Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect?

Several forms of pulmonary disease occur among patients treated with amiodarone, i.e. chronic interstitial pneumonitis, organizing pneumonia, ARDS, a solitary pulmonary mass of fibrosis. The prevalence is estimated to be about 5%. Two major hypotheses of amiodarone-induced pulmonary injury include direct cytotoxicity and a hypersensitivity reaction. Given the frequency and potential severity of amiodarone-induced pulmonary toxicity, early detection is desirable. Unfortunately, there are no adequate predictors of pulmonary toxicity due to amiodarone. Patients who should benefit from amiodarone should be carefully selected and the lowest effective dosage of amiodarone should be taken. Amiodarone-induced pulmonary toxicity is a diagnosis of exclusion. Pulmonary evaluation with chest X-ray and pulmonary function testing, including diffusion capacity for carbon monoxide is recommended when amiodarone is started. A documented decline in the diffusing capacity of greater than 20% is useful in suggesting the need for closer monitoring or for further diagnostic testing. Although the optimal frequency of follow-up has not been determined, most cases of amiodarone-induced lung injury develop during the first 2 years of treatment and disease onset usually is slow. Pulmonary function tests and imaging may be performed every 3-6 months, depending on the presumed individual risk. Treatment of amiodarone pulmonary toxicity consists primarily of stopping amiodarone. Corticosteroid therapy can be life-saving for severe cases and for patients with less severe disease in whom withdrawal of amiodarone is not desirable. Due to its accumulation in fatty tissues and long elimination half-life, pulmonary toxicity may initially progress despite drug discontinuation and may recur after steroid withdrawal. The prognosis of amiodarone lung disease is generally favourable.

Invasive aspergillosis osteomyelitis in children--a case report and review of the literature.

Immunocompromised patients are at high risk of secondary infection associated with high morbidity. In children these complications include fungal osteomyelitis due to continuous infiltration or hematogenous spread. The case of a 4-year-old boy is presented who developed lumbalgia and thigh pain during ongoing chemotherapy for acute lymphatic leukemia. MRI revealed infarct-like lesions in the femur and L5 vertebra, which were biopsied. The histologic diagnosis was consistent with angioinvasive aspergillosis. A multifocal osseous presentation has rarely been described in children and an overview of the literature is presented. Invasive aspergillosis is a rare complication to be considered in children with MRI-detected bony lesions of infarct-like appearance.

Radioguided surgery in urological malignancies.

The current literature was reviewed for articles focusing on radioguided surgery in urological malignancies.In penile cancer sentinel lymph node dissection is part of international guidelines. By detailed histopathological analysis (serial sections, immunohistochemical staining) more micrometastases are detectable improving the histopathological staging.In prostate cancer this technique also improves staging since a high percentage of patients have lymph node metastases located outside the region of standard lymphadenectomy. Compared to extended lymph node dissection radioguided surgery has a lower morbidity, especially a lower rate of lymphoceles.In bladder cancer the sentinel lymph node (SLN) technique has some limitations. Combined with extended lymph node dissection more positive lymph nodes are removed which possibly improves survival.In renal cell and testicular cancer there are only preliminary results. Further investigations will show whether this technique will play an important role in the diagnostics and therapy of these tumors.In all urological malignancies the SLN concept is only a staging procedure. When the sentinel node(s) is (are) negative, the other lymph nodes are negative, too. Since there are no randomized prospective trials comparing the results of sentinel lymphadenectomy with other techniques of lymph node dissection, it is not clear whether sentinel lymph node dissection also has a prognostic impact.

Methylene blue injection into the rectal artery as a simple method to improve lymph node harvest in rectal cancer.

Adequate lymph node assessment in colorectal cancer is crucial for prognosis estimation and further therapy stratification. However, there is still an ongoing debate on required minimum lymph node numbers and the necessity of advanced techniques such as immunohistochemistry or PCR. It has been proven in several studies that lymph node harvest is often inadequate under routine analysis. Lymph nodes smaller than 5 mm are especially concerning as they can carry the majority of metastases. These small, but affected lymph nodes may escape detection in routine analysis. Therefore, fat-clearing protocols and sentinel techniques have been developed to improve accuracy of lymph node staging. We describe a novel and simple method of ex vivo methylene blue injection into the superior rectal artery of rectal cancer specimens, which highlights lymph nodes and makes them easy to detect during manual dissection. Initially, this method was developed for proving accuracy of total mesorectal excision. We performed a retrospective study comparing lymph node recovery of 12 methylene blue stained and an equal number of unstained cases. Lymph node recovery differed significantly with average lymph node numbers of 27+/-7 and 14+/-4 (P<0.001) for the methylene blue and the unstained group, respectively. The largest difference was found in size groups between 1 and 4 mm causing a shift in size distribution toward smaller nodes. Metastases were confirmed in 21 and 19 lymph nodes occurring in five and four cases, respectively. Hence, we conclude that methylene blue injection technique improves accuracy of lymph node staging by heightening the lymph node harvest in rectal resections. In our experience, it is a very simple time and cost effective method that can be easily established under routine circumstances.

Reliability of preoperative diagnostics and location of lymph node metastases in presumed unilateral prostate cancer.

OBJECTIVE: To investigate the reliability of preoperative diagnostics in predicting the true histopathological stage and grade of prostate cancer, and to examine whether lymph node (LN) metastases in unilateral prostate cancer are located unilaterally and therefore whether it is justified to dissect only the ipsilateral LNs in presumed unilateral disease. PATIENTS AND METHODS: LN metastases in clinically localized prostate cancer are often located near the internal iliac vessels. They will be detected by extended or sentinel pelvic LN dissection (PLND). Both techniques might be time-consuming and require extensive surgical experience. In all, 564 men with impalpable or unilateral palpable prostate cancer and positive biopsy cores only in one prostate lobe had a radical prostatectomy (RP) combined with radio-guided PLND and in some cases an extended PLND. RESULTS: A median of six sentinel LNs (mean, seven) and six non-sentinel LNs (mean, seven) were dissected per patient; 52 of 564 men (9.2%) had positive LNs. Most men with unilateral disease had LN metastases on the same side of the pelvis. Comparing the clinical stage and grade with the tumour stage and grade of the RP specimen, there was a high percentage of upstaging and upgrading even in men with only one positive biopsy core. CONCLUSION: Unilateral prostate cancer preferentially metastasizes to the ipsilateral pelvic LNs. Because there are a few cases of bilateral LN metastases even in unilateral disease, and as it is not possible to reliably predict unilateral disease on the basis of biopsy features, PLND only on the tumour-bearing side has a high risk of understaging, and would possibly leave LN metastases behind.

Sentinel lymph node dissection for prostate cancer: experience with more than 1,000 patients.

PURPOSE: We determined the incidence of positive pelvic lymph nodes in men undergoing radical retropubic prostatectomy and describe the correlation with prostate specific antigen, histological grade and stage. We examined whether tumor cells are localized in the sentinel nodes only or also in other nonsentinel lymph nodes. MATERIALS AND METHODS: A total of 1,055 men with prostate cancer underwent radio guided pelvic lymph node dissection and radical retropubic prostatectomy. In men with prostate specific antigen 20 ng/ml or less and biopsy Gleason score 7 or less only sentinel nodes were removed. In men with prostate specific antigen more than 20 ng/ml or Gleason score greater than 7 extended pelvic lymph node dissection was also performed. RESULTS: Positive lymph nodes were found in 207 men (19.6%). In 63.3% of the men these lymph nodes were detected outside of the region of standard lymphadenectomy. The percent of patients with positive nodes was greater than predicted by currently used nomograms. The higher the preoperative prostate specific antigen, pathological stage and grade, the greater the percent of men with positive sentinel and nonsentinel lymph nodes (p<0.001). CONCLUSIONS: When deciding on pelvic lymph node dissection, sentinel or extended lymphadenectomy should be performed since more than half of patients have positive nodes outside of the region of standard lymphadenectomy. In cases of positive sentinel nodes extended lymph node dissection should be performed since tumor cells are also detectable in nonsentinel lymph nodes.

Limitations of radioguided surgery in high-risk prostate cancer.

OBJECTIVES: To determine how many men with high-risk prostate cancer (prostate-specific antigen [PSA]>20 ng/ml or biopsy Gleason score 8-10) have positive lymph nodes (sentinel lymph nodes [SLNs] and nonsentinel lymph nodes [NSLNs]) and whether these positive nodes are localised in the region of SLN dissection or in other regions, too. METHODS: In 228 men with high-risk prostate cancer radical retropubic prostatectomy combined with radioguided pelvic lymph node dissection and extended lymphadenectomy were performed. Serial sections of the SLNs were analysed immunohistochemically. RESULTS: A median of 7 SLNs (mean, 7) and 11 NSLNs (mean, 11) were dissected per patient. Ninety-six of 228 men (42.1%) had lymph node metastases. Most men had positive lymph nodes along the internal iliac artery alone or in combination with other regions. Twenty-two men had only micrometastatic disease. In 94 of 96 men the SLNs were positive. Twenty-six of 96 men had also positive NSLNs. When SLNs and NSLNs were positive, in more than half the patients the NSLNs were localised outside the region of sentinel lymphadenectomy. CONCLUSIONS: The dissection of SLNs in prostate cancer has a high sensitivity in detecting positive nodes. When SLNs are negative, the other pelvic lymph nodes are also negative in a high percentage of men (sensitivity 97.1%). When the SLNs are positive, patients with high-risk disease also have a high incidence of positive NSLNs. Therefore, when it is aspired to remove all pelvic lymph node metastases sentinel and extended lymphadenectomy should be performed.

Combined application of RT-PCR and immunohistochemistry on paraffin embedded sentinel lymph nodes of prostate cancer patients.

The detection of tumor cells in the sentinel lymph node (SLN) is of great importance for the prognosis of cancer patients. At present, immunohistochemistry and RT-PCR for tumor marker expression are the most sensitive techniques available for this analysis. However, so far, most RT-PCR-based analyses of SLNs have been performed on fresh material, excluding a direct comparison with the (immuno)histologic results. In our view, this does not entirely aid routine diagnosis. We established an efficient method for RNA extraction and RT-PCR from paraffin sections of SLNs from prostate cancer patients and compared the results with the (immuno)histologic data of adjacent sections. Amplifiable RNA was obtained from 133 SLNs of 68 prostate cancer patients. Correlation of PSA-specific RT-PCR with (immuno)histologic findings showed a positive and negative predictive value of 83% and 100%, respectively, for the prostate cancer patients investigated. Four of 12 patients with biochemical relapse, but without (immuno)histologically detectable tumor cells were RT-PCR-positive for PSA. We found that single sections of paraffin-embedded SLNs are suitable for routinely performed RT-PCR. Combined with (immuno)histology, PSA-specific RT-PCR is a revealing supplementary technique for the detection of tumor cells in SLNs of prostate cancer patients.

The influence of serial sections, immunohistochemistry, and extension of pelvic lymph node dissection on the lymph node status in clinically localized prostate cancer.

OBJECTIVES: Pelvic lymph node metastases indicate a poor prognosis for patients with clinically localized prostate cancer. The aim of the study was to investigate the value of extended histopathological techniques considering the extent of pelvic lymphadenectomy and preoperative risk factors. METHODS: Total of 194 patients with prostate cancer were examined. At first all patients had a sampling of the sentinel lymph nodes (SLN) followed in most cases by a modified or extended pelvic lymphadenectomy. Step sections, serial sections and immunohistochemistry (IHC, pancytokeratin antibody) were analyzed in all SLN and so-called non-SLN of the first 100 patients. Later serial sections and IHC of non-SLN were left out. RESULTS: In 26.8% lymphatic metastases were found. The detection rate of lymph node-positive patients depend significantly on the chosen extension of pelvic lymphadenectomy. Limiting the histopathological investigation to the lymph node specimen of the obturator fossa only 44.2% of lymph node-positive cases would have been identified. An additional inclusion of all lymph nodes surrounding the external iliac vessels improves the sensitivity to 65.4% (46.7% and 73.3% for the first 100 patients). Compared to the extension of pelvic lymphadenectomy the diagnostic gain of serial section and IHC (13.8% versus 53.3%) was comparably low. CONCLUSIONS: The extension of pelvic lymph node dissection is of outstanding value for the identification of node-positive patients. Limiting the number of lymph nodes to the ones with the highest probability of bearing lymphatic spread (SLN) makes the use of extensive histopathological techniques more feasible.

Neuroendocrine tumours of the duodenum. Clinical aspects, pathomorphology and therapy.

BACKGROUND AND AIMS: Neuroendocrine tumours (NTs) of the duodenum are uncommon neoplasms. They represent a heterogeneous spectrum of subtypes and may be associated with von Recklinghausen's disease type I (VRD) and multiple endocrine neoplasia type I. There are few studies concerning the biological characteristics and adequate therapy of these tumours. PATIENTS AND METHODS: We report on a retrospective analysis of 12 patients with NTs of the duodenum: six non-ampullary (naNTs) and six ampullary tumours (aNTs). These patients were treated between January 1992 and January 2001. Clinical and histopathological features, therapy and follow-up were evaluated retrospectively and compared with the literature. RESULTS: All tumours were located in the first and second portions of the duodenum. Three of six aNTs presented with jaundice, and four of six naNTs were incidental findings. Two patients with naNTs showed Zollinger-Ellison syndrome and two with aNTs VRD. Of the six patients with naNTs, four were treated by local excision (two endoscopically, two surgical resection), one by Kausch-Whipple operation and in one patient the tumour was an incidental finding in the Billroth II specimen. Four of the six patients with aNTs underwent Kausch-Whipple procedure, one patient ampullectomy (gangliocytic paraganglioma) and one patient palliative chemotherapy. The size of the naNTs were less than 0.6 cm, whereas the size of the aNTs ranged from 1.5 cm to 4 cm. Tumour size of aNTs had no correlation with depth of invasion and metastases. Metastases were found in two aNTs and none of the naNTs. Immunohistochemically tumour cells expressed somatostatin in 5 of 6 aNTs and gastrin in 1 of 6 aNTs and in two gastrinomas. There was no hospital mortality. Two patients died for reasons not related to the tumour. Tumour excision of both patients with gastrinomas was not curative. Three patients with naNTs and four with aNTs are alive without disease. One patient with palliative treatment of a metastasising aNT is alive 66 months after diagnosis. CONCLUSION: Non-ampullary duodenal NTs differ clinically, histologically and immunohistochemically as well as with respect to the extent of resection from NTs of the ampulla of Vater.