worked for the Atomic Energy Commission at the University of California in Berkeley, and for the U.S. Navy Radiation Defense Laboratory in San Francisco and published a number of researches on nuclear radiation also told Trend by e-mail.

Now all the people suffering from the disease in Kalachi are diagnosed with encephalopathy of unknown origin, i.e. brain damage by unknown substance. The substance was not defined.

Kazakh Health Ministry informed that the disease had classic signs of narcolepsy and some psychologists and psychiatrists explain the disease by massive psychosis.

“There have been many such unexplained events. Some of them have been caused by agents such as virus that were discovered later, such as von economo encephalitis, others by vaccines, most have been unexplained medically and assumed to be mass hysteria,” Maurice Preter, M.D., Assistant Professor of Clinical Psychiatry on the faculty of Columbia University’s College of Physicians & Surgeons and is Adj. Associate Professor of Neurology at SUNY Downstate Medical Center told Trend by e-mail.

A special commission was created from specialists from several Kazakh ministries to investigate the situation in Kalachi. But the only problem revealed by the commission in the village so far was the higher level of radon gas in air. This gas used in anesthesiology could be the cause of the abnormal sleep, according one of the numerous versions, the scientists say. However the commission does not announce when the investigation is expected to be completed.

Meanwhile extrasensory individuals, sorcerers and ufologists explain the disease by weird by extraterrestrial reasons.

The last wave of the mysterious disease happened on September 1. Nine children fell asleep immediately after festive ceremony on the occasion of new academic year and slept for two days. And this time the patients’ symptoms have aggravated compared to the last year. The diseased people have nightmares, hallucinations and some signs of insanity. Thus, the problem requires prompt solution and should not be delayed. Maybe the truth is out there.

Edited by C.S.

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Neurology.org: Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults

Sleep and cognitive status is a developing hot topic. When will hospitals have to assure a peaceful, uninterrupted night for inpatients?

Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults
  1. Claire E. Sexton, DPhil,
  2. Andreas B. Storsve, MSc,
  3. Kristine B. Walhovd, PhD,
  4. Heidi Johansen-Berg, DPhil and
  5. Anders M. Fjell, PhD

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  1. Correspondence to Dr. Sexton: claire.sexton@ndcn.ox.ac.uk
  1. Published online before print September 3, 2014, doi: 10.1212/WNL.0000000000000774Neurology September 9, 2014 vol. 83 no. 11 967-973

ABSTRACT

Objective: To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure.

Methods: In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates.

Results: Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy.

Conclusions: We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship.

FOOTNOTES

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received February 10, 2014.
  • Accepted in final form June 12, 2014.
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Salt intake is associated with inflammation in chronic heart failure.

Int Cardiovasc Res J. 2014 Sep;8(3):89-93. Epub 2014 Sep 1.

Salt intake is associated with inflammation in chronic heart failure.

Abstract

BACKGROUND:

Chronic Heart Failure (CHF) is highly prevalent and is associated with high morbidity and mortality rates. It has been well established that excessive intake of sodium chloride (salt) induced hypertension in some populations. Although salt seems to induce cardiovascular diseases through elevation of blood pressure, it has also been indicated that salt can induce cardiovascular diseases independently from blood pressure elevation.

OBJECTIVES:

The present study aimed to evaluate the association between salt consumption and inflammation in CHF patients.

PATIENTS AND METHODS:

This study was conducted on 86 patients between 18 and 65 years old who were diagnosed with New York HeartAssociation (NYHA) functional class I and II heart failure. Salt intake was calculated by using 24 hour urine sodium excretion. Besides, the association between inflammation and daily salt intake was evaluated regarding C – reactive protein (CPR), High sensitive CRP (HsCPR), Erythrocyte Sedimentation Rate (ESR), and ferritin and fibrinogen levels using Pearson correlation analysis.

RESULTS:

Our results showed a statistically significant difference between the low (n = 41) and high (n = 45) salt intake groups in terms of serum HsCRP levels (5.21 ± 2.62 vs. 6.36 ± 2.64) (P < 0.048). Additionally, a significant correlation was observed between the amount of salt consumption and HsCRP levels. In this study, daily salt consumption of the enrolled patients was 8.53 gram/day. The medications and even the blood pressures were similar in the two groups, but daily pill count, prevalence of hypertension, and coronary heart disease were higher in the high salt intake group; however, the differences were not statistically significant (P = 0.065). Also, no significant difference was observed between the groups concerning the inflammation markers, such as CRP, ESR, ferritin, and fibrinogen.

CONCLUSIONS:

Neurohumoral and inflammatory factors are thought to contribute to high mortality and morbidity rates in CHF. Yet, inflammatory markers may early diagnose CHF and predict the prognosis. Excessive salt intake also worsens the inflammation as well as volume control.

KEYWORDS:

Heart Failure; Inflammation; Sodium Dietary

PMID:

 

25177670

 

[PubMed] 
PMCID:

 

PMC4109042

 

Free PMC Article

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Neurology.org: Vitamin D and the risk of dementia and Alzheimer disease

 

OPEN ACCESS ARTICLE

Vitamin D and the risk of dementia and Alzheimer disease

  1. Thomas J. Littlejohns, MSc,
  2. William E. Henley, PhD,
  3. Iain A. Lang, PhD,
  4. Cedric Annweiler, MD, PhD,
  5. Olivier Beauchet, MD, PhD,
  6. Paulo H.M. Chaves, MD, PhD,
  7. Linda Fried, MD, MPH,
  8. Bryan R. Kestenbaum, MD, MS,
  9. Lewis H. Kuller, MD, DrPH,
  10. Kenneth M. Langa, MD, PhD,
  11. Oscar L. Lopez, MD,
  12. Katarina Kos, MD, PhD,
  13. Maya Soni, PhD*and
  14. David J. Llewellyn, PhD*

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  1. Correspondence to Dr. Llewellyn: david.llewellyn@exeter.ac.uk
  1. Published online before print August 6, 2014, doi: 10.1212/WNL.0000000000000755Neurology September 2, 2014 vol. 83 no. 10 920-928
  1. Also available:
  2. Figures Only
  3. Data Supplement
  4. PPT Slides of All Figures

ABSTRACT

Objective: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.

Methods: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population–based Cardiovascular Health Study between 1992–1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992–1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria.

Results: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23–4.13) and 1.53 (95% CI: 1.06–2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02–4.83) and 1.69 (95% CI: 1.06–2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

Conclusion: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

FOOTNOTES

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South West Peninsula.

  • * These authors contributed equally to the manuscript.

  • Supplemental data at Neurology.org

  • Received February 3, 2014.
  • Accepted in final form May 28, 2014.

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

RESPONSES TO THIS ARTICLE

  • Vitamin D deficiency and the risk of dementia

    • Robert H Howland

    published online August 28, 2014

  • Disturbed sleep: the trigger for vitamin D deficiency?

    • Sergio Tufik

    published online August 14, 2014

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Print ISSN: 0028-3878
Online ISSN: 1526-632X
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Use of bilateral mastectomy increased significantly throughout California from 1998 through 2011 and was not associated with lower mortality than that achieved with breast-conserving surgery plus radiation.

Original Investigation | September 3, 2014

Use of and Mortality After Bilateral Mastectomy Compared With Other Surgical Treatments for Breast Cancer in California, 1998-2011 FREE

Allison W. Kurian, MD, MSc1,2; Daphne Y. Lichtensztajn, MD, MPH3; Theresa H. M. Keegan, PhD2,3; David O. Nelson, PhD2,3; Christina A. Clarke, PhD2,3; Scarlett L. Gomez, PhD2,3
JAMA. 2014;312(9):902-914. doi:10.1001/jama.2014.10707.
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Supplemental Content
References

Importance  Bilateral mastectomy is increasingly used to treat unilateral breast cancer. Because it may have medical and psychosocial complications, a better understanding of its use and outcomes is essential to optimizing cancer care.

Objective  To compare use of and mortality after bilateral mastectomy, breast-conserving therapy with radiation, and unilateral mastectomy.

Design, Setting, and Participants  Observational cohort study within the population-based California Cancer Registry; participants were women diagnosed with stages 0-III unilateral breast cancer in California from 1998 through 2011, with median follow-up of 89.1 months.

Main Outcomes and Measures  Factors associated with surgery use (from polytomous logistic regression); overall and breast cancer–specific mortality (from propensity score weighting and Cox proportional hazards analysis).

Results  Among 189 734 patients, the rate of bilateral mastectomy increased from 2.0% (95% CI, 1.7%-2.2%) in 1998 to 12.3% (95% CI, 11.8%-12.9%) in 2011, an annual increase of 14.3% (95% CI, 13.1%-15.5%); among women younger than 40 years, the rate increased from 3.6% (95% CI, 2.3%-5.0%) in 1998 to 33% (95% CI, 29.8%-36.5%) in 2011. Bilateral mastectomy was more often used by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute (NCI)–designated cancer center (8.6% [95% CI, 8.1%-9.2%] among NCI cancer center patients vs 6.0% [95% CI, 5.9%-6.1%] among non-NCI cancer center patients; odds ratio [OR], 1.13 [95% CI, 1.04-1.22]); in contrast, unilateral mastectomy was more often used by racial/ethnic minorities (Filipina, 52.8% [95% CI, 51.6%-54.0%]; OR, 2.00 [95% CI, 1.90-2.11] and Hispanic, 45.6% [95% CI, 45.0%-46.2%]; OR, 1.16 [95% CI, 1.13-1.20] vs non-Hispanic white, 35.2% [95% CI, 34.9%-35.5%]) and those with public/Medicaid insurance (48.4% [95% CI, 47.8%-48.9%]; OR, 1.08 [95% CI, 1.05-1.11] vs private insurance, 36.6% [95% CI, 36.3%-36.8%]). Compared with breast-conserving surgery with radiation (10-year mortality, 16.8% [95% CI, 16.6%-17.1%]), unilateral mastectomy was associated with higher all-cause mortality (hazard ratio [HR], 1.35 [95% CI, 1.32-1.39]; 10-year mortality, 20.1% [95% CI, 19.9%-20.4%]). There was no significant mortality difference compared with bilateral mastectomy (HR, 1.02 [95% CI, 0.94-1.11]; 10-year mortality, 18.8% [95% CI, 18.6%-19.0%]). Propensity analysis showed similar results.

Conclusions and Relevance  Use of bilateral mastectomy increased significantly throughout California from 1998 through 2011 and was not associated with lower mortality than that achieved with breast-conserving surgery plus radiation. Unilateral mastectomy was associated with higher mortality than were the other 2 surgical options.

Randomized trials have demonstrated similar survival for patients with early-stage breast cancer treated with breast-conserving surgery and radiation or with mastectomy.1,2 However, older data show increasing use of mastectomy, and particularly bilateral mastectomy, among US patients with breast cancer.3– 5Bilateral mastectomy represents both treatment (for the affected breast) and prevention (for the contralateral breast), with the uncommon exception of patients having bilateral tumors. The causes of the increasing use of bilateral mastectomy are unknown; one possibility is the dissemination of sensitive diagnostic tests such as breast magnetic resonance imaging and genetic testing of BRCA1 (unigene cluster number Hs.194143) and BRCA2 (unigene cluster number Hs.34012).4,6 Although it may be cited as a justification for bilateral mastectomy, evidence for a survival benefit appears limited to rare patient subgroups, including women withBRCA1/2 mutations or strong family history of cancer.7– 9

Because bilateral mastectomy is an elective procedure for unilateral breast cancer and may have detrimental effects in terms of complications and associated costs10,11 as well as body image and sexual function,12,13 a better understanding of its use and outcomes is crucial to improving cancer care. Because patients’ preferences drive its use, patients are unlikely to accept randomization to a less extensive surgical procedure in a clinical trial; thus, observational studies offer a feasible alternative to address an important clinical question. To minimize selection bias, we designed a population-based study of the use and outcomes of bilateral mastectomy compared with other surgical treatments, using the California Cancer Registry (CCR, part of the National Cancer Institute [NCI] Surveillance, Epidemiology and End Results [SEER] program), which comprises about 99% of all breast cancer cases statewide.

Case Ascertainment and Data Collection

The study population consisted of all female California residents newly diagnosed with a first primary breast cancer (International Classification of Diseases–Oncology, 3rd edition, morphology codes C50.0-50.9), of American Joint Commission on Cancer stages 0-III, from January 1, 1998, through December 31, 2011. Approval for human subjects research was obtained from the Cancer Prevention Institute of California institutional review board. We obtained CCR data routinely abstracted from medical records on age at diagnosis, race/ethnicity (from patients’ medical records and registry categorization; assessed because prior research indicates that the use of and survival after surgical procedures vary by race/ethnicity, and because we aimed to evaluate these associations in a population-based context), marital status, stage, tumor grade, tumor size, histology, lymph node involvement, metastasis, and biomarkers.14 Tumors with histologic morphology codes 8500-8508 and 8521-8523 were coded as ductal and those with codes 8520 and 8524-8525 as lobular. We also obtained CCR information on initial treatment (surgery, chemotherapy, and radiation therapy), primary health insurance, census block group of residence at diagnosis, and vital status (determined by CCR through hospital follow-up and database linkages, including the Social Security Administration) as of December 31, 2010, and, for the deceased, the underlying cause of death.

Tumor Biomarker Information

Estrogen-receptor and progesterone-receptor status were each categorized as positive (≥5% nuclear staining), negative, borderline, not tested, not recorded, or unknown. Tumors were considered estrogen receptor–/progesterone receptor–positive if they were estrogen receptor–positive, progesterone receptor–positive, or both, and as estrogen receptor–/progesterone receptor–negative if both were negative. Given that CCR did not systematically collect v-erb-b2 avian erythroblastic leukemia viral oncogene homologue 2 (ERBB2, also known as HER-2/neu, unigene cluster number Hs.446352) testing results before 2006, ERBB2data are not included.

Neighborhood Socioeconomic Information

For each case, we assigned a previously developed measure of neighborhood socioeconomic status (SES). For cases diagnosed in 1998-2005, we used a measure of neighborhood-level SES quintiles based on distribution across California, incorporating block group-level data from the 2000 Census on income, education, housing costs, and occupation.15 For cases diagnosed in 2006-2010, we used data from the American Community Survey of the US Census to derive a similar index.

Hospital-Level Information

The CCR records the facility reporting each case. Using the aforementioned index, we determined the SES distribution of all cases for each facility and identified facilities that were NCI–designated cancer centers.

Statistical Analysis

We used polytomous logistic regression to model surgery use. Survival time was measured in days from diagnosis to death. Women who died from other causes were censored at time of death for the analysis of breast cancer–specific mortality. Women alive at the time of last follow-up or December 31, 2010, were censored then. We used Cox proportional hazards to model the association of various factors with overall and breast cancer–specific mortality. The proportional hazards assumption was confirmed by testing the correlation of Schoenfeld residuals with time. For both models (surgery use and mortality), covariates included age, race/ethnicity, tumor size, grade, histology, nodal and estrogen receptor/progesterone receptor status, receipt of adjuvant chemotherapy and radiation, neighborhood SES quintile, marital and insurance status, the SES composition of patients at the reporting hospital, care at an NCI-designated cancer center, and diagnosis year. Stage was included as a stratifying variable in the Cox regression, allowing baseline hazards to vary by stage. Multicollinearity in the models was assessed using the variance inflation factor. We did not test for a priori interactions but did conduct stratified analyses by age and stage. Missing data were coded as unknown and retained as a separate category for analyses.

We used SAS version 9.3 for all analyses except those of surgical use trends, for which we used Joinpoint (Joinpoint Regression Program version 4.0.4 [Statistical Research and Applications Branch, NCI]). This program uses Monte Carlo Permutation tests to model data and identify up to 3 points (“joinpoints”) at which there was a statistically significant change in linear trend.16 Results of joinpoint analysis were used to inform grouping of diagnosis years in logistic regression analysis.

Propensity score analyses defined surgery type as the patient attribute for which scores were calculated.17We used generalized boosting models, a nonparametric machine-learning classifier, in the R package twang, setting the search limit to 15 000 trees.18 All independent variables in Table 1 and Table 2 were used to calculate per-patient scores, except 3 variables highly correlated with others (radiation therapy with surgery type; chemotherapy and adjuvant treatment with administration of chemotherapy before or after the surgical procedure).

Table 1.  Patient and Tumor Characteristics According to Surgery Type: Bilateral Mastectomy, Breast-Conserving Surgery With Radiation, and Unilateral Mastectomy, Stages 0-III Breast Cancer, 1998-2011, California

Table 2.  Diagnosis and Treatment Characteristics According to Surgery Type: Bilateral Mastectomy, Breast-Conserving Surgery With Radiation, and Unilateral Mastectomy, Stages 0-III Breast Cancer, 1998-2011, California

We used graphical analysis to assess the postbalance maximum standardized effect difference for each variable17 and calculated weights for the average treatment effect (average outcome for the whole population after one surgery vs another); and average treatment effect for those treated (average outcome for those treated after one surgery vs another). The svykm and svylogrank functions from the survey package19 were used to calculate weighted Kaplan-Meier curves and P values; the svycoxph function was used for weighted Cox proportional hazard models, with outcome regressed on treatment and stratified by stage. Weighted CIs for mortality rates were calculated by the survfit function in the R survival package.

Patient Characteristics

A total of 291 117 stages 0-III breast cancer cases were diagnosed and reported to CCR from January 1, 1998, through December 31, 2011. Cases were excluded if missing essential data for categorization or if ineligible for breast-conserving surgery with radiation according to practice guidelines,20 as follows: diagnosed by death certificate or autopsy only (n = 33); tumor larger than 5 cm or unknown, microscopic or diffuse tumor, Paget disease of breast or mammographic diagnosis only, or inflammatory carcinoma (n = 41 853); no pathology report confirmation (n = 283); unknown lymph node involvement (n = 1771); surgery other than bilateral mastectomy, breast-conserving surgery with radiation, or unilateral mastectomy (n = 52 343); and diagnosis of bilateral tumors or a second primary breast tumor within 60 days (n = 5100), resulting in 189 734 women included in analyses of surgery use. Mortality analyses excluded women diagnosed after 2010 because of incomplete mortality data for 2011 (n = 14 331), those having zero or invalid survival time (n = 11), and those having unknown cause of death (n = 475). Mortality analyses included 174 917 women; median follow-up time was 89.1 months (interquartile range, 54.8-129.9 months).

The proportions of all patients who underwent each surgery were 6.2% (95% CI, 6.1%-6.3%) for bilateral mastectomy, 55.0% (95% , 54.8%-55.3%) for breast-conserving surgery with radiation; and 38.8% (95% CI, 38.6%-39.0%) for unilateral mastectomy (Table 1 and eTable in the Supplement). Among all patients, the rate of bilateral mastectomy increased from 2.0% (95% CI, 1.7%-2.2%) in 1998 to 12.3% (95% CI, 11.8%-12.9%) in 2011, an annual increase of 14.3% (95% CI, 13.1%-15.5%) (Table 2 and eTable). The increase in bilateral mastectomy rate was greatest among women younger than 40 years: the rate increased from 3.6% (95% CI, 2.3%-5.0%) in 1998 to 33.0% (95% CI, 29.8%-36.5%) in 2011, increasing by 17.6% (95% CI, 14.9%-20.4%) annually. Use of unilateral mastectomy declined in all age groups (Figure 1).

Figure 1.
Joinpoint Analysis Showing Time Trends in Use of Bilateral Mastectomy, Breast-Conserving Surgery With Radiation, and Unilateral Mastectomy, According to Patient Age in Years at Breast Cancer Diagnosis

Data points indicate observed data.

Multiple Regression Analysis of Characteristics Associated With Surgical Type

Factors associated with having undergone bilateral mastectomy (vs breast-conserving surgery with radiation) included age younger than 50 years, non-Hispanic white race/ethnicity, larger tumor size, nodal involvement, lobular histology, higher grade or estrogen receptor–/progesterone receptor–negative status, care at a hospital predominantly serving patients with lower SES or at an NCI-designated cancer center, having higher neighborhood SES, and recent diagnosis. Factors inversely associated with having undergone bilateral mastectomy (vs breast-conserving surgery with radiation) included age 65 years or older, minority race/ethnicity, receipt of adjuvant therapy, married status, and insurance type other than private (Table 3).

Table 3.  Multiple Regression Odds Ratios for Associations With Receipt of Bilateral Mastectomy or Unilateral Mastectomy vs Breast-Conserving Surgery With Radiation as the Reference Groupa

Characteristics associated with having undergone unilateral mastectomy (vs breast-conserving surgery plus radiation) included diagnosis at age other than 50 to 64 years, Asian, Hispanic, and American Indian race/ethnicity (with notable associations for Filipina and Hispanic women vs non-Hispanic white women), larger tumor size, nodal involvement, lobular histology, higher grade, estrogen receptor–/progesterone receptor–negative status, married status, public/Medicaid insurance, or care at a hospital predominantly serving patients of lower SES (Table 3). Factors inversely associated with having unilateral mastectomy (vs breast-conserving surgery with radiation) included black race, receipt of adjuvant therapy, care at an NCI-designated cancer center, higher neighborhood SES, and recent diagnosis.

Multiple Regression Analysis of Mortality After Surgery

Compared with breast-conserving surgery with radiation, bilateral mastectomy was not associated with a mortality difference (hazard ratio [HR], 1.02 [95% CI, 0.94-1.11]), whereas unilateral mastectomy was associated with higher mortality (HR, 1.35 [95% CI, 1.32-1.39]) (Table 4). Other factors associated with overall mortality included age 65 years or older or younger than 40 years, black race, larger tumor size, nodal involvement, higher grade, estrogen receptor–/progesterone receptor–negative status, lower neighborhood SES, unmarried status, having Medicare or public/Medicaid insurance, and receiving care at a hospital predominantly serving patients of lower SES. Higher mortality was associated with unilateral mastectomy in all age groups. Similar mortality between bilateral mastectomy and breast-conserving surgery with radiation was observed in all age groups except women 65 years or older, whose survival was slightly better after breast-conserving surgery with radiation. Findings were similar for breast cancer–specific mortality (Table 5). Compared with unilateral mastectomy, bilateral mastectomy was associated with lower overall mortality (HR, 0.75 [95% CI, 0.70-0.82]) and breast cancer–specific mortality (HR, 0.85 [95% CI, 0.76-0.94]).

Table 4.  Multiple Regression Hazard Ratios for Associations of Patient and Clinical Characteristics With Overall Mortality, Stages 0-III Breast Cancer, 1998-2010, Californiaa

Table 5.  Multiple Regression Hazard Ratios for Associations of Patient and Clinical Characteristics With Breast Cancer–Specific Mortality, Stages 0-III Breast Cancer, 1998-2010, Californiaa

Propensity Analysis of Marginal Mortality After Surgery

Figure 2A shows estimated mortality among all patients if surgical procedure were randomly assigned (analysis of average treatment effect). The estimated 10-year mortality rates were 18.8% (95% CI, 18.6%-19.0%) for bilateral mastectomy, 16.8% (95% CI, 16.6%-17.1%) for breast-conserving surgery with radiation, and 20.1% (95% CI, 19.9%-20.4%) for unilateral mastectomy. Figure 2B-D shows estimated mortality from another surgical procedure among patients who had a specific surgical procedure (analysis of average treatment effect for those treated). For patients receiving breast-conserving surgery with radiation, bilateral mastectomy would have resulted in marginally higher mortality, on average, and unilateral mastectomy in higher mortality. For patients receiving unilateral mastectomy, bilateral mastectomy would have resulted in unchanged mortality and breast-conserving surgery with radiation in lower mortality. For patients receiving bilateral mastectomy, breast-conserving surgery with radiation would have resulted in unchanged mortality and unilateral mastectomy in higher mortality. Proportional hazards regression models showed similar results (Table 6).

Figure 2.
Propensity-Weighted Kaplan-Meier Plots of Estimated Mortality Among All Patients if Surgical Procedure Had Been Randomly Assigned and of Estimated Mortality if a Different Surgical Procedure Had Been Performed Among Patients Who Had Undergone a Specific Surgical Procedure

A, Estimated mortality among all patients if surgical procedure were randomly assigned (analysis of average treatment effect). B-D, Estimated mortality from another surgical procedure among patients who had a specific surgical procedure (analysis of average treatment effect for those treated). B, For patients receiving breast-conserving surgery with radiation, bilateral mastectomy would have resulted in marginally higher mortality, on average, and unilateral mastectomy in higher mortality. C, For patients receiving unilateral mastectomy, bilateral mastectomy would have resulted in unchanged mortality and breast-conserving surgery with radiation in lower mortality. D, For patients receiving bilateral mastectomy, breast-conserving surgery with radiation would have resulted in unchanged mortality and unilateral mastectomy in higher mortality.

Table 6.  Propensity Score Analysis of Overall Mortality, Showing Average Effect of an Alternative Surgical Procedure on Patients Treated With a Specific Surgical Procedure (Average Treatment Effect of Those Treated)

This observational study comprising 189 734 women with unilateral early-stage breast cancer compared 3 surgical treatments and found a substantial increase in the rate of bilateral mastectomy throughout California from 1998 through 2011. To our knowledge, this is the first side-by-side comparison of all 3 common surgical treatments for early-stage breast cancer. Previous SEER studies have compared 2 treatments at a time: some reported a survival advantage with bilateral vs unilateral mastectomy21,22 and others reported improved survival after breast-conserving surgery with radiation compared with unilateral mastectomy.23,24 By comparing all 3 surgical options for a patient with early-stage breast cancer, we found no mortality benefit associated with bilateral mastectomy compared with breast-conserving surgery, and higher mortality associated uniquely with unilateral mastectomy.

For the surgical treatment of early-stage breast cancer, available randomized trial data are limited to those showing no survival difference between unilateral mastectomy and breast-conserving surgery.1,2 There is no randomized trial evidence to inform whether bilateral mastectomy improves survival, and it is unlikely that such a trial will ever be performed. Thus, conclusions about surgical treatments must rely on observational studies that compare the effectiveness of different procedures in practice21,22,25,26; however, a recent meta-analysis judged the existing data inadequate to enable conclusions about the effect of bilateral mastectomy on survival.27 Patient selection attributable to unmeasured factors probably explains much of the higher mortality that we observed with unilateral mastectomy relative to the other 2 surgical procedures. In prior SEER-based studies, both we24 and Agarwal et al23 reported worse survival associated with unilateral mastectomy vs breast-conserving surgery with radiation, results that persisted after propensity analysis. We agree with previous suggestions that patients with tumor features suggesting poor prognosis, such as lymphovascular invasion or extranodal extension, which SEER does not record and for which we cannot control, are more likely to undergo unilateral mastectomy than breast conservation and also to experience worse survival.23,24 The current study offers another potential explanation, namely confounding related to sociodemographic differences between women who underwent bilateral mastectomy and women who underwent unilateral mastectomy.

Women who underwent bilateral mastectomy were more likely to be non-Hispanic white and privately insured, to live in high SES neighborhoods, and to be treated in NCI-designated cancer centers. By contrast, women who underwent unilateral mastectomy were more likely to be Asian, Hispanic, or non-Hispanic American Indian/other/unknown; to have public/Medicaid insurance, and to be treated in hospitals serving patients of lower SES; they were less likely to live in high SES neighborhoods or to be treated in NCI-designated cancer centers. Cancer registry data lack details about comorbidities and specific regimens of endocrine, radiation, and chemotherapy. However, prior studies enriched for clinical data, including our own within the Kaiser Permanente Northern California health care system, reported treatment-limiting comorbidities (for example, diabetes and myocardial infarction) and reduced treatment intensity among the same racial/ethnic minority, low SES patients who most frequently underwent unilateral mastectomy in our current study.28– 30 In addition to signifying unmeasured poor prognostic factors,21,22 unilateral mastectomy might correlate with subtle disparities in effective access (for example, diabetic neuropathy that limits chemotherapy dosing; lack of transportation to the postsurgical radiation treatments required for breast conservation) that we could not identify using registry data and that may mediate higher mortality. By contrast, patterns of bilateral mastectomy use suggest that affluent non-Hispanic white women, women of high SES, or both seek more aggressive preventive care, consistent with reported associations between greater use of expensive diagnostic tests (such as breast MRI and genetic testing) and bilateral mastectomy within this patient subgroup.4,31

The increase in bilateral mastectomy use despite the absence of supporting evidence has puzzled clinicians and health policy makers. Proposed explanations include the increasing use of highly sensitive breast magnetic resonance imaging, with increases in anxiety-producing recall and biopsy rates that may drive patients to undergo preventive surgery,6,31,32 and the dissemination of genetic testing, which facilitates identification of high-risk patients who benefit from bilateral mastectomy.7,8,33 Although fear of cancer recurrence may prompt the decision for bilateral mastectomy, such fear usually exceeds the estimated risk.34,35 Other studies found recurrence fears less influential than aesthetic considerations, notably those that arise with new reconstruction approaches that achieve cosmetic symmetry through bilateral tissue flap placement.6,36 Because cosmesis may be inferior if both breasts are not reconstructed simultaneously, these new approaches encourage use of immediate bilateral mastectomy. We found that bilateral mastectomy use over time increased most among patients younger than 40 years at diagnosis, which may be attributable to their relatively high probability of carrying genetic mutations (an evidence-based indication for bilateral mastectomy)37 or to the greater likelihood that they have young children and may therefore seek maximal intervention in hope of extending their lives (an emotional rather than evidence-based decision).34,35,38Although some studies reported patient satisfaction after bilateral mastectomy,39 others observed deleterious effects on body image, sexual function, and quality of life12; moreover, repeat operations and complications (including flap failure, necrosis, and infection) are substantially more common with bilateral mastectomy than with other surgical procedures.10,11

In a time of increasing concern about overtreatment,40 the risk-benefit ratio of bilateral mastectomy warrants careful consideration and raises the larger question of how physicians and society should respond to a patient’s preference for a morbid, costly intervention of dubious effectiveness.

Our study used a population-based statewide data set, multiple regression analysis, and propensity scores. However, given its observational design, it cannot prove causation and may be subject to selection bias and uncontrolled confounding. As discussed above, unmeasured patient selection factors related to cancer prognosis and access to care may explain the higher mortality observed with unilateral mastectomy. Other limitations include the lack of SEER data on diagnostic testing (eg, magnetic resonance imaging, genetic testing for BRCA1/2 and other inherited mutations, tumor analysis for ERBB2 amplification, and broader genomic profiling), details of systemic treatments, family cancer history, and comorbidities. Additional information gaps include patient preferences and physician recommendations, which influence surgical decisions.38 Future research with more comprehensive data sets that integrate detailed clinical, treatment, and patient-reported information will be essential to advance understanding of breast surgery use and to enhance the quality of cancer care.

Among all women diagnosed with early-stage breast cancer in California, the percentage undergoing bilateral mastectomy increased substantially between 1998 and 2011, despite a lack of evidence supporting this approach. Bilateral mastectomy was not associated with lower mortality than breast-conserving surgery plus radiation, but unilateral mastectomy was associated with higher mortality than the other options. These results may inform decision-making about the surgical treatment of breast cancer.

Corresponding Author: Scarlett L. Gomez, PhD, Cancer Prevention Institute of California, 2201 Walnut Ave, Ste 300, Fremont, CA 94538 (scarlett.gomez@cpic.org).

Author Contributions: Drs Kurian and Gomez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kurian, Clarke, Gomez.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kurian, Nelson, Clarke, Gomez.

Critical revision of the manuscript for important intellectual content: Kurian, Lichtensztajn, Keegan, Nelson, Clarke, Gomez.

Statistical analysis: Lichtensztajn, Nelson.

Obtained funding: Kurian, Gomez.

Administrative, technical, or material support: Clarke, Gomez.

Study supervision: Kurian, Clarke, Gomez.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Clarke and Dr Gomez reported receiving grants from Genentech outside the submitted work. No other authors reported disclosures.

Funding/Support: This study was supported by the Jan Weimer Junior Faculty Chair in Breast Oncology, the Suzanne Pride Bryan Fund for Breast Cancer Research at Stanford Cancer Institute, and the NCI SEER program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California (CPIC). The collection of cancer incidence data was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the NCI SEER program under contracts HHSN261201000140C awarded to CPIC, HHSN261201000035C to the University of Southern California, and HHSN261201000034C to the Public Health Institute; and the CDC National Program of Cancer Registries, under agreement 1U58 DP000807-01 awarded to the Public Health Institute.

Role of the Funders/Sponsors: None of the funders/sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Disclaimer: The ideas and opinions expressed herein are those of the authors, and endorsement by the University or State of California, the California Department of Health Services, the NCI, or the CDC or their contractors and subcontractors is not intended and should not be inferred.

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Editorial
Contralateral Prophylactic Mastectomy:Is It a Reasonable Option?
JAMA. 2014;312(9):895-897. doi:10.1001/jama.2014.11308.
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