Medicine Correspondence Blog

The Medicine Correspondence Blog allows authors to post Letters to the Editors, Reviews, and other editorial writings that are not considered original research.

Thursday, November 16, 2017

​Ohira et al. [1] in 2016 reported results of thyroid cancer prevalence in children and adolescents aged 18 and younger in Fukushima prefecture during the first four years after the Fukushima Daiichi nuclear accident in March 2011. No association of thyroid cancer prevalence with estimated thyroid dose was observed. This was to be expected from the Chernobyl experience where a clear increase of thyroid cancers in children from Belarus and Ukraine was only observed in 1990, four years after the accident.

Recently, results of the first Full Scale Screening round, conducted in April 2014 through March 2016, have been published on the website of Fukushima Medical University (FMU) [2]. The numbers of suspected or confirmed thyroid cancers and the respective population numbers are listed in [2] for all 59 municipalities of Fukushima Prefecture. The municipalities of Fukushima Prefectures are grouped into four increasing thyroid dose categories: (1) Aizu (lowest exposure), (2) Soma and Iwaki, (3) Naka-dori, and (4) the 13 municipalities of "the nationally designed evacuation zone" (highest exposure).

I conducted a Poisson regression of thyroid cancer rates in the 59 municipalities as a function of dose category and found a significant positive association with dose category (P=0.010). The results for thyroid cancer incidence in the four regions with increasing estimated dose were 7.8 per 100,000 population per year in Aizu, 9.8 in Soma and Iwaki, 12.8 in Naka-dori, and 24.6 in the 13 municipalities of the nationally designed evacuation zone (). The comparison of the incidence in the 13 municipalities with the incidence in the rest of Fukushima Prefecture yields 24.6 and 11.4 per 100,000 per year, respectively, a relative risk of RR=2.15 (P=0.006).

The results of the Initial Screening round from October 2011 through March 2014, termed Preliminary Baseline Screening, can also be found on the FMU website [3]. Using the above classification of municipalities in dose categories, no association of TC-prevalence with dose was found (P=0.93).

The results of the first Full Scale Screening might be the first evidence of an effect of the Fukushima disaster on thyroid cancer incidence. A third screening round started in April 2016 and will end in March 2018; the results will not be available before 2019. Only then a reliable answer to the question will be possible whether the Fukushima accident had an effect on thyroid cancer in children and adolescents.


Alfred Körblein, PhD
Nuremberg, Germany


  1. Ohira T, Takahashi H, Yasumura S, et al. Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident: The Fukushima health management survey. Medicine (Baltimore). 2016 Aug;95(35):e4472.
  2. Fukushima Medical University. Report of Second-Round Thyroid Ultrasound Examinations (First Full-Scale Thyroid Screening Program), 5 June 2017. Available at:
  3. Fukushima Medical University. Interim Report of Thyroid Ultrasound Examination (Initial Screening), 5 June 2015. Available at:

Friday, October 13, 2017

​We have read with interest the article published by Hirase et al (1).

We would like to highlight the scientific novelty and the adequate instruments that have been used in the study. (1) On the contrary, we have identified some issues that could merit further discussion:


First, regarding the statistical analysis that they have used, the authors performed a logistic regression analysis, which we do not consider to be the best method because of the high prevalence of the outcome (>10%) and the fact that odds ratios could overestimate the risk (2-3).

Second, the timed test "up-and-go" test is applied within the evaluations.

In your study the test was performed twice and the best value was recorded. No record of a previous practice was reported. If we review the literature,in several studies the test is applied differently, they begin doing practice to become familiar with the test. After this they perform one or more timed tests and are averaged to have the final result (4-5).



Giancarlo Mendoza-Farfan; Samuel Mori-Belleza

Escuela de Terapia Fisica. Universidad Peruana de Ciencias Aplicadas. Lima, Perú


1. Hirase T, Kataoka H, Inokuchi S, Nakano J, Sakamoto J, Okita M. Factors associated with chronic musculoskeletal pain in Japanese community-dwelling older adults. Medicine Baltimore. 2017: 96 : 23  

2. Barros AJ, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC Medical Research Methodology. 2003; 3: 21.

3. Reichenheim ME, Coutinho ES. Measures and models for causal inference in cross-sectional studies: arguments for the appropriateness of the prevalence odds ratio and related logistic regression. BMC Medical Research Methodology 2010;10: 66

4. Nqyen H, Lebel K, Boissy P, Bogard S, Goubault E, Duval C. Auto detection and segmentation of daily living activities during a Timed Up and Go task in people with Parkinson's disease using multiple inertial sensors. JNeurogeng Rehabil. 2017; 14: 26

​5. Rydwik E, Bergland A, Forséén L, Fräändin K. Psychometric properties of Timed Up and Go in elderly people: a systematic review. Physical & Occupational Therapy in Geriatrics. 2011; 2:102–25

Friday, September 29, 2017

It has come to our attention that the TAFRO case we described in our paper in March was not the first case in Latin America[1]. Our colleague from Argentina, professor di Fonzo, wrote to us informing that he and co-authors had already published, in 2015, another case[2]. However, this was published in a non-indexed journal, the European Journal of Case Reports in Internal Medicine, and it went unnoticed by us[2].

In the previous report, the authors described the case of a 31-years old woman with TAFRO syndrome, treated with methylprednisolone and rituximab, one of a few cases in non-Japanese patients described in the world. Their patient presented with systemic inflammatory symptoms (fever, night sweats), lymphadenopathy, anasarca, renal failure, and hepatosplenomegaly. A right axillary lymph node biopsy revealed histopathological findings consistent with hyaline-variant Castleman's Disease (HV-CD). Bone marrow biopsy had mild fibrosis (grade 1). Blood work showed findings of a systemic inflammatory disorder, with elevated acute phase reactants, severe microcytic anemia (Hb 6.8 g/dL), elevated serum creatinine (1.9 mg/dL) and elevated serum levels of interleukin-6 (IL-6; 60 pg/ml). Pleural effusion and ascites were compatible with exudates. The patient was treated with transfusion of packed red blood cells, high-dose steroids (500 mg/day of methylprednisolone) and 4 weekly doses of rituximab. She had significant clinical improvement and was asymptomatic at the time of the report, 8 months post-diagnosis[2].

This case presents several similarities to the patient published from Brazil[1,2]. Both presented with the cardinal clinical findings of TAFRO syndrome, mainly thrombocytopenia, anasarca, myelofibrosis, renal failure and organomegaly[3], signs of a systemic inflammatory response, manifested by an increase in C-reactive protein and erythroid sedimentation rate. Interestingly, the patient from Argentina presented with more severe anemia than the Brazilian case, and also positivity for the Coombs test, but no signs of hemolysis were noted.

One important difference between both cases was that the patient from Brazil evolved with a severe clinical course during hospital admission, while the other patient had more protracted clinical development. This is probably related to the magnitude of increase in the level of IL-6, that was found to be much higher at the time of the admission of the Brazilian patient in the intensive care unit (722.6 pg/mL versus 60 pg/mL). Both patients received steroids and rituximab, while in Brazil the patient also received the anti-IL-6 monoclonal antibody tocilizumab. While it appears that the combination of steroids and rituximab may be sufficient for therapy of TAFRO syndrome[3,4], as seen in other cases of HHV-8 positive CD, we do believe that in more severe cases, anti-IL-6 therapy is indicated. One possible advantage of therapy with rituximab over tocilizumab is that it appears that maintenance is not needed with the former, and remissions seem to be durable with the anti-CD20 drug, even in other forms of CD[4-6].

In summary, Prof. Di Fonzo and co-authors reported the first case of TAFRO syndrome in Latin America in 2015[2]. Comparison of both cases revealed a similar clinical presentation, but indicate that in some cases the patient may deteriorate quickly and treatment should be initiated promptly[1,6]. In the absence of clinical trials, it appears that steroids, rituximab, and anti-IL-6 antibodies remain the mainstay of therapy in this disease. 



Fabio PS Santos1, Guilherme F Perini1, Ronaldo Piovesan2, Nelson Hamerschlak1

1Hematology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

2Internal Medicine, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil



Nelson Hamerschlak, MD, PhD

Hematology and Oncology Center "Família Dayan Daycoval"

Hospital Israelita Albert Einstein

Avenida Albert Einstein, 627/701, Bloco A, 3o Subsolo, 05651-901

São Paulo, SP, Brazil



1. José FF, Kerbauy LN, Perini GF, et al. A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids: The first case report in Latin America. Medicine (Baltimore) 2017;96(13):e6271.

2. Contardo D, Finocchietto P, Uehara T, et al. TAFRO Syndrome in a Patient of South-American Descent. European Journal of Case Reports in Internal Medicine. 2015;2:doi 10.12890/12015_000220. Available at: Accessed 14 September, 2017.

3. Iwaki N, Fajgenbaum DC, Nabel CS, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol 2016;91(2):220-226.

4. Jain P, Verstovsek S, Loghavi S, et al. Durable remission with rituximab in a patient with an unusual variant of Castleman's disease with myelofibrosis-TAFRO syndrome. Am J Hematol 2015;90(11):1091-1092.

5. Pria AD, Pinato D, Roe J, Naresh K, Nelson M, Bower M. Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients. Blood 2017;129(15):2143-2147.

6. Hiramatsu S, Ohmura K, Tsuji H, et al. Successful treatment by rituximab in a patient with TAFRO syndrome with cardiomyopathy. Nihon Rinsho Meneki Gakkai Kaishi 2016;39(1):64-71. ​

Monday, August 28, 2017

A key challenge in the mechanical ventilation of patients with acute respiratory distress syndrome (ARDS) is improving oxygenation without compounding pre-existing alveolar damage. In addition to a lung-protective ventilation (low tidal volumes and positive end-expiratory pressure), alveolar recruitment-maneuvers (RMs) may be applied to increase oxygenation. Although RMs may transiently increase aerated lung volume, improve gas exchange, and minimize lung stress during tidal-ventilation, the precise mechanisms involved in the therapeutic roles of RMs remain underexplored [1].

In a previous issue of Medicine, Chung and coworkers [2] provide interesting results in 24 ARDS patients who were divided into two groups depending on whether RMs were applied or not on Day 1 in addition to  lung-protective ventilation. RMs improved both oxygenation and the extravascular lung water (EVLW) index, as measured by transpulmonary thermodilution using a PICCO-system (Pulsion). The use of RMs was associated with a decreased use of mechanical ventilation and a decreased length of stay in the intensive care unit (ICU).

The authors hypothesized that a decrease in EVLW after RMs indicates increased pulmonary permeability and oxygenation and that RMs may improve lung water clearance to better distribute aeration in the lung. They also hypothesized that RMs may reduce alveolar epithelial cell injury. We agree with this hypothesis, which outlines mechanistically and biologically plausible relationships between RMs, the extent of lung injury, and the degree of impairment of alveolar fluid-clearance (AFC) in ARDS; but this is much more than a simple hypothesis.

ARDS is characterized by a protein-rich alveolar edema, the amount of which is influenced, at least in part, by active transepithelial fluid transport through epithelial channels. Impaired AFC is frequent during ARDS and is associated with clinical outcomes [3]. By providing alveolar recruitment, RMs reduce lung stretch and the inflammatory reaction caused by mechanical ventilation and, therefore may increase AFC [4]. Furthermore, when RMs induce alveolar recruitment, net AFC is observed, likely resulting in resorption of alveolar edema [5]. Recently, the levels of soluble receptor for advanced glycation end-products (sRAGE) have been reported as reliable predictors of impaired-AFC and increased lung epithelial injury in both mice and patients with ARDS [6,7]. Also, the kinetics of RM-induced changes in plasma sRAGE have recently been explored [8] showing a transient but significant decrease in sRAGE after RM in patients with non-focal ARDS. In this study, baseline sRAGE was associated with a response to RM in terms of improved oxygenation, which supports the hypothesis that RM-induced changes in sRAGE may provide indirect information on AFC, even when RMs do not improve oxygenation [9]. RM-induced increases in regional AFC rates may reduce alveolar edema in some lung regions, as fluid is ''pushed-out'' from the alveoli during RM.

Because AFC is possibly the endotype that explains focal and non-focal ARDS phenotypes [1], RMs seems indicated only in patients with non-focal-ARDS [10]. Such phenotypes, which were initially described using lung CT-scan, have a distinct prognosis, distinct functional pathobiological mechanisms [11, 12], and a differential response to therapy that may impact prognosis [13].


Blondonnet R., Jabaudon M., Constantin J-M.

Department of Perioperative Medicine, CHU Clermont-Ferrand, and Université Clermont Auvergne, CNRS UMR 6293, INSERM U1103, GReD, Clermont-Ferrand, France.


1.           Constantin J-M, Godet T, Jabaudon M, Bazin J-E, Futier E. Recruitment maneuvers in acute respiratory distress syndrome. Ann Transl Med. 2017;5: 290.

2.        Chung F-T, Lee C-S, Lin S-M, Kuo C-H, Wang T-Y, Fang Y-F, et al. Alveolar recruitment maneuver attenuates extravascular lung water in acute respiratory distress syndrome. Medicine . 2017;96: e7627.

3.        Ware LB, Matthay MA. Alveolar Fluid Clearance Is Impaired in the Majority of Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2001;163: 1376–1383.

4.        Koh W-J, Suh GY, Han J, Lee S-H, Kang EH, Chung MP, et al. Recruitment maneuvers attenuate repeated derecruitment-associated lung injury. Crit Care Med. 2005;33: 1070–1076.

5.        Constantin J-M, Cayot-Constantin S, Roszyk L, Futier E, Sapin V, Dastugue B, et al. Response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome. Anesthesiology. 2007;106: 944–951.

6.        Jabaudon M, Blondonnet R, Roszyk L, Bouvier D, Audard J, Clairefond G, et al. Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2015;192: 191–199.

7.        Blondonnet R, Constantin J-M, Sapin V, Jabaudon M. A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome. Dis Markers. 2016;2016: 3501373.

8.        Jabaudon M, Hamroun N, Roszyk L, Guérin R, Bazin J-E, Sapin V, et al. Effects of a recruitment maneuver on plasma levels of soluble RAGE in patients with diffuse acute respiratory distress syndrome: a prospective randomized crossover study. Intensive Care Med. 2015;41: 846–855.

9.        Constantin J-M, Jaber S, Futier E, Cayot-Constantin S, Verny-Pic M, Jung B, et al. Respiratory effects of different recruitment maneuvers in acute respiratory distress syndrome. Crit Care. 2008;12: R50.

10.      Constantin J-M, Grasso S, Chanques G, Aufort S, Futier E, Sebbane M, et al. Lung morphology predicts response to recruitment maneuver in patients with acute respiratory distress syndrome. Crit Care Med. 2010;38: 1108–1117.

11.      Mrozek S, Jabaudon M, Jaber S, Paugam-Burtz C, Lefrant J-Y, Rouby J-J, et al. Elevated Plasma Levels of sRAGE are Associated with Non-Focal CT-Based Lung Imaging in ARDS patients.: A Prospective Multicenter Study. Chest. 2016; doi:10.1016/j.chest.2016.03.016

12.      Jabaudon M, Blondonnet R, Lutz J, Roszyk L, Bouvier D, Guérin R, et al. Net alveolar fluid clearance is associated with lung morphology phenotypes in acute respiratory distress syndrome. Anaesth Crit Care Pain Med. 2016; doi:10.1016/j.accpm.2015.11.006

13.      Jabaudon M, Godet T, Futier E, Bazin J-É, Sapin V, Roszyk L, et al. Rationale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): Study protocol for a randomised controlled trial. Anaesth Crit Care Pain Med. 2017; doi:10.1016/j.accpm.2017.02.006

Thursday, August 17, 2017

We read with great interest the systematic review and meta-analysis of Lv et al (1) about the impact of remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma. The authors conclude that pT0 patients with remnant lymph node metastases have a poor survival.

We congratulate the author with this important work, but a couple of points in their manuscript merit discussion:

First, the definition of ypT0N1 in the manuscript is "complete response in the primary tumor with residual tumor in lymph nodes". Complete response in the primary tumor means that not a single viable tumor cell is present anymore or tumor regression grade 1 according to Mandard (TRG1) (2).  From the manuscript of Reynolds et al (3) the authors included survival of TRG1 and TRG2 which is information of 61 patients in the ypT0N0 group instead of the correct number of 36 and 14 patients in the ypT0N+ group instead of the correct number of only 1 patient.  On the other hand, TRG1N1 and TRG2N1 might follow a similar survival curve, as both are categorized as "major responders" (4). 

Second, building on the same ypT0N1 definition, this means that the number of invaded lymph nodes is not defined, although the authors refer to American Joint Committee on Cancer (AJCC) esophageal staging 7th edition, were N1 is defined as 1 or 2 invaded lymph nodes. However, most included papers in the analysis - but not all (5) - made use of the AJCC esophageal staging 6th edition, were N1 was defined as one or more invaded locoregional lymph nodes. Further analysis of the included studies showed that at least 8 patients are N2 or N3 according to the 7th edition. Furthermore there is a significant difference in overall survival between ypT0N1 and ypT0N2/3 according to AJCC 7th edition (6).

Third, the authors did not include the largest study performed on this topic by Chao et al (6) in 1102 patients of which 319 ypT0N0, 50 ypT0N1 according to the 6th edition or 41 ypT0N1 according to the 7th edition, but they might have had a good reason for that.

Altogether this means that in the very small group of 131 ypT0N1 patients in the analysis, at least 13 patients should be removed and potentially 50 patients should be added depending on the definitions used. This is worth a recalculation of overall survival curves for ypT0N1 according to the 6th edition, for ypT0N according to the 7th edition and even for TRG1+TRG2N1.

Therefore we suggest correct definitions for ypT0N1 in esophageal carcinoma to be able to compare all results in future trials. Nevertheless, the main message that complete response in the primary tumor with residual tumor in lymph nodes portens poor survival, will probably stand even after recalculation.  Indeed the final remark that ypT0N1 should be included in a modified staging was heard and ypT0N1 was suggested to become Stage IIIA while ypT0N2 became stage IIIB in current AJCC esophageal staging 8th edition (7).


The authors have no potential conflicts of interest to declare.


Lieven Depypere

Department of thoracic surgery, University hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium


1 Lv HW, Li Y, Zhou MH, Cheng JW, Xing WQ. Remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma impact on prognosis: A systematic review and meta-analysis. Medicine. 2017 Jun;96(26):e7342.

2 Mandard AM, Dalibard F, Mandard JC, et al.. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–2686.

3 Reynolds JV, Muldoon C, Hollywood D, Ravi N, Rowley S, O'Byrne K, Kennedy J, Murphy TJ. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer.  Ann Surg 2007;245:707-716.

4 Depypere L, Moons J, Lerut T, et al. Neoadjuvant chemoradiation treatment followed by surgery for esophageal cancer: there is much more than the mandard tumor regression score. Acta Chir Belg. 2016 Jul 29:1-7.

5 Blackham AU, Yue B, Almhanna K, Saeed N, Fontaine JP, Hoffe S, Shridhar R, Frakes J, Coppola D, Pimiento JM. The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer patients with complete primary tumor response. J Surg Oncol. 2015 Nov;112(6):597-602.

6 Chao YK, Chen HS, Wang BY, Hsu PK, Liu CC, Wu SC. Prognosis of patients with pathologic T0 N+ esophageal squamous cell carcinoma after chemoradiotherapy and surgical resection: results from a nationwide study. Ann Thorac Surg. 2016 May;101(5):1897–902.

7 Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Apperson-Hansen C, Blackstone EH, et al. Recommandations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016 Nov;29(8):906-912.