EMBRYO EXTRACTS OPOTHERAPY REDUCES Alpha-FETOPROTEIN LEVELS IN hepatocellular carcinoma PATIENTS

Blackwell Science, LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192005 Blackwell Publishing Asia Pty LtdSeptember 200520914641473Letter to EditorLetters to the EditorLetters to the Editor

Journal of Gastroenterology and Hepatology (2005) 20, 1464–1473

DOI: 10.1111/j.1440-1746.2005.03848.x

LETTERS TO THE EDITOR

SUCCESSFUL TREATMENT WITH ADALIMUMAB IN INFLIXIMABRESISTANT CROHN’S DISEASE To the Editor, Treatment of Crohn’s disease remains a challenge, particularly if conventional medical therapies fail. We report the induction of remission with adalimumab in a patient whose disease had been resistant to other medical interventions. The patient is a 60 year-old female with a 30-year history of Crohn’s disease who so far had required six resections and reanastomosis surgeries (last one in 1993) involving her terminal ileum and proximal colon. Two flare ups in her condition occurred in 1994 and 1997 and were treated with oral corticosteroids which were tapered over a few weeks. The patient’s Crohn’s disease had been quiescent thereafter and she was off any Crohn’s medications for more than 4 years. In addition, she has been suffering from coronary heart disease, for which she has received six stent placements for anginal complaints. In September 2002, the patient was hospitalized with severe abdominal pain and cramping, a flare up of Crohn’s disease was diagnosed and 80 mg/d of oral prednisolone was initiated with advice for further tapering. This, however, was impossible below 30 mg/d because of relapses of symptoms requiring average corticosteroid dosages of 60 mg/d. Although azathioprine at 150 mg/d was started and in January 2003 infliximab infusions were added at 5 mg/kg given over 5 months, no significant reduction in steroid requirements could be achieved. Azathioprine had to be discontinued because of severe hair loss; oral methotrexate therapy at 15 mg weekly (which later had to be reduced to 10 mg/ week) was substituted. Alternative diagnosis, such as short bowel syndrome and psychogenic dependency on corticosteroid medications, were intermittently considered because of lack of convincing findings on colonoscopies, abdominal computed tomography (CT), and Sellink-contrast radiographies. However, magnetic resonance imaging (MRI) demonstrated ileac wall thickening with significant enhancement after i.v. contrast, convincingly arguing for active inflammatory small bowel changes consistent with Crohn’s disease1 (Fig. 1). In December 2003, adalimumab, a fully humanized anti TNFa-neutralizing monoclonal antibody, was started at a dose of 40 mg s.c. self-administered every 2 weeks. The patient’s symptoms improved, and she could be tapered off steroids within 3 months. Crohn’s disease activity index (CDAI) improved from 226 to 21. Cushing symptoms diminished. After 3 months, adalimumab was discontinued because of the patient’s well-being and her theoretical concerns of heart failure as a possible side-effect of adalimumab (reported at that

time as a possible side-effect of infliximab2), despite repeated extensive cardiac evaluations documenting stable ejections fractions and cardiac function tests. Three months after discontinuation of adalimumab the patient was doing well on only 10 mg of weekly methotrexate and was not taking systemic corticosteroids. A subsequent flare responded again immediately to treatment with adalimumab. Although we were aware of ongoing controlled clinical trials at the time this patient was treated with adalimumab, reports of a positive response of Crohn’s disease to adalimumab had not been published. In contrast, infliximab, a similar but chimeric antibody, had documented efficacy for the induction and maintenance of remission in patients with active disease, who did not adequately respond or were intolerant to conventional therapies.3 Unfortunately, only approximately 60% of patients with active Crohn’s disease respond to a first infliximab infusion, with only up to 45% of those patients receiving remission after repeated infusions,3 leaving a need for alternative treatment options. Positive response to a different TNFa-neutralizing agent after failing another is a frequent observation in the treatment of rheumatoid arthritis. However, etanercept (a TNFa capturing IgG-fusion molecule), although being effective in the treatment of Crohn’s disease associated arthritis, failed to show efficacy for the treatment of Crohn’s inflammatory bowel disease.4 As our case supports, adalimumab, which closely resembles infliximab but in contrast to the latter is fully humanized, appears to be more promising for the treatment of Crohn’s inflammatory bowel disease. Adalimumab has so far only received approval for the treatment of rheumatoid arthritis, but we think it should be considered in otherwise resistant cases of Crohn’s disease (meanwhile also supported by study reports of others5,6,7). S.c. administration allows outpatient management of patients otherwise needing hospitalization. Of particular interest is, as documented in our case, a possible mechanism of response even after failing infliximab, clearly deserving further study. H Richard Barthel,* Thomas Gille,* Alfred Halbsguth,† Martin Kramer* *Internal Medicine Practice, Frankfurter Str. 7, Koenigstein, †Radiology Practice, Mainzer Landstrasse 191, Frankfurt, Germany

REFERENCES 1 Broglia L, Gigante P, Papi C et al. Magnetic resonance enteroclysis imaging in Crohn’s disease. Radiol. Med. (Torino) 2003; 106: 28–35.

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(a)

(b)

(c)

(d)

Figure 1 (a) HASTE T2-weighted gradient graded echo-sequences; (b) T1-weighted gradient echo-sequences with fat suppression after i.v. gadolinium show magnetic resonance imaging (MRI) sequences before treatment with adalimumab, demonstrating thickening of small bowel loops (see arrow) adjacent to the bladder with enhancement after i.v. contrast (see double arrow), both near normalizing after treatment with adalimumab in corresponding sequences (see c and d).

2 Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 2003; 138: 807–11. 3 Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9. 4 Marzo-Ortega H, Mcgonagle D, O’Connor P, Emery P. Efficacy of etanercept for treatment of Crohn’s related spondyloarthritis but not colitis. Ann. Rheum. Dis. 2003; 62: 74–6. 5 Papadakis KA, Shaye OA, Vasiliauskas EA et al. Safety and efficacy of adalimumab in Crohn’s disease patients with an attenuated response to infliximab. Am. J. Gastroenterol. 2005; 100: 75–9. 6 Youdim A, Vasiliauskas EA, Targan SR et al. A pilot study of adalimumab in infliximab-allergic patients. Inflamm. Bowel Dis. 2004; 10: 333–8. 7 Sandborn WJ, Hanauer S, Loftus EV Jr et al. An open-label study of the human anti-TNF monoclonal antibody adali-

mumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am. J. Gastroenterol. 2004; 99: 1884–9.

IODIZED OIL EMBOLIZATION TO BRAIN FOLLOWING TRANSCATHETER ARTERIAL EMBOLIZATION OF LIVER To the Editor, Use of Lipiodol (Andre Guebet, Aulnay-sous-Bios, France), an iodized oil, in transcatheter arterial chemoembolization (TAE) for hepatocellular carcinoma (HCC) treatment has been found to be associated with a number of complications. These include fever, pain and occasional embolic injury to the liver, biliary and gastroenteric systems, and the lungs.1 To date, there are no reports in the literature of embolic

1466 injury to the brain associated with iodized oil in TAE. We report here on a patient who developed oil emboli in her brain after TAE treatment of HCC. An 81-year-old female (bodyweight 78 kg) diagnosed with HCC, a 14 ¥ 10 cm well demarcated tumor at right hepatic lobe with thoracic invasion, developed a massive hemothorax. Emergency TAE was performed to stop the bleeding by infusion of Lipiodol 15 mL and gelatin sponge particles (Gelform; Upjohn, MI, USA) into the tumor vessels. After TAE, the hemothorax was controlled, however, the patient then developed respiratory complications. Iodized oil pulmonary embolism was diagnosed 4 days later as the computed tomography (CT) showed hyperattenuating substance at the bilateral basal lungs (Fig. 1). The patient’s condition was stabilized and she was discharged 2 weeks later. The patient returned for the second course of TAE 2 months later. CT before TAE showed more cephalic invasion and enlargement of the tumor mass, the previous pulmonary iodized oil emboli were clear. Laboratory data showed serum total bilirubin 1.17 mg/dL, serum albumin measured 3.4 g/dL and prothrombin time 11.8 s (control: 11.9 s). There were neither ascites nor encephalopathy, which was comparable to ChildPugh classification A. The angiogram revealed the HCC was supplied from the right inferior phrenic artery and right internal mammary artery. With coaxial methods, an emulsified 20 mL of iodized oil and anticancer agent (epirubicin) was injected through these two arteries, followed by gelatin sponge particles. The TAE procedure was uneventful, however, the patient experienced epigastric discomfort and mild tachypnea. Throughout the procedure, all the vital signs remained stable and the patient fell asleep towards the end of the procedure. However, on waking the patient complained of loss of vision and weakness in the upper and lower limbs. Both the non-contrast enhanced brain CT (Fig. 2) and

Figure 1 Four days later after first transcatheter arterial chemoembolization, the without contrast-enhanced computed tomography (CT) demonstrated hyperattenuating oil deposition within the bilateral collapsed basal lungs (arrow). Oil deposition was clear on the follow-up CT study 2 months later. Incomplete oil retained in the hepatic tumor was also noted (arrow head).

Letters to the Editor magnetic resonance imaging (MRI) showed disseminated hyperattenuating and hyperintensive punctatepatchy gural lesions in the cerebrum and cerebellum. A diagnosis of iodized oil induced brain embolism was made. Five hours later, the patient’s condition deteriorated. Laboratory data revealed no evidence of hepatic failure 2 days later. Chest X-ray showed right pleural effusion and bilateral diffuse parenchymal infiltration 4 days post TAE. Echocardiography revealed no atrial septal defect or other intracardiac shunt. The patient died from respiratory complications 45 days later. Iodized oil induced embolism in the brain has been reported following lymphangiography,2 however, cerebral complications following TAE of hepatic tumor has never been reported. It is suggested that the risk of iodized oil induced brain embolism is greatly increased if there is a right-to-left shunt, and/or a large dose of Lipiodol oil is administered.3,4 Intracardiac right-to-left shunt can occur in some congenital heart diseases, such as patent foramen ovale. Research found that among 1100 non-selected autopsies, 386 cases had patent foramen ovale and 83% had foramen ovale less than 0.2 cm in diameter.5 The small foramen ovale, which is often undetectable on routine echocardiography, can allow transient right-to-left shunt when the right heart pressure is raised following oil trapping in the lung. Patients who have congenital pulmonary vascular malformation, acute and or chronic pulmonary disease, pulmonary tumor and advanced liver disease are likely to have pulmonary arteriovenous

Figure 2 Patient complained of loss of vision and other neurological symptoms after second transcatheter arterial chemoembolization. Non-contrast enhanced brain computed tomography (CT) revealed disseminated hyperattenuating punctate-patchy gural lesions (arrows) in frontal, parietal, temporal, occipital lobes and cerebellum.

Letters to the Editor shunt.6 Inferior phrenic artery to pulmonary vasculatures shunt is also suggested as a possible route for right-to-left shunt.1 Oil pulmonary embolization has been reported in patients receiving more than 20 mL of iodized oil after TAE of HCC.1,4 Kishi et al.’s study found that when Lipiodol was infused into hepatic artery at four different doses, the amount of Lipiodol oil deposition in the dog’s lungs was proportional to the Lipiodol dose infused and there were intravascular oil droplets in the dog’s choroidal plexus.7 These findings suggest a dosedependent circulation of oil droplets via hepatic sinusoids to pulmonary capillaries, then via the pulmonary capillaries into the systemic circulation which allows some Lipiodol droplets entering the choroidal plexus. In this case, the most probable cause of Lipiodol induced brain embolism after the second TAE may be due to the combination of a right-to-left shunt and the dose-dependent effect. After the first TAE, even though the CT showed iodized oil deposition in both lungs, there were neither neurological signs or symptoms to suggest systemic embolization. The echocardiography of the patient was unremarkable. Bases on these findings, we excluded the ‘large’ intracardiac shunt and intrapulmonary arteriovenous shunt as contributing factors to the brain embolization. The patient was initially admitted with hemothorax caused by the tumor mass, the link between her systemic vessels and pulmonary vessels may have occurred via the adhesive pleurae or tumor invasion into the thoracic cavity. With Lipiodol injection via the inferior phrenic artery, some oil droplets may have entered the pulmonary circulation via these pathways. Combined with an increased dose of Lipiodol during the second course of TAE, the patient suffers a greater risk of having oil deposition in the brain. Currently, there are no concrete guidelines recommending the optimal dose of iodized oil for TAE. There are conflicting findings in the literature, with one study suggesting 0.1–0.3 mL/kg of iodized oil as the optimal dose whilst another study suggesting that the total dose of Lipiodol should be kept below 20 mL, that is, 0.25 mL/kg to avoid vital organ embolization (e.g. lungs).4,8 The findings of our case would suggest that to reduce the risk of oil embolization to the brain, the total dosage of Lipiodol used in TAE for HCC should not exceed 20 mL, particularly if there is tumor invasion into thorax. Reng-Hong Wu, Wen-Sheng Tzeng, Chin-Ming Chang Department of Radiology, Chimei Fundation Medical Center, Tainan, Taiwan

REFERENCES 1 Sakamoto I, Aso N, Nagaoki K et al. Complications associated with transcatheter arterial embolization for hepatic tumors. Radiographics 1998; 18: 605–19. 2 Winterer JT, Blum U, Boos S et al. Cerebral and renal embolization after lymphography in a patient with nonHodgkin lymphoma: case report. Radiology 1999; 210: 381– 3.

1467 3 Sato M, Kishi K, Shioyama Y et al. Effects of experimental hepatic artery embolization with lipiodol and gelatin sponge on liver tissue. Nippon Igaku Hoshasen Gakkai Zasshi 1990; 50: 107–13. 4 Chung JW, Park JH, Im J et al. Pulmonary oil embolism after transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology 1993; 187: 689–93. 5 Thompson T, Evans W. Paradoxical embolism. Q. J. Med. 1930; 23: 135–49. 6 Krowka MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest 1994; 105: 1528–37. 7 Kishi K, Sonomura T, Satoh M et al. Acute toxicity of lipiodol infusion into the hepatic arteries of dogs. Invest. Radiol. 1994; 29: 882–9. 8 Kan Z, Sato M, Ivancev K et al. Distribution and effect of iodized poppyseed oil in the liver after hepatic artery embolization: experimental study in several animal species. Radiology 1993; 186: 861–6.

EMBRYO EXTRACTS OPOTHERAPY REDUCES A -FETOPROTEIN LEVELS IN HEPATOCELLULAR CARCINOMA PATIENTS To the Editor, Hepatocellular carcinoma (HCC) represents worldwide the third leading cause of cancer-related death and is accompanied by a-fetoprotein (AFP) rise. Therapeutic success in non-resectable HCC is very poor. Treatment with interferon, tamoxifen, antiandrogens, octreotide, and in particular with chemotherapeutic agents, has been disappointing. The efficiency of fluorouracil (5-FU) in treatment of HCC, which in the past was proposed as an appropriate drug, has been demonstrated in recent studies to yield no results.1 Because tumor development within the embryo is reduced when cell differentiation is in progress, opotherapy with embryonic extracts might have a theoretical role in human cancer therapy.2 Tumor implantation in animals is indeed hampered by the treatment with embryonic proteins obtained during the blastodermal stage.3 This is confirmed in vitro when using Zebrafish embrionic derivatives (ZED).4 In the present report, six patients with advanced HCC, who were not soundly eligible for other therapies, were treated with ZED alone (Synchro-Levels, Alphrema) in two cases, or with ZED combined with 5FU weekly in four cases. Embryonic opotherapy was administered per os at a dose of 0.06 g of embryo extracted proteins per day in three divided doses; weekly 5-FU was administered intravenously in bolus at a dose of 600 mg/sqm. All patients exhibited a 0–2 Performance Status (PS) (ECOG scale) and had histologically proven HCC with measurable nodules. Baseline serum AFP levels in the six patients were 1571, 23, 4600, 27500, 228 and 510 hg/mL. No patient treated with the drug combination showed an increase of tumor mass ≥25% during the follow up of 7 months, as determined by echograms and computed tomography (CT) scans. Of the two patients treated

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Letters to the Editor mixtures from embryonic cells. Med. Hypotheses 2003; 60: 489–93. 3 Biava PM, Carluccio A. Efficacy of embryo extracts on Lewis tumor growth in experimental animals. Biol. Med. 1995; 5: 247–9. 4 Biava PM, Bonsignorio D, Hoxha M. Cell proliferation curves of different human tumor lines after in vitro treatment with Zebrafish embryonic extracts. J. Tumor Marker Oncol. 2001; 16: 195–201. 5 Therasse P. Evaluation of response: new and standard criteria. Ann. Oncol. 2002; 13 (Suppl. 4): 127–9.

100

% of baseline serum AFP level

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Months of follow up after treatment Figure 1 a-fetoprotein (AFP) variation in two patients treated with (…) Zebrafish embrionic derivatives (ZED) and in four patients treated with (—) ZED + fluorouracil (5-FU).

with ZED, only one remained stable whereas the other showed slight tumor progression. However, in all six patients the AFP levels decreased. Figure 1 shows the serial change of serum levels of AFP after treatment in these six patients, expressed as a percentage of baseline AFP. In those patients who received a combination treatment with 5-FU (four out of six patients), although it must be remembered that indolent tumor enlargement can be a spontaneous event in advanced HCC, besides the serological result we apparently achieved disease stabilization according to both International Union Against Cancer (UICC) and Response Evaluation Criteria in Solid Tumor (RECIST) criteria.5 A larger investigation with the administration of embryo extracts in HCC, and more generally in cancer patients, is warranted. In the case of ZED, this would deserve unequivocal determination of the active molecule(s) and exact definition of its/their therapeutic dose. Fabrizió Franchi,* Tommaso Ielapi,* Mariano Bizzarri,† Patrizia Seminara* *Department of Clinical Medicine, Oncology Unit, and † Department of Experimental Medicine and Pathology, University of Roma, La Sapienza, Italy

REFERENCES 1 Gebbia V, Maiello E, Serravezza G et al. 5-Fluorouracil plus high dose levofolinic acid and oral hydroxyurea for the treatment of primary hepatocellular carcinomas: results of phase II multicenter study of the Southern Italian Oncology Group (G.O.I.M.). Anticancer Res. 1999; 19: 1407–10. 2 Berger G, Frayssinet C, Berger M, Lafarge Frayssinet C. Proposition of treatment of cancer cells by nuclear protein

CYTOPHAGIC HEMORRHAGIC PANNICULITIS AND SEVERE STEATOHEPATITIS: CHALLENGING COMBINATION To the Editor, Accumulation of fat in hepatocytes with or without concomitant inflammation and fibrosis is in Western societies the most common cause of elevated aminotransferases. Non-alcoholic simple steatosis is generally benign chronic disease, however, in certain circumstances, such as jejuno-ileal bypass surgery, fast reduction of body mass or total parenteral nutrition, macrovesicular steatosis may develop or worsen rapidly and become a life-threatening condition.1 We report on a patient in whom an exacerbation of cytophagic hemorrhagic panniculitis (CHP) was associated with pronounced metabolic syndrome and steatohepatitis. A 36-year-old man with no past medical history presented in April 2001 with an episode of icterus, asthenia, low-grade fever and progressive loss of weight. Laboratory investigations showed moderate pancytopenia and mixed hepatitis (total bilirubin 8 mg/dL, alkaline phosphatase 305 U/L, gamma glutamyltransferase [GGT] 2492 U/L, alanine aminotransferase [ALT] 95 U/L and aspartate aminotransferase [AST] 365 U/ L). Hepatic injury was associated with marked hyperlipidemia (cholesterol 255–520 mg/dL, triglycerides 710–1268 mg/dL) and elevated ferritin level 2185 ng/ mL with normal transferrin saturation index. Repeated microbial blood cultures, autoantibodies screening tests and bone marrow examination were negative. Prothrombin time, serum albumin and serum a1-antitrypsin levels and urine copper excretion were normal. The patient denied consumption of alcohol and had negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Image of the liver at ultrasonography and computed tomography was consistent with diffuse steatosis, however, liver biopsy revealed only scanty infiltrates within portal tracts and dispersed foci of necrotic hepatocytes. After several weeks all biochemical abnormalities resolved spontaneously. In January 2003 the patient presented similar hepatic and metabolic symptoms with development of cutaneous hemorrhagic lesions on his chest, thighs and right arm (Fig. 1). A biopsy of the skin lesion showed non-specific lobular panniculitis with fat necrosis and histiocytic infiltrate (CD68 positive immunostaining), which was consistent with the diagnosis of CHP.2 The

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Figure 1 arm.

Cutaneous hemorrhagic lesion on patient’s right

1469 produced by proliferating clones of subcutaneous Tlymphocytes. In accordance, there is evidence for high serum levels of tumor necrosis factor (TNF)-a in the systemic circulation of patients with CHP.7,8 CHP is a relapsing disease and if consecutive flares are not prevented or are resistant to immunosuppressive therapy, they may run a progressively downhill clinical course, terminating in hemorrhagic diathesis and liver failure.2,9 In the reported patient, an exacerbation of CHP was associated with an acute metabolic syndrome and severe steatohepatitis. This report therefore suggests that liver failure developing in most relentless varieties of CHP results from subacute steatohepatitis. Several explanations may be proposed for the association of CHP with steatohepatitis. First, inflammation might not be limited to subcutaneous adipose tissue but extend to mesenteric fat, resulting in liberation of inflammatory cytokines directly to the portal vein system. The second explanation is a direct infiltration of liver by activated histiocytes. Alegre et al.10 showed that in patients with CHP the hemophagocytic or normal histiocytes may be found in the liver, spleen and bone marrow. Finally, the hepatic steatosis could result from lipodystrophy associated with remarkable loss of weight occurring during flares of CHP. Sustained remission in both the CHP and hepatic injury achieved with cyclosporine implies a close relationship between these two conditions. Marek Hartleb,* Andrzej Pluta,† Wojciech Szczepañski,‡ Andrzej Nowak,* Jerzy Stachura,‡ Krzysztof Gutkowski† *Silesian Medical School, Department of Gastroenterology, Katowice, †County Hospital, Department of Internal Diseases and Hematology, Rzeszów, and ‡Collegium Medicum, Jagiellonian University, Department of Pathomorphology, Kraków, Poland

Figure 2 Severe mainly macrovesicular steatosis with moderate portal and lobular inflammation.

serum bilirubin level was 2.3 mg/dL, alkaline phosphatase 280 U/L, GGT 1638 U/L, ALT 95 U/L and AST 190 U/L. The second liver biopsy disclosed severe steatosis of hepatocytes associated with lobular inflammation (Fig. 2). Cyclosporine 300 mg daily as treatment for CHP had been given and this therapy was followed by marked laboratory (bilirubin 0.85 mg/dL, ALT 78 U/L, AST 55 U/L) and clinical improvement. On follow-up, 8 months later, the patient showed no signs of disease recurrence. Association of Weber-Christian disease with hepatic steatosis was reported, although neither biochemical basis nor natural history of liver injury has been clarified.3–5 CHP is a less frequent and more aggressive form of systemic panniculitis than Weber-Christian disease. In CHP, morphologically benign histiocytes, which infiltrate adipose tissue, engulf surrounding inflammatory cells causing necrosis and hemorrhage.6 It is believed that histiocytes are activated by cytokines

REFERENCES 1 Diehl AM. Nonalcoholic steatohepatitis. Semin. Liver Dis. 1999; 19: 221–9. 2 Phelps RG, Shoji T. Update on panniculitis. Mt. Sinai J. Med. 2001; 68: 262–7. 3 Wasserman JM, Thung SN, Berman R, Bodenheimer HC, Sigal SH. Hepatic Weber-Christian disease. Semin. Liver Dis. 2001; 21: 115–18. 4 Kimura H, Kako M, Yo K, Oda T. Alcoholic hyalins (Mallory bodies) in a case of Weber-Christian disease: electron microscopic observations of liver involvement. Gastroenterology 1980; 78: 807–12. 5 Miyasaki K, Ooiso Y, Nakamura I et al. An unusual case which began with subcutaneous panniculitis followed by fever, sever hepatic involvement and hyperlipidemia. Acta Pathol. Jpn 1977; 27: 213–24. 6 Craig AJ, Cualing H, Thomas G, Lamerson C, Smith R. Cytophagic histiocytic panniculitis – a syndrome associated with benign and malignant panniculitis. Case comparison and review of the literature. J. Am. Acad. Dermatol. 1998; 39: 721–36. 7 Nakane S, Kawabe Y, Eguchi K et al. A case of cytophagic histiocytic panniculitis: successful treatment of recurrent

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attacks with steroid pulse therapy and oral cyclosporin A. Clin. Rheumatol. 1997; 16: 417–21. 8 Pettersson T, Kariniemi AL, Tervonen S, Franssila K. Cytophagic histiocytic panniculitis: a report of four cases. Br. J. Dermatol. 1992; 127: 635–40. 9 Crotty CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure and terminal hemorrhagic diathesis. J. Am. Acad. Dermatol. 1981; 4: 181–94. 10 Alegre VA, Winkelman RK. Histiocytic cytophagic panniculitis. J. Am. Acad. Dermatol. 1989; 20: 177–85.

LONG-TERM COMPLETE REMISSION OF METASTATIC GASTRIC CANCER AFTER WEEKLY DOCETAXEL, 24 H INFUSION OF HIGH-DOSE 5-FU/LEUCOVORIN AND CISPLATIN To the Editor, With current ‘standard’ chemotherapy regimens, complete objective regression is uncommon and sustained long-term tumor-free survival is even rare in metastatic gastric cancer.1,2 Median survival of such patients ranged from 7 to 10 months. During a phase I study of weekly docetaxel followed by 24 h infusion of high-dose 5-FU/leucovorin and cisplatin in advanced gastric cancer, objective tumor response was achieved in 61.5% (16/26, 95% confidence interval 41.5–81.6%) of evaluated patients, with a complete response in two patients (8%).3 We hereby present the two complete responders who are alive and remain disease-free, 57 and 48 months after start of chemotherapy, respectively. Their long-term tumor-free survival highlights the potential of this novel regimen. The first patient was a 54 year-old woman with locally advanced gastric cancer who had palliative total gastrectomy, segmental resection of transverse colon and regional lymph node dissection in June 1999. Four weeks after surgery, follow-up examinations showed bilateral, multiple liver metastases (Fig. 1a), hepatoduodenal lymphadenopathy and high serum carcinoembryonic antigen (CEA) level, 57.1 ng/mL (upper normal limit, 6 ng/mL). The patient consented to enter a phase I study and received a 2 h infusion of docetaxel 40 mg/m2 followed by 24 h infusion of 2000 mg/m2 of 5-FU and 300 mg/m2 of leucovorin, and then 3 h infusion of cisplatin 30 mg/m2 at day 1 and 8 every 3 weeks. Her tumors responded promptly to the chemotherapy and were rendered into complete response after four cycles of treatment. An additional three cycles of chemotherapy were given and completed in January 2000. Without further therapy, the patient currently remains in remission, with a tumor-free survival for more than 54 months (Fig. 1b). The second patient, a 63 year-old man of advanced gastric cancer with massive retroperitoneal lymphadenopathy, underwent palliative subtotal gastrectomy, Billorth-II reconstruction and regional lymph node dissection in April 2000. One month later, computed tomography disclosed confluent enlarged lymphaden-

Figure 1 Representative computed tomography images. (a) Case 1: multiple liver metastases, prior to docetaxel-5fluorouracil/leucovorin-cisplatin therapy and (b) sustained complete regression, 54 months after the start of chemotherapy. (c) Case 2: massive retroperitoneal lymphadenopathy with encasement of aorta before chemotherapy, and (d) sustained complete remission 40 months after the start of chemotherapy.

opathy at the para-aortic and retrocaval regions, with the largest lesion measuring 5 ¥ 6 ¥ 10 cm in size (Fig. 1c). This patient consented and received the same treatment as the first patient had. The index lesion at left renal hilum shrunk to 2.5 cm after four cycles of treatment and showed no further regression after additional two cycles of treatment. In December 2000, sono-guided fine-needle aspiration of residual index lesion failed to demonstrate metastatic adenocarcinoma cells. Explorative laparotomy was performed and a thorough pathological examination of dissected para-aortic nodes only revealed extensive fibrotic changes. The patient remains disease-free for more than 40 months at this presentation (Fig. 1d). The unusual durable complete remission (54+ and 40+ months) in our patients, a phenomenon that never occurred in patients treated with 24 h infusion of highdose 5-FU/leucovorin with or without cisplatin,4,5 highlights the synergistic activity between docetaxel and intermittent infusion of high-dose 5-FU/leucovorin and cisplatin in advanced gastric cancer. A similar triplet combination, docetaxel, capecitabine (an oral fluoropyrimidine) and cisplatin, has recently been shown to be highly active in advanced gastric cancer (67.5% response rate).6 Among the 10 patients who underwent surgery after disappearance of metastatic lesions, four were shown to have complete pathologic response. Three remained disease-free for 16–20 months after surgery (Kang Y, personal communication, 2004). Although our results require further evaluation by largescale prospective studies, they may have shed some light on metastatic gastric cancer, suggesting that long-term survival or even tumor-free survival may be a realistic possibility after novel chemotherapy.

Letters to the Editor Chung-Huang Chan,* Tsang-Wu Liu,* Li-Tzong Chen,*,† Jang-Yang Chang,* Jacqueline Whang-Peng* *Division of Cancer Research, National Health Research Institutes, Taipei, †Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

REFERENCES 1 Vanhoefer U, Rougier P, Wilke H et al. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J. Clin. Oncol. 2000; 18: 2648–57. 2 Waters JS, Norman A, Cunningham D et al. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br. J. Cancer 1999; 80: 269–72. 3 Chen LT, Liu TW, Wu CW et al. A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer. Oncology 2002; 63: 239–47. 4 Hsu CH, Yeh KH, Chen LT et al. Weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of advanced gastric cancers: an effective and low-toxic regimen for patients with poor general condition. Oncology 1997; 54: 275–80. 5 Lin YC, Chen JS, Wang CH et al. Weekly high-dose 5fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer. Jpn J. Clin. Oncol. 2001; 31: 605–9. 6 Kang Y, Kim T, Chang H et al. A phase I/II trial of docetaxel, capecitabine and cisplatin as first line chemotherapy for advanced gastric cancer. Gastrointestinal Cancers Symposium Program/Proceedings. Am. Soc. Clin. Oncol. 2004: 78.

DETERMINANTS OF NONRESPONSE IN HELICOBACTER PYLORI ERADICATION TRIALS

1471 sian patients that extensive metabolizers (EM) of CYP2C19 have approximately 15% lower eradication success rates when compared to heterozygous (het) EM and poor metabolizers (PM).2 Based on a meta-analysis of all studies or concentrating on studies with omeprazole and lansoprazole (n = 8), the significant risk difference averaged 0.14 (95% CI: 0.07–0.21) and 0.18 (95% CI: 0.12–0.25), respectively.3 In a cohort study of Helicobacter pylori positive German patients treated with quadruple therapy, the 18% lower eradication rate (P < 0.01) in EM was associated with lower (P < 0.001) serum concentrations of lansoprazole in EM, and we concluded that this sub-population would benefit from a higher PPI dose.3 In our statistical calculation, other potential confounding factors such as age, smoking habits, diagnosis or antibiotic resistance have been taken into consideration. Thus, we believe that the CYP2C19 genotype is a major determinant of the clinical outcome of PPI-based treatment of acid related disorders including Helicobacter pylori eradication.2 This conclusion is confirmed by a recent study from Japan.4 The PPI-based 1-week standard triple therapy (+ clarithromycin and amoxicillin) resulted in higher eradication failures in EM (28%) in comparison to het EM (6%) and PM (2%). Interestingly, an additional new confounding factor was established. Polymorphism in interleukin (IL)-1b, which is the most potent inhibitor of acid secretion, affected to a similar extent as the CYP2C19 genotype the eradication of Helicobacter pylori; differences of approximately 5–15% were observed between defined IL-1b-511 genotypes.4 Thus, based on these new data, more information on the tested patients are needed (e.g. combination analysis of IL-1b polymorphism with CYP2C19) in future clinical studies to better differentiate and explain nonresponders versus responders, not only in Helicobacter pylori eradication trials but also in the treatment of peptic ulcer, gastroesophageal reflux disease and chronic gastritis.2 Ulrich Klotz,* Gerhard Treiber,† Matthias Schwab* *Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr, Stuttgart, and †Department of Gastroenterology/Hepatology, University Hospital of Magdeburg, Magdeburg, Germany

REFERENCES To the Editor, In a recent editorial in the Journal on the variable clinical results of Helicobacter pylori eradication rates, Katelaris1 discussed various confounding factors such as compliance, strain factors, antibiotic resistance, drug regimens, smoking habits and methodological issues. He also briefly mentioned that variability in the host metabolism of proton pump inhibitors (PPI), which is accomplished by the polymorphically expressed CYP2C19, can affect successful eradication. It was noted that the relationship between CYP2C19 genetic polymorphism and clinical outcome after PPI-based eradication therapy has not been clearly delineated. There is accumulating and clear evidence from 10 studies in Asian populations and two studies in Cauca-

1 Katelaris PH. Helicobacter pylori: why are eradication results so variable? J. Gastroenterol. Hepatol. 2004; 19: 606–9. 2 Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin. Pharmacol. Toxicol. 2004; 95: 2–8. 3 Schwab M, Schaeffeler E, Klotz U, Treiber G. CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori. Clin. Pharmacol. Ther. 2004; 76: 201–9. 4 Furuta T, Shirai N, Xiao F et al. Polymorphism of interleukin-1b affects the eradication rates of Helicobacter pylori by triple therapy. Clin. Gastroenterol. Hepatol. 2004; 2: 22– 30.

1472

Letters to the Editor

ACUTE PORTAL VEIN OCCLUSION IN A PATIENT WITH CROHN’S DISEASE To the Editor, We report a rare case of a patient with Crohn’s disease who presented with acute abdominal pain caused by thrombotic occlusion of the portal vein and its main tributaries. The patient responded well to anticoagulation therapy. A 23-year-old female with Crohn’s disease was admitted to our hospital because of severe abdominal pain that had started 4 days earlier. The patient had been diagnosed with Crohn’s ileo-colitis at the age of 13 years. Since then, she had been followed-up and treated medically by gastroenterologists. Three years ago the patient underwent a total colectomy due to poor response to medical therapy given for extensive involvement of the entire colon. A month prior to her admission, the patient had been seen at the clinic. It was noted that she had had active disease with a Crohn’s disease activity index (CDAI) of 393 and leukocyte count of 16 000 WBC/mm3. The patient started taking 6-mercaptopurine during the last month after no improvement was observed with 5-aminosalicylic acid treatment. Physical examination on admission was normal except for upper abdominal tenderness. Laboratory tests demonstrated microcytic-hypochromic anemia (Hb 7.0 g%). All other laboratory data including blood chemistry, renal and liver function were within normal range and her coagulation profile was normal. A detailed coagulation work-up ruled out hypercoagulability derangements such as anti-thrombin III, protein C, protein S, and factor V Leiden deficiency, and anti phospholipids syndrome. Also, the patient did not take oral contraceptive pills. Esophagogastroscopy and enteroscopy showed multiple superficial ulcerations in the distal esophagus, gastric antrum and terminal ileum. Endoscopic examination revealed no signs of portal hypertension including esophageal and gastric varices. Abdominal color Doppler ultrasonography revealed thrombotic occlusion of the portal vein, superior mesenteric vein and splenic vein. This diagnosis was confirmed by an abdominal computed tomography (CT) scan (Fig. 1). The patient received intravenous heparin, which was substituted later by coumadin treatment. After 2 weeks of an uneventful course the patient was discharged. Doppler ultrasonography, performed 1 month later, demonstrated a patent portal system. Portal vein occlusion is a rare but serious complication of Crohn’s disease. It has been noted that patients with inflammatory bowel disease (IBD) have a threefold increased risk of venous thromboembolism.1 The first description of pylephlebitis associated with IBD dates back to 1949.2 However, the first case report of portal vein thrombosis specifically occurring in Crohn’s disease was published by Talbot et al. in 1986.3 In that large series of 7199 patients with IBD, thromboembolic complications developed in 92 patients. Only five of these patients were diagnosed with mesenteric occlusion due to Crohn’s disease. Most cases of mesenteric and portal vein thrombosis were post surgical complications. Remzi4 has also made an association between

Figure 1 Abdominal computerized tomography scan with intravenous contrast material. The portal vein (arrow head) is occluded by a large thrombus. The thin arrows indicate occluded intrahepatic portal veins.

portal vein thrombosis and proctocolectomy in patients with IBD. The case we present had active chronic Crohn’s disease, manifested by repeated exacerbations despite good compliance with medical treatment. However, the patient did not manifest one of the major risk factors attributed to the thrombotic tendency of IBD patients: septic complication of Crohn’s disease and recent operation (CT scan performed after she had a colectomy showed a patent portal vein system). Although not all patients with IBD have a particular risk factor for hypercoagulability, they do have coagulation disturbances that increase their thrombogenic tendency. Among these disturbances are thrombocytosis, decreased levels of antithrombin III, and increased concentrations of fibrinogen and clotting factors V and VIII.5 In the present patient we can not point to a particular risk factor, except for the fact that she had been in an acute phase of her disease during the month that preceded her admission. Miehsler et al.6 compared IBD to other chronic bowel diseases and to other inflammatory conditions. They found that in 60% of thromboembolism cases in the IBD group, at least one IBD specific factor (active disease, stenosis, fistula, abscess) was present at the time thromboembolism occurred. They concluded that thromboembolism is a specific feature of IBD. The role of anticoagulation therapy and the mode of its administration are under debate. In one case report a patient who had suffered from portal vein thrombosis was treated by combined systemic and selective superior mesenteric artery infusion of anticoagulation therapy.7 In contrast, other authors reported that the majority of their patients with portal vein thrombosis were not treated4. Our patient received intravenous heparin, which was replaced by oral coumadin treatment. In summary, portal vein thrombosis is an unusual complication in patients with Crohn’s disease. This complication should be suspected in patients with IBD who demonstrate abdominal pain with or without other gastrointestinal symptoms. Symptomatic patients can be treated by systemic anticoagulation. Color Doppler ultrasonography and CT scan are the

Letters to the Editor imaging tools used for diagnosis and follow-up of patients. Gad Shaked,* David Czeiger,* Alex Rozental† *Departments of Surgery and †Gastroenterology, Soroka Medical Center and Ben-Gurion University, Beer Sheva, Israel

REFERENCES 1 Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb. Haemost. 2001; 85: 430–4. 2 Taylor FW. Regional enteritis complicated by pylephlebitis and multiple liver abscesses. Am. J. Med. 1949; 7: 838–40.

1473 3 Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular complications of inflammatory bowel disease. Mayo Clin. Proc. 1986; 61: 140–5. 4 Remzi FH, Fazio VW, Oncel M et al. Portal vein thrombi after restorative proctocolectomy. Surgery 2002; 132: 655– 61. 5 Lam A, Borda IT, Inwood MJ, Thomson S. Coagulation studies in ulcerative colitis and Crohn’s disease. Gastroenterology 1975; 68: 245–51. 6 Miehsler W, Reinisch W, Valic E et al. Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism? Gut 2004; 53: 542–8. 7 Tsujikawa T, Ihara T, Sasaki M, Inoue H, Fujiyama Y, Bamba T. Effectiveness of combined anticoagulant therapy for extending portal vein thrombosis in Crohn’s disease. Report of a case. Dis. Colon Rectum 1996; 39: 823–5.