ATM mutations in Finnish breast cancer patients.
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Adult↗
Biomedical subjects
L Jansen
Publications and source records attributed to L Jansen.
Evidence for a putative senescence gene locus within the chromosomal region 10p14-p15.
High-risk human papillomavirus (HPV) types 16 and 18 are involved in the multistep process of cervical cancer. Transfection of normal keratinocytes with high-risk HPV-DNA generally gives rise to immortal cultures. This may be explained by the loss of senescence genes as a consequence of HPV-induced genetic instability. On the basis of the dominance of cellular senescence over immortality, fusion of normal keratinocytes with HPV-immortalized cells results in complementation of these putative gene defects. In a previous study, we showed that underrepresentation of chromosome 10 is a characteristic phenomenon during the early phase of immortalization. Here we show that introduction of a normal copy of chromosome 10 into HPV16-immortalized cells (HPKII) by Microcell-mediated chromosome transfer resulted in senescence of a significant number of hybrids. By using several derivatives of chromosome 10 for further fusion experiments, the chromosomal region responsible for senescence could be assigned to 10p14-p15. The potential significance of loss of gene function in this region is underlined by the high frequency (38.7%) of loss of heterozygosity in cervical cancers including early stage tumors.
Carcinoma, Squamous Cell↗
Is lymphatic mapping in breast cancer adequate and safe?
Lymphatic mapping with selective lymphadenectomy requires a concerted effort from the nuclear medicine physician, surgeon, and pathologist. Application of preoperative lymphoscintigraphy, and intraoperative use of both a gamma detection probe and a vital dye are recommended. This combined approach increases the likelihood of finding all sentinel nodes without removing nonsentinel nodes. A literature review of current experience reveals that the sentinel node can be found in more than 90% of the patients. When confirmatory lymphadenectomy follows, the false-negative rate can be kept down to about 5% after a certain learning phase. The sensitivity of this novel approach to detect lymphatic dissemination is currently overestimated because lymph node metastases in patients with a tumor-free sentinel node are probably overlooked. This shortcoming will be compensated by the more accurate pathologic evaluation of a sentinel node and the finding of sentinel nodes outside the axilla. Therefore the procedure is probably adequate and safe in patients at low risk of having disseminated disease. Lymphatic mapping with sentinel node biopsy is rapidly becoming the standard of care.
Breast Neoplasms↗
Penile lymphoscintigraphy for sentinel node identification.
Lymphoscintigraphy for sentinel node (SN) identification has been extensively validated in breast cancer and melanoma. The aim of this study was to evaluate the findings of lymphoscintigraphy for SN identification in carcinoma of the penis. Lymphoscintigraphy was performed in 74 consecutive patients (mean age 62.2 years, range 28-87 years) with clinically lymph node-negative squamous cell carcinoma of the penis (stage T2 or greater). Following local anaesthesia by xylocaine 10% spray, technetium-99m nanocolloid (mean dose 64.8 MBq, range 40-131 MBq) in a volume of 0.3-0.4 ml was injected intradermally around the tumour. Shortly after injection, a 20-min dynamic study was performed with a dual-head gamma camera; subsequently, static anterior and lateral images were obtained at 30 min and 2 h using simultaneous cobalt-57 flood source transmission scanning. 57Co-assisted skin marking defined SN location for gamma probe/blue dye-guided biopsy, which was performed the next day. The SN visualization rate was 97% (72/74). Lymphatic drainage was bilateral in 81% of the cases (58/72), exclusively to the left groin in 13% (9/72) and only to the right groin in 6%. Bilateral lymph node drainage was synchronous in 38% (22/58) and asynchronous in 62% (in 18 patients the initial route was the left groin, and in the other 18, the right groin). Visualization before 30 min occurred in 66 patients (93%), in 64 of them (88%) already during the dynamic study. A total of 173 SNs were visualized (85 in the right groin, 88 in the left groin). Pitfalls were caused by inguinal skin contamination during injection (four patients) and intracavernous administration (one patient). At surgery, a total of 161 SNs were identified and removed. Sixteen patients (22%) had a tumour-positive SN and underwent standard regional lymph node dissection subsequently. During follow-up (median 28 months, range 3-74 months), two patients with a negative SN developed lymph node metastases in the mapped basin. It is concluded that penile lymphoscintigraphy is a valid and well-tolerated method for lymphatic mapping and SN identification. Although bilateral early inguinal drainage is the most frequent pattern, late imaging is recommended principally in patients with initial unilateral drainage in order to exclude delayed lymph node filling in the contralateral groin. SN identification may lead to a more accurate staging and avoid extensive lymph node dissection in the majority of patients with penile carcinoma.
Adult↗
Sentinel nodes outside lymph node basins in patients with melanoma.
BACKGROUND: Lymphoscintigraphy occasionally reveals hot spots outside lymph node basins in patients with melanoma. The aim of this study was to evaluate such abnormally located hot spots. METHODS: Sentinel node biopsy was studied prospectively in 379 patients with clinically localized cutaneous melanoma. One day after lymphoscintigraphy, sentinel node biopsy was performed guided by vital blue dye and a gamma ray detection probe. RESULTS: Persisting hot spots outside the regional node basins were seen in 25 patients (6.6 per cent). Several specific drainage patterns were discerned. In five patients, aberrant sentinel nodes were not explored. The hot spot represented a lymphangioma in two patients. Radioactive lymph nodes were identified in the remaining 18 patients (4.7 per cent). Four patients had metastasis in one of these aberrant lymph nodes. CONCLUSION: Sentinel nodes were found outside a lymph node basin in 5 per cent of patients. Particular drainage patterns exist. It is recommended to incorporate such sites in the late scintigraphy images and to pursue aberrant sentinel nodes, as they may be the only sites of metastasis.
Biopsy↗
Comment on "Cuprate superconductivity: dependence of T(c) on the c-axis layering structure"
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Journal Article↗
Lymphatic mapping with intralesional tracer administration in breast carcinoma patients.
BACKGROUND: The objectives of the study were to determine how often a sentinel lymph node is visualized by lymphoscintigraphy in breast carcinoma patients, how often the sentinel lymph node is identified during surgery, and the sensitivity of these procedures to identify the presence of axillary lymph node metastasis. METHODS: A total of 136 patients were enrolled in 2 hospitals. Preoperative dynamic and static lymphoscintigraphy were performed; in addition, both a vital dye and a gamma detection probe were used intraoperatively. The tracers were injected into the primary lesion. Sentinel lymph node biopsy was followed by completion axillary lymph node dissection. The sentinel lymph nodes and other axillary lymph nodes were examined routinely and by immunohistochemical staining. RESULTS: A sentinel lymph node was visualized by lymphoscintigraphy in 118 patients (87%). During the operation a sentinel lymph node was localized in 126 patients (93%). A total of 224 sentinel lymph nodes were harvested (average of 1.7 and range of 1-4 sentinel lymph nodes per patient). Of all the sentinel lymph nodes, 37 were blue (17%), 68 were radioactive (30%), and 119 were both blue and radioactive (53%). The sentinel lymph nodes contained metastatic disease in 56 patients (44%). Three sentinel lymph node biopsies were false-negative (sensitivity 95%). CONCLUSIONS: Sentinel lymph node biopsy with preoperative lymphoscintigraphy after intralesional tracer administration and intraoperative use of both a gamma detection probe and a vital dye is a reliable technique for staging the axilla of breast carcinoma patients.
Adult↗
Acceleration of lymphomagenesis in mismatch-repair deficient mice by exposure to genotoxic agents.
Hemizygosity for genes that are essential for DNA mismatch repair (MMR) was found to underlie cancer predisposition in hereditary nonpolypsis colorectal cancer (HNPCC). Loss of the wild-type allele generates a MMR-deficient cell compartment with a high propensity to oncogenic transformation. MMR deficiency not only accelerates spontaneous mutagenesis resulting from DNA replication errors, but also affects the cellular response to genotoxic agents. To study the consequences of MMR deficiency in vitro and to provide experimental access to HNPCC we have generated MMR-deficient cell lines and mice. The combination of MMR deficiency and exposure to genotoxic agents strongly accelerated lymphomagenesis.
Animals↗
Sentinel node biopsy for melanoma in the head and neck region.
BACKGROUND: Lymphatic drainage in the head and neck region is known to be particularly complex. This study explores the value of sentinel node biopsy for melanoma in the head and neck region. METHODS: Thirty consecutive patients with clinically localized cutaneous melanoma in the head and neck region were included. Sentinel node biopsy was performed with blue dye and a gamma probe after preoperative lymphoscintigraphy. Average follow-up was 23 months (range, 1-48). RESULTS: In 27 of 30 patients, a sentinel node was identified (90%). Only 53% of sentinel nodes were both blue and radioactive. A sentinel node was tumor-positive in 8 patients. The sentinel node was false-negative in two cases. Sensitivity of the procedure was 80% (8 of 10). CONCLUSIONS: Sentinel node biopsy in the head and neck region is a technically demanding procedure. Although it may help determine whether a neck dissection is necessary in certain patients, further investigation is required before this technique can be recommended for the standard management of cutaneous head and neck melanoma.
Adult↗
Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.
The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8-1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease-causing alleles were characterized. Thirty-seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in-frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease-causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein.
Alternative Splicing↗
Reliability of lymphoscintigraphy in indicating the number of sentinel nodes in melanoma patients.
BACKGROUND: This study was undertaken to establish the reliability of lymphoscintigraphy in indicating the number of sentinel nodes in patients with melanoma. METHODS: Lymphoscintigraphy was performed with dynamic imaging after injection of 60 MBq 99mTc-nanocolloid (1.6 mCi) and static imaging after 2 hours in 200 patients with clinically localized primary melanoma of the skin. The following day, sentinel nodes were retrieved with the blue dye technique and a gamma detection probe (Neoprobe 1000/1500). The discrepancies between the number of sentinel nodes indicated by lymphoscintigraphy and the actual number of sentinel nodes as established by the surgeon were evaluated. RESULTS: Lymphoscintigraphy showed drainage to 393 sentinel nodes in 255 lymphatic fields in 199 patients. In 48 lymphatic fields (19%) in 46 patients (23%), the number of sentinel nodes was different from the number that was visualized with scintigraphy. Additional sentinel nodes were found by the surgeon because a lymphatic vessel was not seen on the lymphoscintigraphy (43%), because a sentinel node was not visualized separately from other hot nodes or vessels or the injection site (36%), or because a sentinel node was blue and not hot (4%). Fewer sentinel nodes were found than suggested by scintigraphy because a lymphangioma was mistaken for a sentinel node (4%) or because a single elongated node was depicted as two hot spots (6%). CONCLUSIONS: Although lymphoscintigraphy is indispensable for lymphatic mapping, the predicted number of sentinel nodes is accurate in only 81% of lymph node fields. The limited discriminating power of the gamma camera is an important cause of discrepancies.
Adolescent↗
Reliability of sentinel lymph node biopsy for staging melanoma.
BACKGROUND: The aim of this study was to evaluate the reliability of sentinel lymph node biopsy for staging melanoma. METHODS: Two hundred consecutive patients with a cutaneous melanoma of at least 1. 0 mm Breslow thickness, without palpable regional lymph nodes, were included from 1993 in a prospective cohort study in a single tertiary care hospital. One day after lymphoscintigraphy, sentinel node biopsy was performed, guided by a gamma probe and patent blue dye. Lymph node dissection was performed only if metastasis was found in a sentinel node. Median follow-up was 32 (range 3-61) months. No patient was lost to follow-up. RESULTS: A sentinel node was removed in 199 of 200 patients (mean 2.2 nodes per patient). Forty-eight patients (24 per cent) had metastasis in a sentinel node. Fifteen patients developed recurrence after removal of a tumour-negative sentinel node; six relapsed in the previously mapped basin (false-negative rate 11 per cent (six of 54)). The overall survival at 3 years was 93 per cent if the sentinel node was negative and 67 per cent if it was positive. Sentinel node status and Breslow thickness were strong predictors of recurrence and survival. Minor complications were seen in 18 patients. CONCLUSION: The sentinel node status was a strong prognostic factor, even with a false-negative rate of 11 per cent. Published in abstract form as Eur J Nucl Med 1999; 26(Suppl): S57
Adolescent↗
Clinical relevance of sentinel lymph nodes outside the axilla in patients with breast cancer.
BACKGROUND: Lymphatic mapping in patients with breast cancer can reveal sentinel lymph nodes that are not located at level I-II of the axilla. Little is known about the clinical relevance of these nodes. METHODS: Some 113 consecutive patients with clinical stage T1-3 N0 M0 breast cancer were studied. Based on preoperative lymphoscintigraphy, sentinel node biopsy was performed guided by a gamma probe and patent blue dye. All sentinel nodes that were visible on lymphoscintigraphy were sought. Pathological examination of the sentinel nodes included step-sections and staining with CAM 5. 2. Axillary node dissection was performed regardless of sentinel lymph node status. RESULTS: Twenty-one (19 per cent) of 113 patients had sentinel lymph nodes outside level I-II of the axilla, mostly in the internal mammary chain. Twenty-two of the 30 sentinel nodes at these sites were harvested. Three patients had sentinel nodes only outside the axilla. Four other patients had metastases outside the axilla. This changed postoperative treatment in three patients. No postoperative complication occurred. CONCLUSION: Sentinel lymph nodes outside level I-II of the axilla were present in 19 per cent of patients with breast cancer in this series. Biopsy of these nodes was technically demanding but was performed without additional morbidity. The clinical impact was limited; treatment changed in only 3 per cent. Presented to the 52nd annual meeting of the Society of Surgical Oncology in Orlando, Florida, USA, March 1999 and the First International Congress on the Sentinel Node in Diagnosis and Treatment of Cancer in Amsterdam, The Netherlands, April 1999, and published in abstract form as Eur J Nucl Med 1999; 26(Suppl): S71
Adult↗
CORRESPONDENCE: Authors' reply
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Journal Article↗
Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure.
PURPOSE: We evaluated the so-called dynamic sentinel node procedure in patients with penile cancer. This new staging technique consists of excisional biopsy of the first lymph node onto which a tumor drains the so-called sentinel node, based on individual mapping of lymphatic drainage. MATERIALS AND METHODS: From 1994 to 1998, 55 consecutive patients with stage T2 or greater bilateral or unilateral node negative squamous cell carcinoma of the penis were prospectively entered in this study. Tumor stage was T2N0 in 42, T2N1 in 4 and T3N0 in 9 cases. To locate the sentinel node each patient underwent lymphoscintigraphy with 99mtechnetium nanocolloid injected intradermally around the tumor. The following day the sentinel node was identified intraoperatively using patent blue dye injected intradermally around the tumor and a gamma detection probe. Regional lymph node dissection was restricted to patients with a tumor positive sentinel node only. RESULTS: Scintigraphy revealed 125 sentinel nodes in 107 inguinal regions, including no sentinel node in 2 patients, 1 or more unilateral nodes in 10 and bilateral drainage in 43. At surgery 108 sentinel nodes were removed. In 8 patients with 2 or more sentinel nodes on lymphoscintigraphy only 1 was noted intraoperatively and in 9 an additional sentinel node was removed, which was not identified by scintigraphy. All nodes were identified with the gamma detection probe. In 1 patient a wound abscess developed. Regional lymph node dissection was performed in 11 patients with sentinel node metastasis. Median followup was 22 months (range 4.1 to 61). In 1 patient lymph node metastasis was noted at followup despite prior excision of a tumor-free sentinel node. CONCLUSIONS: The dynamic sentinel node procedure is a promising staging technique to detect early metastatic dissemination of penile cancer based on individual mapping of lymphatic drainage, and enables identification of patients with clinically node negative disease requiring regional lymph node dissection.
Adult↗
Evaluation of mammary lymphoscintigraphy by a single intratumoral injection for sentinel node identification.
UNLABELLED: The aim of this study was to evaluate the findings of mammary lymphoscintigraphy by a single intratumoral injection in 150 patients with breast carcinoma: 100 patients (group A) investigated in the validation phase of the study and 50 (group B) studied after the tracer dose was optimized. METHODS: Immediately after injection of 99mTc-nanocolloid using a 25-gauge needle and a 0.2-mL volume, simultaneous anterior and lateral images were acquired with a dual-head gamma camera during 20 min followed by sequential static anterior and prone lateral breast images after 30 min and after 2 and 4 h. 57Co-assisted skin marking defined the sentinel node location for subsequent gamma probe, blue dye-guided sentinel node biopsy. RESULTS: In group A (mean dose, 61.6 MBq; range, 42-88 MBq) scintigraphy revealed lymph nodes in 83 patients (83%), with an increase in the rate of visualization from 72% for the first 40 patients to 90% for the last 60; patient age (P = 0.01) and administered tracer dose (P = 0.04) were found to be significant factors for visualization, with optimal results obtained from doses higher than 65 MBq. Lymph nodes were visible in 34 patients (41%) during the first 30 min after injection, whereas in 49 patients appearance occurred at 2-4 h. A total of 97 lymphatic basins were visualized (80 axillary, 3 clavicular, 14 internal mammary). In group B (mean dose, 90.8 MBq; range, 68-124 MBq), the visualization rate was 94%, with early lymph node appearance in 27 patients (57%) and a total of 53 basins (45 axillary, 8 internal mammary). In combination with intraoperative blue dye mapping and y probing, the identification rate increased to 90% in group A and 98% in group B. Prone lateral images contributed to identification of intramammary lymph nodes in a total of 14 patients and axillary nodes close to the injection site in 8 other patients. CONCLUSION: Mammary lymphoscintigraphy by single intratumoral injection is a valid method for lymphatic mapping and identification of both axillary and nonaxillary sentinel nodes. Lymph node visualization appears to be improved with higher tracer doses. The compactness of the injection site enables high-quality additional lateral images that can depict intramammary or axillary lymph nodes adjacent to the injection site.
Adult↗
Lymphoscintigraphy in oncology: a rediscovered challenge.
The validation of the sentinel node concept in oncology has led to the rediscovery of lymphoscintigraphy. By combining preoperative lymphatic mapping with intraoperative probe detection this nuclear medicine procedure is being increasingly used to identify and detect the sentinel node in melanoma, breast cancer, and in other malignancies such as penile cancer and vulvar cancer. In the past lymphoscintigraphy has been widely applied for various indications in oncology, and in the case of the internal mammary lymph-node chain its current use in breast cancer remains essential to adjust irradiation treatment to the individual findings of each patient. In another diagnostic area, lymphoscintigraphy is also useful to document altered drainage patterns after surgery and/or radiotherapy; its use in breast cancer patients with upper limb oedema after axillary lymph-node dissection or in melanoma patients with lower-extremity oedema after groin dissection can provide information for physiotherapy or reconstructive surgery. Finally, the renewed interest in lymphoscintigraphy in oncology has led not only to the rediscovery of findings from old literature reports, but also to a discussion about methodological aspects such as tracer characteristics, image acquisition or administration routes, as well as to discussion on the study of migration patterns of radiolabelled colloid particles in the context of cancer dissemination. All this makes the need for standardized guidelines for lymphoscintigraphy mandatory.
Breast Neoplasms↗
Lymphatic mapping and sentinel lymph node biopsy in breast cancer.
Lymphatic mapping with selective lymphadenectomy is an attractive approach in breast-cancer patients. It uses existing technology to exploit logical anatomic and physiological principles to identify occult regional lymph-node metastases. The lymphatic flow is visualized and the first (sentinel) lymph node on a direct drainage pathway from the primary tumour is identified. This is the node at greatest risk of harbouring metastatic deposits. Retrieving this node requires a concerted effort from the nuclear medicine physician, surgeon and pathologist. Lymphoscintigraphy can indicate the number of sentinel nodes and their location. The surgeon can use two techniques to find the node. A vital dye injected at the tumour site will stain the lymphatic duct as well as the sentinel node and allow their visual identification. Alternatively, a lymph-node-seeking radiopharmaceutical will also migrate from the tumour site to the sentinel node and will enable its retrieval with the use of a gamma detection probe. The pathologist has a number of techniques to identify tumour deposits in the lymph node. A review of the literature shows that the sentinel node can be found in more than 90% of the patients. With experience, the false-negative rate can be kept down to about 5%. This novel approach of lymphatic mapping with selective lymphadenectomy may lead to a substantial reduction in the need for axillary node dissection in patients with breast cancer without compromising survival and regional control, and without loss of prognostic and staging information. This development will translate into a great reduction in patient morbidity and medical expenses.
Breast Neoplasms↗