[The critically ill CAR T-cell patient : Relevant toxicities, their management and challenges in critical care]. / Der kritisch kranke Patient nach CAR-T-Zell-Therapie : Relevante Nebenwirkungen, deren Management und Herausforderungen an die Intensivmedizin.

BACKGROUND: CAR­T cell therapy has been implemented as clinical routine treatment option during the last decade. Despite beneficial outcomes in many patients severe side effects and toxicities are seen regularly that can compromise the treatment success. METHODS: Literature review: CAR T­cell therapy, toxicities and their management RESULTS: The cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS) are seen regularly after CAR T­cell treatment. CRS symptoms can range from mild flu-like symptoms to severe organ dysfunction requiring vasopressor therapy, mechanical ventilation and other intensive care support. ICANS symptoms usually develop later and can range from disorientation and aphasia to potentially life-threatening brain edema. IL­6 is a key factor in the pathophysiology of CRS. The pathophysiology of ICANS is not fully understood. The ASTCT consensus grading is recommended to stratify patients for different management options. An interdisciplinary team including hematologist, intensivist, neurologists and other specialties is needed to optimize the treatment. DISCUSSION: Severe and potentially life-threatening toxicities occur regularly after CAR T­cell therapy. Treatment strategies for CRS and ICANS still need to be evaluated prospectively. Due to the increasing number of patients treated with CAR T­cells the number of patients requiring temporary intensive care management due to CRS and ICANS is expected to increase during the next years.

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer.

BACKGROUND: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles (3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. RESULTS: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses (median cumulative dose 339 mg/m(2)) was administered (range: 2-18). The overall response rate was 48.1% (95% CI: 34-61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months (intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. CONCLUSION: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status.

Are serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin?

BACKGROUND: Serial kinetics of serum CA 19-9 levels have been reported to reflect response and survival in patients with pancreatic cancer undergoing surgery, radiotherapy, and chemotherapy. We prospectively studied serial kinetics of serum CA 19-9 levels of patients with locally advanced or metastatic disease treated with gemcitabine and cisplatin. PATIENTS AND METHODS: Enrolled in the study were 87 patients (female/male = 26/61; stage III/IV disease = 24/63). Patients received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 plus cisplatin 50 mg/m(2) on days 1 and 15, every 4 weeks. Serum samples were collected at the onset of chemotherapy and before the start of a new treatment cycle (day 28). RESULTS: 77 of 87 patients (88.5%) with initially elevated CA 19-9 levels were included for evaluation. According to imaging criteria, 4 (5.2%) achieved a complete remission and 11 (14.3%) achieved partial remission, yielding an overall response rate of 19.5%. 43 (55.8%) patients were CA 19-9 responders, defined by a > or = 50% decrease in CA 19-9 serum levels within 2 months after treatment initiation. Except for one, all patients who had responded by imaging criteria (n = 14) fulfilled the criterion of a CA 19-9 responder. Despite being characterized as non-responders by CT-imaging criteria (stable/progressive disease), 29 patients were classified as CA 19-9 responders (positive predictive value 32.5%). Independent of the response evaluation by CT, CA 19-9 responders survived significantly longer than CA 19-9 nonresponders (295 d; 95% CI: 285-445 vs. 174 d; 95% CI: 134-198; p = 0.022). CONCLUSION: CA 19-9 kinetics in serum serve as an early and reliable indicator of response and help to predict survival in patients with advanced pancreatic cancer receiving effective treatment with gemcitabine and cisplatin.

Leukapheresis in chronic myelomonocytic leukemia with leukostasis syndrome: elevated serum lactate levels as an early sign of microcirculation failure.

We present the course of three patients suffering from chronic myelomonocytic leukemia (CMML), who presented with a markedly increase of their WBC (>200 G/l). All patients were started on chemotherapy consisting of ARA-C given as continuous infusion. Due to acute respiratory insufficiency, all patients were treated in the ICCU with ventilation support. Respiratory insufficiency was most likely due to pulmonary leukostasis since pulmonary infection or edema were excluded by X-ray in all patients. Therapeutic leukapheresis was therefore initiated and resulted in a dramatic improvement in one patient. Two patients died due to multiorganic failure despite effective leukocyte depletion (>40%) and maximum supportive care. At the onset of symptoms, two patients had markedly elevated serum lactate levels most likely due to microcirculatory failure. Both patients died because of deteriorating sequelae of pulmonary leukostasis, however, the patient with marginally elevated serum lactate levels survived. Leukapheresis is an established therapeutic approach in patients with hyperleukocytosis and leukostasis, which improves the prognosis of high-risk patients. In our opinion, patients presenting with asymptomatic hyperleukocytosis may benefit from early leukapheresis, particularly when increasing serum lactate levels indicate the early onset of microcirculatory failure.

Capecitabine as second-line treatment for metastatic cholangiocarcinoma: a report of two cases.

BACKGROUND: The management of recurrent, metastatic cholangiocarcinoma still remains a problem since this tumor entity is classified as chemotherapy-resistant. When advanced or metastatic disease is diagnosed, the therapeutic efforts are essentially directed toward palliation. PATIENTS AND METHODS: We report on 2 patients suffering from metastatic cholangiocarcinoma. Both had received previous chemotherapy for metastatic disease, including hepatic artery infusion [5-fluorouracil (5-FU) / folinic acid (FA) and oxaliplatin] and a combination therapy consisting of 5-FU/FA and gemcitabine. Since a progression of the disease was diagnosed, both patients were started on oral capecitabine at a daily dose of 2,500 mg/m(2) in 2 divided doses for 2 weeks, followed by 1 week rest. RESULTS: Capecitabine was tolerated well and severe side effects were not observed. A stop of progression, documented by imaging procedures and tumor marker kinetics, was achieved in both patients. CONCLUSION: Capecitabine could potentially be used for secondline treatment in patients with progressive metastatic cholangiocarcinoma.

Weekly irinotecan in a patient with metastatic colorectal cancer on hemodialysis due to chronic renal failure.

BACKGROUND: The cytotoxic treatment of patients suffering from advanced or metastatic cancer undergoing hemodialysis due to chronic renal failure still remains a problem, since for those patients pharmacokinetic and pharmacodynamic data on most cytotoxic agents are lacking. CASE REPORT: We report a 45-year-old male who suffered from chronic renal failure and was diagnosed with stage-3 colorectal cancer (CRC) in February 2000. After surgical removal of the tumor an adjuvant chemotherapy of dose-reduced i.v. bolus 5-fluorouracil and folinic acid was begun (Mayo protocol). Due to excessive gastrointestinal toxicity, therapy was discontinued after the first cycle. In April 2000 liver metastases were diagnosed. The patient was then put on a weekly schedule of dose-reduced CPT-11 (50 mg/m(2), 80 mg total). No hematological or non-hematological toxicity grade 3/4 was observed. Due to excellent tolerability and lack of severe side effects the dose was increased up to 80 mg/m(2) (140 mg total) weekly. A dose escalation to 100 mg/m(2) (180 mg total) resulted in severe diarrhea (grade 4). Within 2 months of treatment the patient achieved a lasting partial remission until April 2001 (12 months). A significant progression of hepatic metastases required an alternative treatment regimen beginning in July 2001 (HAI, hepatic artery infusion). CONCLUSION: This case report demonstrates the feasibility and efficacy of a weekly treatment with dose-reduced CPT-11 in a patient with metastatic CRC on hemodialysis due to chronic renal failure.

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer.

BACKGROUND: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. PATIENTS AND METHODS: Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). RESULTS: Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). CONCLUSIONS: The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.

[Magnetic resonance tomography studies of the hypophysis in children with growth hormone deficiency, born with umbilical cord entanglement]. / Kernspintomographische Untersuchungen der Hypophyse bei Kindern mit Wachstumshormonmangel, geboren mit Nabelschnurumschlingung.

Eight children with either panhypopituarism, severe growth hormone deficiency or neurosecretory dysfunction for growth hormone with a common history of umbilical cord encirclement around the neck underwent magnetic resonance imaging of the pituitary gland and the hypothalamus. Panhypopituitarism was associated with small to absent adenohypophysis, narrow or absent stalk and ectopic neurohypophysis whereas patients with partial GHD showed normal anatomical structures. Etiology of the endocrinopathy could be a primary malformation of the pituitary gland, an apoplexy of the gland or disturbation within the hypothalamus. We believe that the latter cause is predominant in umbilical cord encirclement.

Kallman syndrome versus idiopathic hypogonadotropic hypogonadism at MR imaging.

PURPOSE: To identify morphologic differences between Kallman syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH) and establish a role for magnetic resonance (MR) imaging in these disorders. MATERIALS AND METHODS: Twenty-eight patients were compared with 10 eugonal male volunteers. Eighteen patients had KS (hypogonadotropic hypogonadism with anosmia) and 10 had IHH. All participants underwent hormone analysis, a sniff-bottle smell test, and gadolinium-enhanced MR imaging. Changes in the hypothalamic-hypophyseal region and the rhinencephalon were evaluated. RESULTS: MR imaging revealed intracranial morphologic changes in all patients on plain T1-weighted sections. Seventeen patients with KS demonstrated aplasia of an olfactory bulb; one olfactory sulcus was absent in six, rudimentary in four, and normal in eight. Olfactory bulbs were present in all 10 IHH patients and three showed one slightly hypoplastic bulb. Ten patients with KS and three with IHH showed an enlarged paranasal sinus system. Further MR findings were similar. CONCLUSION: MR imaging demonstrates abnormalities of the rhinencephalon present in KS patients and occasionally absent in IHH patients.

MR and MR angiography of Sturge-Weber syndrome.

PURPOSE: To assess the potential of magnetic resonance angiography (MRA) as an adjunct to spin-echo sequences in evaluating the cerebral vascular anomalies seen in Sturge-Weber syndrome. METHODS: Four pediatric patients with Sturge-Weber syndrome were evaluated with conventional MR imaging and with arterial and venous MRA. Resultant images were evaluated for evidence of volume loss, cortical enhancement, vascular anomalies, and enlarged choroid plexus. RESULTS: Venous MRA revealed reduced flow of the transverse sinuses and jugular veins, prominent deep collateral venous system, and a lack of superficial cortical veins. Arterial MRA, performed in all cases, revealed a reduced flow signal from the left middle cerebral artery in one hemiparetic patient and angiomatous changes of high branches of a middle cerebral artery in two patients. CONCLUSION: Arterial and, in particular, venous MRA can be useful adjuncts to standard spin-echo sequences in diagnosing Sturge-Weber syndrome.

MR angiography in children with cerebral neurovascular diseases: findings in 31 cases.

OBJECTIVE: We evaluated the suitability of MR angiography for routine use in children with suspected intracranial vascular disease. SUBJECTS AND METHODS: Thirty-one children, 6 months to 14 years old, with intracranial lesions or clinically suspected vascular malformations were studied prospectively with conventional MR imaging and time-of-flight MR angiography. In nine cases, MR angiographic findings were verified with digital subtraction angiography or conventional angiography. All MR studies were performed on a 1.5-T MR system using a circularly polarized head coil. RESULTS: Arterial MR angiography, performed in 24 cases, revealed congenital abnormalities of the arterial vessels in 20 cases. Vessel stenosis was observed in nine patients, and displacement of intracranial arteries due to tumors could be seen in 10 patients. Seven children had no abnormal findings. Venous MR angiography was performed in seven children, with depiction of sinus thrombosis in six cases. The comparative analysis of MR angiography and digital subtraction angiography showed equivalent results in nine patients; in one patient the degree of stenosis was overestimated with MR angiography. CONCLUSION: MR angiography, when combined with MR imaging, reveals information about soft-tissue and vascular structures in a single setting. At this point, MR angiography can replace invasive conventional angiography or digital subtraction angiography only in selected cases because of software and hardware limitations. Arterial or venous MR angiography can be helpful as an additional scan in MR examinations of children with suspected cerebral neurovascular diseases, and its noninvasive nature makes it well suited for routine use in children.

[MR angiography in neuropediatric problems: the technic and the clinical results]. / MR-Angiographie bei neuropädiatrischen Fragestellungen: Technik und klinische Ergebnisse.

31 children aged between 6 months and 14 years with various neurovascular abnormalities were examined by MR angiography in a prospective study. In order to test the sensitivity and specificity of the MR results, these were compared in 8 cases with the findings of digital subtraction angiography or conventional angiography. In 24 patients arterial MR angiography was performed; in 17 these showed anomalies or abnormalities of the intracranial vascular system. In 7 patients venous MR angiography was performed and demonstrated the presence of sinus thrombosis in 6 of these. Comparison between MR angiography and DSA showed agreement in 7 cases; in one patient the degree of a stenosis was exaggerated by MR. The results of this study indicate that arterial and venous MR is of great value as an additional study in paediatric neurovascular problems.

Vibrio species associated with mortality of sharks held in captivity.

Two urease-positiveVibrio spp. were isolated from a brown shark (Carcharhinus plumbeus) that died in captivity at a national aquarium. Morphological, biochemical, and molecular genetic studies revealed one of the isolates to beV. damsela; the other isolate was unique and has been classified asV. carchariae sp. nov. BothV. damsela andV. carchariae were found to be virulent for spiny dogfish (Squalus acanthias), causing death in less than 18 hours after intraperitoneal injection of ca. 4×10(6) cells.V. damsela was strongly cytotoxic for Y1 adrenal cell monolayers;V. carchariae exhibited weak cytotoxicity for Y1 cells.V. damsela contained cryptic plasmids and both isolates were urease positive.V. carchariae was able to utilize urea as sole source of carbon and nitrogen.