[Markers of brain injury in non-invasive biological fluids]. / Markers of brain injury in non-invasive biological fluids.

Hypoxia-ischemia (H-I) constitutes the main phenomenon responsible for brain-blood barrier permeability modifications leading to cerebral vascular autoregulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present article is aimed at investigating the role of dosage biochemical markers in non-invasive biological fluids such as S100B, a calcium binding protein, activin A, a protein expressed in Central nervous System (CNS).

Nebulized liposomal amphotericin B and combined systemic antifungal therapy for the treatment of severe pulmonary aspergillosis after allogeneic hematopoietic stem cell transplant for a fatal mitochondrial disorder.

Nebulized liposomal amphotericin B (20-15 mg twice daily by nebulizer) was combined with high dose intravenous liposomal amphotericin B (10 mg/kg/day) and high dose caspofungin (100 mg/m(2)) for the treatment of severe, recurrent pulmonary aspergillosis following allogeneic hematopoietic stem cell transplantation from alternative donor in a patient with mitochondrial disease (Pearson's syndrome). This combined treatment was administered for 8 days. Nebulized liposomal amphotericin B was well tolerated. Since severe transplant complications developed, nebulized administration was withdrawn and intravenous doses of liposomal amphotericin B and caspofungin were tapered to usual schedules. Pulmonary aspergillosis responded well to 45 days of combined intravenous antifungal therapies which were maintained for 2 years with secondary prophylaxis, because of persistent immunosuppressive treatment.

Pregnancy and tyrosinaemia type II.

A female patient with tyrosinaemia type II is reported having undergone two untreated pregnancies. During pregnancies, plasma tyrosine was raised. The outcomes of both offspring show that maternal tyrosinaemia may have an adverse effect on the developing fetus.

Radioguided sentinel lymph node biopsy in breast cancer surgery.

The concept of sentinel lymph node biopsy in breast cancer surgery relates to the fact that the tumor drains in a logical way through the lymphatic system, from the first to upper levels. Therefore, the first lymph node met (the sentinel node) will most likely be the first to be affected by metastasis, and a negative sentinel node makes it highly unlikely that other nodes are affected. Because axillary node dissection does not improve prognosis of patients with breast cancer (being important only to stage the axilla), sentinel lymph node biopsy might replace complete axillary dissection to stage the axilla in clinically N0 patients. Sentinel lymph node biopsy would represent a significant advantage as a minimally invasive procedure, considering that, after surgery, about 70% of patients are found to be free from metastatic disease, yet axillary node dissection can lead to significant morbidity. Furthermore, histologic sampling errors can be reduced if a single (sentinel) node is assessed extensively rather than few histologic sections in a high number of lymph nodes per patient. Although the pattern of lymph drainage from breast cancer can be variable, the mammary gland and the overlying skin can be considered as a biologic unit in which lymphatics tend to follow the vasculature. Therefore, considering that tumor lymphatics are disorganized and relatively ineffective, subdermal and peritumoral injection of small aliquots of radiotracer is preferred to intratumoral administration. (99m)Tc-labeled colloids with most of the particles in the 100- to 200-nm size range would be ideal for radioguided sentinel node biopsy in breast cancer. Lymphoscintigraphy is an essential part of radioguided sentinel lymph node biopsy because images are used to direct the surgeon to the site of the node. The sentinel lymph node should have a significantly higher count than that of background (at least 10:1 intraoperatively). After removal of the sentinel node, the axilla must be reexamined to ensure that all radioactive sites are identified and removed for analysis. The sentinel lymph node should be processed for intraoperative frozen section examination in its entirety, based on conventional histopathology and, when needed, immune staining with anticytokeratin antibody. The success rate of radioguidance in localizing the sentinel lymph node in breast cancer surgery is about 94%--97% in institutions where a high number of procedures are performed and approaches 99% when combined with the vital blue dye technique. At present, there is no definite evidence that negative sentinel lymph node biopsy is invariably correlated with negative axillary status, except perhaps for T1a-b breast cancers, with a size of < or =1 cm. Randomized clinical trials should elucidate the impact of avoiding axillary node dissection on patients with a negative sentinel lymph node on the long-term clinical outcome of patients.

Sentinel lymph node mapping in early-stage breast cancer: technical issues and results with vital blue dye mapping and radioguided surgery.

BACKGROUND AND OBJECTIVES: Axillary lymph node status is the most important prognostic factor in patients with operable breast cancer. Recent studies have demonstrated the possibility of identifying the sentinel lymph node (sN) as a reliable predictor of axillary lymph node status in both cutaneous melanoma and breast cancer. Sentinel lymph node identification proved feasible by either peritumoral dye injection (Patent Blue-V) or radiodetection, with identification rates of 65-97% and 92-98%, respectively. However, some important issues need further definition, namely (a) optimization of the technique for intraoperative detection of the sN, (b) predictive value of the sN with regard to axillary lymph node status, and (c) reliability of intraoperative histology of the sN. We reviewed our experience in sN detection in patients with stage I-II breast cancer to assess the feasibility and accuracy of lymphatic mapping, by vital blue dye or radioguided surgery, and sN histology as a predictor of axillary lymph node status. METHODS: Two groups of patients (55 and 48) were recruited between May 1996 and May 1997 and between October 1997 and February 1998; the patients of the first series underwent vital blue dye lymphatic mapping only, whereas those of the second series had a combined approach with both vital blue dye mapping and radioguided detection of the sN. RESULTS: In the first set of patients, the sN was identified in 36/55 patients (65.4%); sN histology predicted axillary lymph node status with a 77% sensitivity (10/13), a 100% specificity (23/23), an 88.5% negative predictive value (23/26), and an overall 91.5% accuracy (33/36). The sN was the quasi-elective site of lymph node metastases because in clinically N0 patients nodal involvement was 20-fold more likely at histology in sN than in non-sN (30% and 1.5%, respectively). In the second set of patients, 49 lymphadenectomies were performed because 1 patient had bilateral breast cancer; the sN was identified in 45/49 lymphadenectomies (92%). The sN was intraoperatively negative at frozen-section examination in 33 cases, and final histology confirmed the absence of metastases in 31/33 cases (94%), whereas in 2 cases (6%) micrometastases only were detected. Final histology of the sN predicted axillary lymph node status with an 87.5% sensitivity (14/16), a 100% specificity (29/29), a 93.5% negative predictive value (29/31), and an overall 95.5% accuracy (43/45). CONCLUSIONS: Sentinel lymphadenectomy can be better accomplished when both mapping techniques (vital blue dye and radioguided surgery) are used. In this group of patients, agreement of intraoperative histology of the sN with the final diagnosis was 94%, and sN histology accurately predicted axillary lymph node status in 43/45 lymphadenectomy specimens (95.5%) in which an sN was identified.

Radioimmunoguided surgery with different iodine-125 radiolabeled monoclonal antibodies in recurrent colorectal cancer.

Sixty-four patients with recurrent or metastatic colorectal cancer underwent radioimmunoguided surgery (RIGS). Thirty patients (Group A) were preoperatively injected with radiolabeled monoclonal antibody (MAb) B72.3, a whole IgG1 that reacts with tumor-associated glycoprotein (TAG-72) antigen. Thirty-four patients (Group B) were given monoclonal antibody FO23C5, an F(ab')2 which reacts with the carcinoembryonic antigen (CEA). The use of F(ab')2 antibodies ensured a lower time interval from the preoperative injection of the radiolabeled MAb to surgery. This interval was 22.7 days for Group A patients and 10.9 days for Group B patients. The correct RIGS identification of tumor sites occurred in 80.4% of Group A patients and in 92.6% of Group B patients. Additional information capable of modifying surgical strategy was obtained in 23.3% of Group A patients and in 8.8% of Group B patients. This difference was due to the different patterns of biodistribution and pharmacokinetics of the two MAbs. Although FO23C5 yields an improved diagnostic resolution for macroscopic tumor sites, we believe that B72.3 or other whole IgG1 should be the first choice for RIGS in recurrent or metastatic colorectal cancer patients.

Radioimmunoguided surgery benefits in carcinoembryonic antigen-directed second-look surgery in the asymptomatic patient after curative resection of colorectal cancer.

Radioimmunoguided surgery (RIGS) with radiolabeled monoclonal antibodies (MoAbs) has been reported as useful in second-look colorectal cancer procedures to improve surgical decision-making by helping avoid needless extensive surgery and expanding curative resection to sites of recurrence that have been missed previously. Sixteen asymptomatic patients with an history of colorectal cancer surgery underwent second-look surgery using the RIGS system, solely on the basis of rising serum levels of carcinoembryonic antigen (CEA). All patients were injected preoperatively with the anti-tumor-associated glycoprotein (TAG) 125I-labeled MoAb B72.3. Both traditional and RIGS exploration were used to determine the extension of a possible recurrence and its resectability for cure. Recurrent disease was observed in 14 of the 16 patients as the result of this combined exploration. Exploration alone showed the presence of recurrent disease in 9 of 16 patients (56.2%). Thus, RIGS found overlooked tumor in five patients (31.2%). All the additional RIGS-detected tumor sites were locoregional recurrences resectable for cure; conversely, no diagnostic improvements were shown in patients with liver metastases. Resection for cure was obtained by this approach in 9 of 16 patients (56.2%). Two patients without disease at the exploratory laparotomy recurred within 2 months at sites away from the abdomen. RIGS improved the results of colorectal cancer CEA-guided second-look procedures in asymptomatic patients by recruiting one-third of patients to curative resections.

Sentinel lymph node mapping opens a new perspective in the surgical management of early-stage breast cancer: a combined approach with vital blue dye lymphatic mapping and radioguided surgery.

Recent studies have demonstrated the possibility of identifying the sentinel lymph node (sN) as a reliable predictor of axillary lymph node status in both cutaneous melanoma and breast cancer. However, some important issues need further definition: (1) optimization of the technique for intraoperative detection of the sN; (2) predictive value of the sN as regards axillary lymph node status, and (3) reliability of intraoperative histology of the sN. We report our experience in sN mapping in patients with Stage I-II breast cancer, with the aim of assessing: (1) the feasibility of lymphatic mapping with a combined approach (vital blue dye lymphatic mapping and radioguided surgery); (2) the agreement of the intraoperative histologic examination of the sN, by means of hematoxylin and eosin staining with final histology, and (3) the accuracy of sN histology as a predictor of axillary lymph node status.

Sentinel node biopsy in patients with cutaneous melanoma.

The role of elective lymph node dissection (ELND) for treatment of cutaneous melanoma is still debated. Initially, lymphatic mapping technique was performed by an intradermic injection of vital blue dye; subsequently, it was improved by the use of radioguided surgery (RGS). Preliminary experience with this technique proved effective for detection of clinical occult lymph node metastasis; it may also enable the surgeon to perform a selective lymph node dissection (SLND) to concentrate on pathologic node-positive patients for the same potential benefits that have been provided by ELND. We performed sentinel node biopsy on 48 patients with stage pT3N0M0 melanoma. Vital blue dye mapping only was carried out on 39 patients; the remaining nine patients had a combined lymphatic mapping with both blue dye and RGS. The sentinel lymph node (SLN) was identified in 46 of 48 patients (95.8%). Ten patients (20.8%) were found to have metastatic melanoma cells in their SLN(s); all these patients underwent SLND of the affected basin. Our findings confirm that the intraoperative lymphatic mapping of the SLN using both blue dye and radiodetection is an appropriate and simple technique for selecting patients who are more likely to benefit from lymph node dissection.

[The role of the general practitioner and dentist in the early diagnosis of preneoplastic and neoplastic lesions of the oral cavity]. / Il ruolo del medico generico e dell'odontostomatologo nella diagnosi precoce delle lesioni preneoplastiche e neoplastiche del cavo orale.

Early detection of oral cancer allows for a 90% 5-year survival rate. Unfortunately, nowadays 60% of these tumors are detected in advanced stages with a 5-year survival of about 20%. Therefore, early diagnosis is of the greatest importance. Both the GP and the dentist have a primary role in early diagnosis and are also responsible for informing the population regarding the risk factors in oral cancer. GPs and dentists should systematically check the oral cavity mucous membranes in heavy smokers and/or drinkers above all when over 40. Lesions become suspicious when they persist for more than two weeks after detection. The high-risk pts and suspicious lesions should undergo the following diagnostic procedures: micronucleus test, vital staining, scraping and biopsy for cytological and histological examination. The above mentioned methods will increase the early diagnosis of tumours and improve its prognosis.

HIV is trapped and masked in the cytoplasm of lymph node follicular dendritic cells.

To gain further insight into the pathogenesis of human immunodeficiency virus (HIV) infection, lymph nodes from seven asymptomatic HIV+ subjects were analyzed during the latent phase of disease. Both ultrastructural and immunohistochemical analyses revealed that, in all of the cases, plasma cells producing IgM/gamma were present in germinal centers. Secreted immunoglobulins formed extracellular deposits mimicking the follicular dendritic cell network. Immunoglobulin produced by germinal center plasma cells are specific for HIV because they bind the HIV env protein gp 120. Plasma cells producing antibodies with the same specificity were also abundant in the extrafollicular regions of lymph nodes. During the latent phase of infection, the virus largely accumulates within the germinal centers. Therefore, extracellular immunoglobulin may form immune complexes, as shown by the presence of HIV-specific antibodies, HIV particles, and complement components C3c, C3d, and C1q in the interdendritic spaces. When the ultrastructural localization of HIV in germinal centers was analyzed, abundant virus particles were found in the interdendritic spaces. In addition to this extracellular localization of HIV, receptor-mediated endocytosis of viral particles by follicular dendritic cells was observed. Complete HIV particles were found within the endosomal compartment of the follicular dendritic cells and, as complete viral particles, free in the cytoplasm, indicating that the virus may escape from the endocytic compartment. As the virus is abundant in the cytoplasm, this event leads to formation of a hidden reservoir within follicular dendritic cells. In this location, HIV escapes recognition by cytotoxic T lymphocytes. In contrast, virus budding indicating a productive infection of follicular dendritic cells that would render them susceptible to T-cell-mediated lysis has been seldom observed.

Pseudomixoma peritonei: a case report.

Pseudomixoma peritonei is a rare neoplasm characterized by mucinous ascites and the mucinous involvement of peritoneal surfaces, omentum and bowel loops. Usually pseudomixoma peritonei is associated with benign or malignant mucinous tumor of the appendix or ovary. The diagnosis of pseudomixoma peritonei is difficult because laboratory and radiology results are frequently nondiagnostic. We report a case that was initially mistaken for carcinomatosis of unknown origin and that underwent cytoreductive procedure and omentectomy as the treatment of choice.

[Long-term central venous access in oncology. Review of a caseload of 750 cases]. / Accessi venosi centrali a lungo termine in oncologia. Revisione di una casistica relativa a 750 casi.

Totally implantable central venous accesses systems are presently widely used in cancer patients. Perioperative and long-term morbidity of 750 consecutive implants performed from 1985 to 1994 were retrospectively reviewed. Our Series consisted in 616 (82.1%). Ports and 134 (17.9%) external tunnelled catheters with subcutaneous Dacron cuff (Hickmann or similar catheters) implanted by percutaneous access route in local anesthesia. Subclavian vein was the elective access route in 700 (93.3%) patients while in the remaining 50 (6.7%) the access was performed in the femoral vein, due to peculiar clinical conditions. One-day surgery was only required for 19 (2.6%) patients while outpatient surgery was the routine in 731 (97.4%) patients. Perioperative morbidity was at all similar both for Port and external catheters Series (p > 0.07). Late morbidity requiring the removal of the device occurred in 27/134 patients (18.7%) and in 40/616 (6.5%) for external catheters and Port Series, respectively (p < 0.002). The rate of infection, 2.3% for ports (p < 0.002). Patient's compliance was higher for Ports compared to external catheters. Apart from peculiar clinical conditions such as hematologic cancers, bone marrow transplantation or short life expectancy, Ports seem to guarantee for a lower morbidity coupled with better long-term results.

Epidemic HIV-related Kaposi's sarcoma: a retrospective analysis and validation of TIS staging. GICAT. Gruppo Italiano Collaborativo AIDS e Tumori.

BACKGROUND: We wished to assess the clinical value in terms of treatment choice and establishment of the prognosis of the ACTG classification modified (TNM-TIS) according to the recent guidelines of CDC for the classification of the HIV infection in patients with HIV-related epidemic Kaposi's sarcoma (EKS). PATIENTS: We retrospectively studied 296 HIV-positive individuals with EKS. Patients were initially classified according to the NYU system and then reclassified according to the TNM-TIS proposal which considers three major parameters: T, anatomical extent of the lesion; I, immune system status; S, HIV-related systemic illness. METHODS: Survival analyses according to patient characteristics and the different TNM-TIS classification stages were performed; curves were compared using the Kaplan-Meyer method, and predictive factors for survival using the Cox model. RESULTS: Of the parameters considered in the TNM-TIS staging system, the T variable was not predictive of survival. Conversely, I and S variables revealed predictive value in the survival analyses, when considered separately and together. CONCLUSIONS: The extent of cutaneous or mucosal lesions of Kaposi's sarcoma did not correlate with prognosis. However, both CD4+ cell count and history of systemic illness were predictive of survival. Indicators of HIV infection must be included in the clinical evaluation of EKS patients and taken into account when choosing optimal treatment.

Pre-operative localization of non-palpable lesions in breast cancer by charcoal suspension.

The use of preoperative localization procedures for non-palpable breast lesions (NPBL) is becoming more and more widespread, increasing the detection of early breast cancers. From October 1987 to July 1992, at our Institution, 253 patients (pts) with clinically non-palpable lesions underwent surgical treatment. Of the 253 pts, the lesions have been localized in 95 cases by a needle system, and in the other 158 cases by a dye injection of a 3% sterile charcoal suspension using stereotactic method (118 cases) or sonography (40 cases). The patients' mean age was 53 years (range 30-75). Mammography revealed regular opacities in 133 cases, clustered microcalcification in 75, diffuse microcalcification in 24, opacities with irregular borders in nine and opacities with internal microcalcifications in 12. The histological findings showed benign breast disease in 175 cases (69.2%), borderline breast disease in 23 (9.1%) and malignancy in 55 (21.7%). The benign/malignant/borderline lesions ratio was 3.2:1. The majority (70%) of these malignant lesions were small cancers (less than 1 cm in diameter) and without lymph-node involvement. The biopsy cost (benign/malignant/borderline ratio, patients discomfort and cosmetic result) has been acceptable.

[Merkel's tumor. Some comments and the authors' personal cases]. / Tumore di Merkel. Considerazioni e casistica personale.

The clinical features of 7 cases of primary neuroendocrine carcinoma of the skin (Merkel cell tumor) are reported. This cancer arises in the dermis and subcutaneous tissues of elderly individuals. Natural history is characterized by local recurrences (30%), regional lymph node metastases (65%) and distant metastases (40%). Surgery is the elective treatment, chemotherapy and radiotherapy resulted in only short-term palliative response.

[The diagnosis and therapy of recurrent tumor of the rectum]. / Considerazioni sulla diagnosi e terapia del tumore recidivo del retto.

The authors review the pathogenesis of locoregional recurrences of rectal cancer, pointing out clues for the diagnosis and staging of the disease which are valuable for the definition of a treatment strategy. Surgery is the mainstay of any attempt to cure those recurrences that are amenable to radical resection; over and above the diagnostic role of second-look laparotomy in suspected cases, surgery must include those measures able to reduce actinic damage whenever postoperative radiotherapy is required. On the other hand, palliative surgery is necessary to resolve the presence of intestinal obstruction, fistulous tract, or the removal of abscess and necrotic tissue. In these cases, the quality of life seems to be the prime factor in the choice of therapy (radiotherapy, loco-regional or systemic chemotherapy, hyperthermia).

Role of diagnostic lymphnode biopsies in 56 anti-HIV positive patients.

The authors have examined two separate series of samples from 33 and 23 anti-HIV positive patients with persistent generalized lymphadenopathy (PGL) undergoing lymphnode biopsy. For the first group of patients, the aim was to evaluate the diagnostic and prognostic correlation between clinical and laboratory features and histologic findings. For the second group, an assessment was made of the indications for lymphnode biopsy as determined by the rate of positive histopathologic findings. Histologic alterations were classified into four types according to Ràcz, without knowledge of clinical and laboratory data. At the time of biopsy, the first sample (n = 33) included 21 lymphadenopathy associated syndrome (LAS) (64%), 6 ARC (18%), and 6 AIDS (18%) patients; a significant prevalence of type 1 histologic features was evident in LAS/ARC patients, while type 4 was exclusively present in the AIDS group. These preliminary results suggested that only symptomatic anti-HIV positive patients (ARC/AIDS) should have been selected for lymphnode biopsy, because of the expected high rate of opportunistic infections, malignant lymphoma, or Kaposi's sarcoma (KS) in this specific subset of patients. Actually, in the second sample of 23 patients (ARC = 8: AIDS = 15) the detection rate of AIDS-related neoplasms included ten Kaposi's sarcoma and three Hodgkin's disease. These findings suggest that diagnostic lymphnode biopsies should be limited to selected anti-HIV positive patients with evidence of AIDS-related neoplasms or treatable opportunistic infections, or for the purpose of detecting histopathologic features of prognostic significance.

Long-term postoperative results in 54 cases of early gastric cancer: the choice of surgical procedure.

Surgical experience on the management of early gastric carcinoma (EGC) related to a series of 54 subjects was observed from 1974 to 1984. Thirty-four patients were male, 20 were female; median age was 61.84 (range 22-79) years. Malignancy always occurred in the middle or distal third of the stomach. A partial subtotal gastrectomy (two-thirds of the stomach) with Roux en Y or Billroth II reconstruction was performed. Omentectomy and lymph node dissection of the primary and secondary groups of nodes, according to General Rules, was always performed. Age-corrected 5- and 10-year survival rates were 95.7% and 84.3%, respectively. Based on their experience, the authors discuss the surgical approach to EGC stressing the need for an accurate lymph node dissection and pointing out that results of subtotal gastrectomy are similar to that reported in the literature for total gastrectomy. The only absolute need for a total gastrectomy may be the presence of an EGC in the proximal third of the stomach. To this end the authors compare their results with 5- and 10-year series from Japanese and western countries reported in the literature.