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Choreito, a formula from Japanese traditional medicine (Kampo medicine), for massive hemorrhagic cystitis and clot retention in a pediatric patient with refractory acute lymphoblastic leukemia.

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Keywords: Choreito Kampo medicine Japanese herbal medicine Polyporus umbellatus Wolfiporia extensa Alisma orien tale

Massive hemorrhagic cystitis Pediatric Acute lymphoblastic leukemia

ABSTRACT

Hemorrhagic cystitis is critical in patients with hemato-oncological disorders. Unlike adult patients, there are limited modalities and invasive procedures are often not well tolerated in children with poor general conditions. We report a pediatric patient with refractory acute lymphoblastic leukemia who developed life-threatening massive gross hematuria. Along with platelet infusion every other day due to suppressed hematopoiesis, his gross hematuria and clot retention in the bladder were successfully treated with chor-eito, a formula from Japanese traditional medicine (Kampo medicine). He survived free from hematuria for more than four months. Choreito was well tolerated, and no adverse effects were observed throughout the course.

[C] 2012 Elsevier GmbH. All rights reserved.

Introduction

Hemorrhagic cystitis (HC) is one of the critical conditions found in patients with hemato-oncological disorders. Alkylating agents, radiation, viruses and bacteria may lead to the damage of transitional epithelium in the bladder and urethral tract which contribute to the pathogenesis of HC (Hassan 2011). In patients undergoing hematopoietic stem cell transplantation, HC is facilitated by viral infections as a result of impaired immune response and worsened by co-existed thrombocytopenia or coagulopathy (Decker et al. 2009). HC manifests as diffuse vesical bleeding and its management is often challenging due to limited evidence-based medical and surgical treatment approaches (Decker et al. 2009). Some patients present with massive gross hernaturia (MGH) that further is complicated by the formation of blood clots. Eventually it progresses to renal failure and rupture of the bladder. MGH requires emergent treatment of the underlying disease and intravenous fluids, as well as manual or continuous bladder irrigation via Foley catheter. However, it is often difficult to perform the continuous irrigation in children due to the limited availability of suitable devices (Hassan 2011; Hicks and Li 2007). Invasive surgical treatments are not often well-tolerated in children with poor general conditions, especially in a palliative case.

We present a pediatric patient with refractory acute lymphoblastic leukemia (ALL) whose course was complicated with HC during palliative therapy. Although MGH progressed, administration of Japanese traditional herbal medicine (Kampo medicine), choreito successfully led to the excretion of clots from the bladder, and eventually microscopic hematuria became negative. Choreito was well tolerated, and no adverse effects were observed throughout the course.

Patient

A 10-year-old Japanese boy presented with prolonged fever, and had a diagnosis of B-cell precursor ALL at age 8 in an outside hospital. He received the standard combination of chemotherapy and was in remission until week 76 of maintenance therapy after induction chemotherapy when he had relapse of ALL. Subsequently, he received re-induction chemotherapy, but had residual blasts in the bone marrow and gradually blasts were seen in the peripheral blood. He was then referred to our hospital for further therapy.

On admission, he had anemia but was otherwise in good general condition. The laboratory data were significant for a peripheral white blood cell count (WBC) 5.0 x [10.sup.9]/1 (blast cells 44%), hemoglobin 9.2 g/c11 and a platelet count 35 x [10.sup.9]/1. His bone marrow aspirate showed a nucleated cell count 276 x [10.sup.9]/1 comprised 90% of blasts.

He received re-induction therapy according to JACLS ALL F-protocol (Suzuki et al. 2010), which succeeded in the reduction of blasts in the peripheral blood. However, his bone marrow aspirate was full of blasts after the therapy. He was administered additional chemotherapy, but none of them were effective.Thus, he was provided palliative care, Ten days after the chemotherapy, his neutrophil count became less than 0.1 x [10.sup.9]/1 and lasted for more than five months. He also had thrombocytopenia that required platelet infusion every other day in order to maintain platelet count more than 20 x [10.sup.9]/1. Although he had febrile neutropenia three weeks after chemotherapy, it was controlled by fourth-generation cephalosporin, as well as voriconazole for fungal prophylaxis and acyclovir for herpes prophylaxis.

He suddenly manifested grade II HC, 5 days after the onset of febrile neutropenia (day 1). His urine cultures were negative, and polymerase-chain reactions for adenovirus, BK virus or JC virus were also negative. He was given G-CSF daily, but he did not recover from neutropenia and HC progressed to grade III from day 10. From the same day, he required a platelet infusion every day. He was infused large-volume crystalloid fluids and diuretics for HC along with danaparoid for prevention of clots in the bladder, but his hematuria progressed to grade IV and MGH from day 17. Ultrasound revealed a large clot in his bladder and an enlarged right pelvis of the kidney (Fig. 1A). A Foley catheter 14 Fr was inserted and vigorous manual irrigations were initiated three times a day in order to maintain urine output. The catheter, however, was occluded by blood clots and needed to be re-inserted frequently. Three-way catheter or cystoscopy was not used due to the unavailability of the appropriate size, and surgical treatment was not undertaken considering the unstable hemostasis. Since he needed less invasive treatment, he was administered Japanese traditional medicine (Kampo medicine), choreito. Choreito is indicated in patients with "dampness-heat" in lower abdomen that causes dysuria, incomplete voiding and thirst. His Kampo pulse examination revealed floating, rapid and slippery pulse, and his abdominal examination was significant for lower abdominal hotness and hardness, which may be attributable to clot retention in the bladder. Those results coincided with the pattern of choreito. He was administered a pharmaceutical grade-medicine, choreito extract granules (Tsumura & Co., Tokyo, Japan) 0.2 g/kg p.o. daily in divided doses from day 20 (HPLC fingerprint of the extract is shown in Fig. 2). On day 23, he became free from lower abdominal discomfort and HC improved to grade I. Ultrasound revealed a normal pelvis of the kidneys, although small amount of clots retained in the bladder. The number of platelet infusion was reduced, and the bladder irrigation was discontinued from day 26.

He stopped taking choreito from day 29, which resulted in the more severe form of MGH. He required intensive albumin, packed red blood cells and daily platelet infusions along with vigorous bladder irrigations to maintain hemodynamics and urine outflow. Ultrasound revealed a large blood clot occupying nearly 80% of the volume of bladder with bilateral enlarged pelvises of the kidneys (Fig. 1B). He was administered choreito again from day 38. From day 39, he started to excrete fragmented blood clots from the side of catheter as he had the sensation of "constriction of the bladder". On day 43, his urine became clear again and the clots in bladder were not visible under ultrasound (Fig. 1C). Although his WBC was below 0.1 x 109/l for more than three months, his HC was controlled under grade I by choreito. No adverse effects were seen throughout the course. He was finally able to withdraw from the catheter and choreito was discontinued without exacerbation of HC until his death of multiple organ failure due to ALL two month later.

Discussion

Unlike immunocompetent patients, HC is a life-threatening issue among immunocompromised patients with hemato-oncological diseases, especially among patients undergoing hematopoietic stem cell transplantation (Hale et al. 2003). To date, there are no standard treatment guidelines for HC and its treatment often requires prolonged care and invasive interventions (Decker et al. 2009). In the pediatric population, the treatment modality is more limited, because of fewer reports on pediatric indications for most medical therapy and surgical instruments (Decker et al. 2009; Hassan 2011).

Conservative therapy includes intensive intravenous hydration and forced diuresis, but it is usually ineffective once large clot retention occurs, as in our case. Surgical treatment including cystoscopy with clot evacuation is of use even in a palliative setting (Ritch et al. 2010). However, patients with unstable hemostasis may suffer from uncontrollable bleeding, and the invasive treatment may result in significant morbidity and mortality. Intravenous and intravesical treatment has been reported with some success in pediatric patients (Bae et al. 2011; Bogris et al. 2009; Cesaro et al. 2003; Gorczynska et al. 2005). However, most of the treatment is reported in few patients and effectiveness and adverse effects among pediatric patients are not well evaluated. Hyperbaric oxygen therapy is less invasive (Furness et al. 1999), but it requires a special facility and may not be suitable for patients in an unstable condition.

Choreito is a formula from Japanese traditional medicine, Kampo medicine. Traditional Chinese medicine (TCM) was adopted in Japan as the orthodox medicine in the sixth century (Fuyuno 2011; Otsuka 2010), and since then, it has developed uniquely from TCM, although it shares many of basic theories and formulae with TCM. Modern medicine took over Kampo medicine for more than a century, but some of the Kampo formulae are still officially registered by the Japanese Ministry of Health, Labour and Welfare and covered by national health insurance (Fuyuno 2011). Kampo formulae are prescribed according to the collection of subjective and objective symptoms, namely pattern (Otsuka 2010). They are prescribed in accordance with the patients' pathophysiology which is thought to be reflected on pattern (Otsuka 2010; Terasawa 2004). The indication of choreito in Kampo medicine is "dampness-heat" in the lower abdomen with characteristic symptoms of dysuria, hotness in lower abdomen and thirst (Otsuka 2010). It could be interpreted as inflammation and blood clots in the bladder.

Choreito (compatible as Zhu Ling Tang in TCM) consists of Polyporus umbellatus sclerotium, Wolfiporia extensa sclerotium, Alisma orien tale rhizome, Talc and Gelatin. Together, choreito has a protective potency in the urinary tract proven in animal models (Buffington et al. 1997; Kubo et al. 1989). Ergone isolated from Polyporus umbellatus prevented early renal injury in a rat model of nephropathy (Zhao et al. 2011), and may also have a central role in protecting the urinary tract. Choreito is frequently prescribed in female adults with acute simple cystitis (Otsuka 2010), and successfully ameliorated 92.9% of pollakisuria in an open-label, single-arm study of 30 patients who received choreito for lower urinary tract symptoms (Horii and Maekawa 1988). Choreito is also administered in patients with urolithiasis in order to enhance evacuation of stones after extracorporeal shock wave lithotripter. The rate of voiding stones was significantly higher (p < 0.05) in 681 patients who received choreito (45%) than in 126 patients who did not (31%), when the stone size ranged between 10 and 20 mm (Wada et al. 2001). However, none of the reports have described applying choreito to MGH and clot retention in the bladder. The reported adverse effect was restricted to drug allergy and mild gastric discomfort, and no severe adverse effect has been reported. Since mere diuretics were not effective in our patient, we speculate that choreito has a potency in directly protecting transitional epithelium, and thereby, hemostasis of HC. This protecting effect is not attributable to enhancement of his immune system via leukocytes, considering his WBC less than 0.1 x [10.sup.9]/l for several months. In addition, large clot retention was resolved by voiding the fragmented clots from the bladder, possibly by constricting the bladder. No adverse effects were observed for a long duration and its feasibility and safety was evident.

In conclusion, choreito is a safe and considerably effective treatment for patients with critical HC and clot retention in the bladder. Choreito is effective irrespective of patients' immunostatus, and could be administered as a first-line treatment for HC even in a life-threatening setting. Further researches needs to be evaluated.

Conflict of interest

The authors declare no conflict of interest.

* Corresponding author at: Division of Hematology/Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya 453-8511, Japan. Tel.: +81 52 481 5111: fax: +81 52 482 7733.

E-mail address: kwnozomu@med.nagoya-u.ac.jp (N. Kawashima). 0944-7113/$--see front matter

0944-7113/$--see front matter [c] 2012 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2012.06.012

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Nozomu Kawashima*, Teykia E. Deveaux, Nao Yoshida, Kimikazu Matsumoto, Koji Kato

Division of Hematology/Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital. Nagoya, Japan
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Title Annotation:Short communication
Author:Kawashima, Nozomu; Deveaux, Teykia E.; Yoshida, Nao; Matsumoto, Kimikazu; Kato, Koji
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9JAPA
Date:Sep 15, 2012
Words:2697
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