Long-term sequelae after 1,311 primary inguinal hernia repairs.

BACKGROUND: Aim of this study was to analyze long-term sequelae, risk factors, and satisfaction after inguinal hernia primary repair. METHODS: A postal questionnaire was mailed to all patients operated between January 1997 and December 2004 for inguinal hernia repair. Patients who had a lump in the groin and patients who experienced chronic problems were invited for a physical examination. Patients who reported having chronic pain were asked to fill out the short-form McGill Pain Questionnaire (SF-MPQ). RESULTS: Chronic pain was present in 18.1% of cases. The strongest risk factors were presence of recurrence, use of heavyweight mesh, and age younger than 66 years. By means of the SF-MPQ, we found that the pain reported by most patients was sensory-discriminative in quality, with "tender" and "aching" being the most common descriptors used. About 71.3% of replies used descriptors typical of nociceptive pain, 8.9% of neuropathic pain, and 19.8% of nociceptive plus neuropathic. Chronic pain was severe in 2.1% of patients and interfered with normal activities, work, and exercise. The cumulative recurrence rate was 2.1%. There was a strong correlation between lump and recurrence. Patients declared themselves satisfied with the result of the operation in 93.1% of cases. Due to chronic pain, 6.5% of patients were unsatisfied. CONCLUSIONS: This study demonstrates that the main problem after inguinal hernia repair remains chronic pain, which was the primary reason of dissatisfaction. The SF-MPQ is feasible and easy to administer to all patients and provides important information about qualitative features of the pain.

Analysis of post-surgical pain after inguinal hernia repair: a prospective study of 1,440 operations.

BACKGROUND: Pain remains a significant clinical problem after inguinal hernia repair. We prospectively assessed post-surgical pain following herniorrhaphy in 1,440 operations with the aim of describing the characteristics and identifying predisposing factors for pain. METHODS: Pain quality was assessed with the short-form McGill Pain Questionnaire (SF-MPQ); pain character was estimated as either nociceptive or neuropathic in nature. RESULTS: A total of 38.3% of replies reported pain (acute or chronic), and 18.7% reported chronic pain. Independent risk factors for pain were young age, BMI >25, day surgery, and use of Radomesh. In patients with chronic pain, independent risk factors were young age, BMI >25 and use of Radomesh. Analysis of the SF-MPQ revealed that the pain reported by most patients was sensory-discriminative in quality. The most common descriptors were tender and aching. Patients with chronic pain reported more intense pain and used sensory descriptors of greater mean intensity than patients with acute pain. A total of 73.9% of replies used descriptors typical of nociceptive pain, 6.5% used descriptors typical of neuropathic pain and 19.6% used nociceptive plus neuropathic descriptors. Patients considered to have nociceptive pain used significantly more sensory descriptors than those considered to have neuropathic pain. By contrast patients with neuropathic pain used more affective descriptors than those with nociceptive pain. Neuropathic pain was reported as more difficult to treat with analgesics than nociceptive pain and neuropathic plus nociceptive pain. CONCLUSIONS: Our study confirms that herniorrhaphy frequently produces chronic pain, which can reduce quality of life. The SF-MPQ is a useful instrument to administer to all patients and provides important information about qualitative properties of the pain.

Preoperative CEA, NSE, SCC, TPA and CYFRA 21.1 serum levels as prognostic indicators in resected non-small cell lung cancer.

In 62 patients affected by resectable non-small cell lung cancer (NSCLC) submitted to radical surgery we evaluated the prognostic significance of CEA, NSE, SCC, TPA, and CYFRA 21.1 serum levels at diagnosis, as well as the predictive ability of these tumor markers with respect to histological type and pathological stage. The group was composed of 56 male and 6 female patients; the median age was 62 years (range 29-73 years). Thirty-four patients had a histological diagnosis of adenocarcinoma and 28 of squamous cell carcinoma; with regard to pathological stage, 32 patients had stage 1, 4 patients stage II and 23 patients stage IIIA disease. A good predictive ability with respect to histological type was obtained with SCC serum levels; as for pathological stage, TPA and CYFRA 21.1 were found to have moderate predictive ability. In this series of patients, at a median follow-up of 55 months after surgery, we found that both TPA and CYFRA 21.1 serum levels at diagnosis were reliable predictors of overall survival, high values of these markers being associated with a worse prognosis.

Neuron-specific enolase evaluation in patients with neuroblastoma.

Neuron-specific enolase (NSE) may be of interest for the prognostic evaluation and follow-up surveillance in patients with neuroblastoma. We evaluated NSE levels in 80 patients with neuroblastoma. The marker correlated with stage (in stage 1 patients, the median NSE level was 9.9 ng/ml, in stage 2, 45.1 ng/ml, in stage 3, 49 ng/ml, in stage 4, 93.9 ng/ml, in stage 4S, 53.4 ng/ml) and with survival. In patients with a favorable or a poor outcome, the difference in basal NSE serum levels was statistically significant (p = 0.0001). Serial measurements revealed that there was a good correlation between NSE levels and disease course. We concluded that NSE is a good marker for neuroblastoma and its quantitative determination in serum is valuable in the management of these patients to confirm the diagnosis, monitor the effect of treatment and detect recurrent disease.

S100 protein serum levels in cutaneous malignant melanoma.

We investigated the utility of serum S100 determined by means of immunoradiometric assay in a cohort of 438 patients affected by cutaneous melanoma (126 untreated and 312 previously treated). Using 0.2 microg/l cut-off value, determined in 134 healthy blood donors, the sensitivity was 4.2% in stage I patients (4/94), 5.3% in stage II patients (1/19), and 38.5% in stage III patients (5/13). Even though the sensitivity increased progressively from stage I to stage II and III, these differences were not statistically significant. The prognostic significance of S100 evaluation at diagnosis was investigated in terms of survival but no statistical correlation between S100 basal levels and survival was found. In the 312 previously treated patients serum S100 levels were correlated to disease extent, high levels of the marker were observed in 42.8% (9/21) of patients with local recurrence, in 32% (16/50) of patients with lymph node and/or in-transit metastases, in 77.3% (17/22) of patients with distant metastases, and in patients with NED, the specificity of the marker was 96.8% (212/219). The difference between these groups were statistically significant. In conclusion, S100 protein was abnormally high in patients with metastatic malignant melanoma. Serial S100 measurements in a follow-up study are necessary to test the importance of the protein in the management of patients with metastatic malignant melanoma.

P53 accumulation in primary breast cancer: a comparison between immunohistochemistry and a novel luminometric immunoassay.

The accumulation of p53 protein was evaluated by a novel luminometric immunoassay (LIA) in cytosol samples from a series of 245 primary breast cancers. The cytosolic p53 content was not related to nodal status or hormone receptor status, but it was significantly and directly associated with tumor size and cell proliferation. A matched comparison between immunohistochemistry (IHC) and LIA results of individual tumors showed a significant association, albeit with a correlation coefficient of only 0.41. The agreement of results from the two assays was higher in node-positive, estrogen-receptor-negative and rapidly proliferating tumors than in the complementary subgroups. Overall, there was a significant trend in favor of an increase in p53 levels as determined by LIA with the increase in p53-positive cells shown by IHC. However, taking IHC detection as a reference, the sensitivity of the LIA was better for negative (86%) than for positive (61%) values. Based on these findings, a comparative assessment of the clinical relevance of LIA versus IHC results has to be recommended.

Breast cancer seeking agents: basic approach.

The knowledge of biochemical and physiological mechanisms involved in tissue localization is important so as to understand the information given by diagnostic nuclear medicine imaging, and eventually to design new radiopharmaceuticals. The cellular mechanisms which permit a high cancer uptake involve the perfusion and metabolism around the tumour tissue, the interference with normal function, the altered perfusion and/or metabolism within the tumour. All these phenomena can contribute to a high concentration of particular radiotracers in cancer and can create a favourable tumour/background ratio uptake sufficient for cancer imaging. Those molecules might be also powerful tools for reaching an advanced understanding of neoplastic and even "normal" cell biology. During these last years, some radiotracer specifically designed for different applications proved to be promising radiopharmaceuticals for breast cancer imaging. This is the case of monoclonal antibodies (Mabs) developed in the past against membrane cancer antigens. Other tracers, originally proposed for the study of vascular perfusion (cardiovascular tracers), have also revealed a capacity to be taken up by cancer cells. The radiopharmaceuticals mostly used as tumour seeking agents today (Radiothallium, Sestamibi, Tetrophosmin) were generated with other applications in mind. In this paper we review the mechanisms of uptake of the most relevant agents currently proposed for breast cancer imaging, including 18F-fluorodeoxyglucose (FDG). The radiotracers will be examined on the basis of the available scientific evidence regarding their cellular uptake and release. Moreover, we report our preliminary studies on the cellular uptake and release of these and other compounds recently introduced in clinical trials.

Development of a rapid and ultrasensitive RIA method for estrogen (E2, E1, E1-S) determination with selective solid phase extraction.

The inhibition of the proliferative stimulation exercised by estrogens on neoplastic cells is the goal of all endocrine therapies in breast cancer. Under various circumstances, e.g. with the use of aromatase inhibitors, this result can be obtained by blocking the synthetic pathway and, consequently, by lowering the circulating levels of estradiol (E2), estrone (E1), and estrone sulfate (E1-S). The evaluation of these hormones in plasma could therefore represent a useful indicator of the biological efficacy of the therapy. However, the measurement of circulating steroids in a large series of patients is often a complicated procedure. Indirect methods of extraction are time consuming and expensive while the analytical sensitivity of direct methods is not sufficient to measure the residual levels of E2, E1, and E1-S. In this paper we describe a novel extraction method for the evaluation of plasma levels of E2, E1, and E1-S. This new method consists of solid phase extraction followed by a highly specific radioimmunoassay. The sensitivity of the assay is 0.6 pg/ml, 2.0 pg/ml and 7.0 pg/ml for E2, E1, and E1-S, respectively.

Structure, function and gene expression of epithelial mucins.

In this review the main characteristics, i.e., structure, function and gene expression, of the different mucins are discussed. Mucin-type molecules consist of a core protein moiety (apomucin) where a number of carbohydrate chains are attached to serines and threonines by glycosidic bonds. O-linked carbohydrates form up to 80% of the molecule and the length of the glucidic side chains varies from one to more than 20 residues. At least eight mucin-like genes have been isolated so far, and the main characteristic is the presence of a central domain composed of a variable number of "tandem repeats". The sequence homology of the central domain among the different members of the mucin-type family is limited, indicating that this internal domain is unique for each mucin. Thanks to the integrated results of genetic, immunological and biochemical studies, it is now possible to identify eight apomucin genes, namely MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6 and MUC7. MUC1 is the best characterized mucin and it is expressed on the apical surface of most polarized epithelial cells. The MUC1 gene has been cloned and sequenced. The MUC2 gene encodes a typical secretory gel-forming mucin which represents the predominant form in human intestinal and colon tissues. Another intestinal mucin is MUC3. The MUC4, MUC5AC and MUC5B genes have been isolated from a bronchial tissue cDNA library. The MUC4 and MUC5AC genes are mainly expressed in the respiratory tract, in gastric and reproductive mucosa, while MUC5B is highly detectable only in the bronchial glands. The MUC6 gene is expressed by gastric tissue and, recently, MUC7 has been cloned and sequenced using a salivary cDNA library.

Comparison of three different methods for radiolabelling human activated T lymphocytes.

One approach in the treatment of ovarian cancer patients involves the infusion of autologous T lymphocytes coupled with a bispecific monoclonal antibody MOv18/anti-CD3 (biMAb OC/TR), which recognizes a 38-kDa glycoprotein expressed on ovarian carcinomas and the CD3 T cell receptor. However, little is known about the in vivo biodistribution of injected activated lymphocytes, information that could be obtained by scintigraphic imaging of radiolabelled T cells in order to visualize the migratory pattern. We compared the efficiency, stability and toxicity of technetium-99m hexamethylpropylene amine oxime (HMPAO), indium-111 oxine and fluorine-18 2-fluoro-2-deoxy-d-glucose (FDG) in radiolabelling activated lymphocytes targeted with biMAb OC/TR. The mean labelling efficiencies of 111In-oxine and 18F-FDG using 2.5x10(8) lymphocytes (68% and 64%, respectively) were more than twice that of 99mTc-HMPAO (31%). Retention of the radionuclide in the cell was highest in the case of 111In-oxine labelling (less than 25% of the initial cell-bound activity released after 240 min, as compared with 44% of the 99mTc label in the same period and 45% of 18F radionuclide released after 150 min). None of the three radiolabelling reagents induced any significant alteration in cell viability or immunophenotype. However, both 111In-oxine and 18F-FDG induced a loss of cytotoxic activity of lymphocytes against the ovarian carcinoma cell line IGROV1, and all three radiolabelling reagents caused a significant reduction in the proliferative ability of labelled lymphocytes compared to controls, with cell death occurring after 8-9 days. Radiolabelling with the more stable 111In-oxine reagent using a higher number of lymphocytes (1.4x10(9)) but the same total activity (around 55.5 MBq) resulted in improved labelled T cell viability and proliferative ability, although the mean labelling efficiency decreased (35.8%). Together the data suggest that 111In-oxine at low activity per cell is the most appropriate reagent for radiolabelling activated retargeted T lymphocytes useful for in vivo biodistribution studies.

Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane.

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.

Effects of steroid-free fetal serum and steroid supplementation on MUC1 gene expression in human breast cancer cell line MCF7.

MUC1 is a gene expressed by many normal epithelial tissues and aberrantly expressed by carcinomas. Studies regarding the expression of MUC1 in endometrial tissues and the constitution of its promoter region suggest a possible role for hormonal regulation of this gene. The aim of the present work was to evaluate the regulation of MUC 1 expression by 17 beta-estradiol (E2), progesterone (Pg) and by steroid-free fetal calf serum (FCS) in the hormone-sensitive cell line MCF7. MUC1 mRNA proved to be detectable by means of Northern-blot analysis in MCF7 cells, and its levels were strongly increased in cells grown with 10% steroid-free FCS. By contrast, the steady-state MUC1 mRNA levels of steroid-supplemented cells did not change compared to those of unsupplemented cells (controls). In conclusion, MUC1 expression is regulated by substances present in the steroid-stripped FCS (growth factors, e.g. Insulin-like Growth Factor). The lack of any observed MUC1 modulation by steroids could be due to: a) a low FCS concentration preventing the manifestation (permissive action) of possible gene regulation; b) an immediate stimulatory effect occuring in the first phases of the treatment, which could subsequently be lost.

Effects of aromatase complex selective inhibition on insulin-like growth factor 1 and insulin-like growth factor binding protein 3 circulating levels in breast cancer.

The aim of our study is to evaluate insulin-like growth factor (IGF) and IGF binding protein (IGFBP)-3 circulating levels in postmenopausal women treated with type I aromatase inhibitor formestane for breast cancer. Sixty-three patients at their first relapse entered the trial and were randomly given formestane at 250 mg or 500 mg i.m. fortnightly. Effects of the endocrine treatment on IGF-1 and IGFBP-3 were measured before and during therapy at scheduled times. IGF-1 and IGFBP-3 seems to slightly increase in both the dose groups, but only IGFBP-3 levels showed statistically significant fluctuation (baseline vs 4 weeks, p=0.01925; baseline vs 10 weeks, p=0.04537). These modifications are unlikely to be related to clinical status because they were observed both in responsive and unresponsive patients. This report demonstrates that hormonal treatments for breast cancer (particularly, aromatase inhibitor administration) can modify growth factor disposition to tumour.

Potential circulating markers for the management of kidney cancer (Review).

The prognosis of renal cell carcinoma (RCC) is generally poor. An easier detection of this tumor and a better monitoring of RCC patients would be possible if serum markers with acceptable sensitivity and specificity were available. In RCC, as opposed to other cancers, no circulating serum markers with sufficient renal specificity have been discovered. In fact, even when the hybridoma technology allowed the production of several monoclonal antibodies against RCC structures, none of them led to any available diagnostic immunoassays. Other possible circulating tumor markers of potential application in RCC patients include different substances such as acute phase reactant proteins, enzymes, mucins, cytokeratins, proteins, interleukins, that demonstrated some relationship with the presence and the changes in the RCC evolution. In this general review we report and discuss the results in the literature obtained by serum assays of these substances which have been shown to be of some help for the prognosis and monitoring of RCC. The greater part of these biomolecules are already measured in clinical practice for the management of other malignancies, but their application in RCC could give interesting clinical information.

Preliminary results of clinical evaluation of the free/total prostate-specific antigen ratio in a multicentric study.

AIMS AND BACKGROUND: The free/total (F/T) prostate-specific antigen (PSA) ratio is probably the most promising tool proposed to increase the specificity of PSA in the diagnosis of prostate cancer. The aim of the present study was to evaluate the clinical value of the F/T ratio in 138 patients with benign hyperplasia, 101 with untreated prostate cancer, and 176 apparently healthy men. METHODS: We used a new immunometric assay of free PSA (FPSA-RIACT, CIS Diagnostici, Italy) which has shown good analytical performance; sample handling and storage under routine conditions did not affect the antigen stability. RESULTS: The diagnostic efficiency of the F/T ratio was significantly better than that of total PSA. In patients with total PSA ranging from 4 to 10 ng/ml, at a specificity level of 95% total PSA showed a sensitivity of 7%, whereas the sensitivity of F/T increased to 70%. Using the F/T ratio as a decision tool in association with total PSA and considering all cases candidate to biopsy (total PSA greater than 3.79 ng/ml corresponding to the 95% level), we demonstrated a 35% reduction of total biopsies that would have been required on the basis of total PSA alone. CONCLUSIONS: The determination of the percentage of F/T serum PSA significantly improves the specificity of the marker, particularly in the 4-10 ng/ml dose range where unnecessary prostate biopsies can be reduced.

Axillary lymph node metastases detection with nuclear medicine approaches in patients with newly diagnosed breast cancer.

Three different tracers, Tc-99m-Sesta MIBI, In-111-Pentetreotide and F-18-FDG, were evaluated in a preliminary study in three different groups of 10 breast cancer patients programmed for breast cancer resection and axillary dissection. Planar scintigraphy and single photon emission tomography (SPET) technique were used for imaging with Tc-99m-Sesta-MIBI and In-111-Pentetreotide, positron emission tomography (PET) was used for imaging with F-18-FDG. We studied 30 breast cancer patients; their clinical stage according to the TNM classification was 30 T1-T2, 1 T4 and 1 Tx (one patient had bilateral cancer and one had bifocal cancer). The lymph nodal status ranged from NO to N2 (14 NO, 16 N1, 1 N2). Tc-99m-Sesta MIBI, In-111 Pentetreotide SPET and F-18-FDG PET were randomly performed before surgery to visualize the primary tumors and to detect axillary lymph node invasion. Tc-99m-Sesta MIBI correctly visualized 10 out of 11 primary cancers in 10 patients. In-111-Pentetreotide detected 9 out of 10 primary cancers. F-18-FDG imaged all the tumors (10). As regards the axillary nodes, Tc-99m-MIBI excluded axilla involvement in 7 out of 7 negative axillae (N-), while it was positive in 2 out of 3 positive cases (N+); In-111-Pentetreotide correctly identified 7 out of 8 negative axillae (N-), while it detected 2 of 3 positive sites. F-18-FDG visualized all positive axillary lymph nodes (4 out of 4 N+ patients) and correctly excluded involvement in all negative patients (6 out of 6 N- cases). This study demonstrated that all three tracers are adequate to be proposed as tumor seeking agents with the aim of developing non-invasive diagnostic methods for pre-operative detection of axillary metastases, so that surgical dissection can be limited to selected patients. The authors discuss the advantages and disadvantages of the different radiopharmaceuticals and conclude that in centers with PET facilities F-18-FDG is the best tumor seeking agent for the evaluation of axillary status. Between Tc-99m-Sesta MIBI and In-111-Pentetreotide the former seems to present more advantages in this kind of application, considering also its lower cost and easier availability. These results encourage further study, including the simultaneous comparison of these tracers in breast cancer staging.

Reliability of immunoradiometric assays for sex-hormone binding globulin, androstenedione, 17-Beta estradiol and tumor-markers cea and cb15.3 to assess the biological response of megestrol-acetate treatment in patients with advanced breast-cancer.

This study evaluated the effect of megestrol acetate administration on the serological assessment of some sex steroid hormones in women with advanced hormone-sensitive breast cancer. The serum levels of 17-beta estradiol, androstenedione and sex hormone binding globulin (SHBG) were measured by means of radioimmunometric assays, before and during drug administration. A significant suppressive effect on SHBG and androstenedione levels in comparison with the baseline values was reached in 100% (40/40) and 51% (20/39) of patients, respectively, after two months of therapy; by contrast, 17-beta estradiol levels showed an increase above the baseline levels in 18 out of 22 patients. These findings might be explained on the basis of a possible interference in vivo of megestrol acetate metabolites particularly in the estradiol assay, since a direct influence of the solubilized megestrol acetate was not observed in vitro. The hormone levels generally did not shaw any relationship with the course of the disease, so their serial determinations do not seem to be useful to assess the clinical status or evaluate response to therapy. In our group of patients, CEA and CA15.3 serum determinations were also carried out to monitor the efficacy of treatment. CEA and CA15.3 levels reflected the course of the disease in 58.9% (23/39) and 65.8% (25/38) of patients, respectively. The two tumor markers displayed a similar sensitivity in detecting cancer progression (64% CEA and 63% CA15.3), but CA15.3 seemed to have a better diagnostic value in evaluating the response to therapy and signalling tumor relapse.