Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies.

BACKGROUND: Ki67 labeling index (Ki67 LI), the percentage Ki67 immunoreactive cells, is a measure of tumor proliferation, with important clinical relevance in breast cancer, and it is extremely important to standardize its evaluation. AIM: To test the efficacy of computer assisted image analysis (CAIA) applied to completely digitized slides and to assess its feasibility in routine practice and compare the results obtained using two different Ki67 monoclonal antibodies. MATERIALS AND METHODS: 315 consecutive breast cancer routinely immunostained for Ki-67 (223 with SP6 and 92 with MM1 antibodies previously examined by an experienced pathologist, have been re-evaluated using Aperio Scanscope Xs. RESULTS: Mean human Ki67 LI values were 36%± 14.% and 28% ± 18% respectively for SP6 and MM1 antibodies; mean CAM Ki67 LI values were 31%± 19% and 22% ± 18% respectively for SP6 and MM1. Human and CAIA evaluation are statistically highly correlated (Pearson: 0.859, p<0.0001), although human LI are systematically higher. An interobserver variation study on CAIA performed on 84 cases showed that the correlation between the two evaluations was linear to an excellent degree. DISCUSSION: Our study shows that a) CAIA can be easily adopted in routine practice, b) human and CAIA Ki67 LI are highly correlated, although human LI are systematically higher, c) Ki67 LI using different evaluation methods and different antibodies shows important differences in cut-off values.

A nationwide audit of the use of radiotherapy for rectal cancer in Italy.

BACKGROUND: There is good evidence that radiotherapy is beneficial in advanced rectal cancer, but its application in Italy has not been investigated. METHODS: We conducted a nationwide survey among members of the Italian Society of Colo-Rectal Surgery (SICCR) on the use of radiation therapy for rectal cancer in the year 2005. Demographic, clinical and pathologic data were retrospectively collected with an online database. Italy was geographically divided into 3 regions: north, center and south which included the islands. Hospitals performing 30 or more surgeries per year were considered high volume. Factors related to radiotherapy delivery were identified with multivariate analysis. RESULTS: Of 108 centers, 44 (41%) responded to the audit. We collected data on 682 rectal cancer patients corresponding to 58% of rectal cancers operated by SICCR members in 2005. Radiotherapy was used in 307/682 (45.0%) patients. Preoperative radiotherapy was used in 236/682 (34.6%), postoperative radiotherapy in 71/682 (10.4%) cases and no radiotherapy in 375 (55.0%) cases. Of the 236 patients who underwent preoperative radiotherapy, only 24 (10.2%) received short-course radiotherapy, while 212 (89.8%) received long-course radiotherapy. Of the 339 stage II-III patients, 159 (47%) did not receive any radiotherapy. Radiotherapy was more frequently used in younger patients (P < 0.0001), in patients undergoing abdominoperineal resection (APR) (P < 0.01) and in the north and center of Italy (P < 0.001). Preoperative radiotherapy was more frequently used in younger patients (P < 0.001), in large volume centers (P < 0.05), in patients undergoing APR (P < 0.005) and in the north-center of Italy (P < 0.05). CONCLUSION: Our study first identified a treatment disparity among different geographic Italian regions. A more systematic audit is needed to confirm these results and plan adequate interventions.

Development and daily use of an electronic oncological patient record for the total management of cancer patients: 7 years' experience.

BACKGROUND: We describe our experience with an electronic oncological patient record (EOPR) for the total management of cancer patients. METHODS: The web-based EOPR was developed on the basis of a user-centred design including user education and training, followed by continuous assistance; user acceptance was monitored by means of three questionnaires administered after 2 weeks, 6 months and 6 years. RESULTS: The EOPR has been used daily for all in-ward, day hospital and ambulatory clinical activities since July 2000. The most widely appreciated functions are its rapid multipoint access, the self-updated summary of the patients' clinical course, the management of the entire therapeutic programme synchronised with working agendas and oncological teleconsultation. Security and privacy are assured by means of the separate storage of clinical and demographic data, with access protected by login and a password. The questionnaires highlighted appreciation of rapid data retrieval and exchange and the perception of improved quality of care, but also revealed a sense of additional work and a negative impact on doctor-patient relationships. CONCLUSIONS: Our EOPR has proved to be effective in the total management of cancer patients. Its user-centred design and flexible web technology have been key factors in its successful implementation and daily use.

[Gastrointestinal stromal tumors]. / I tumori stromali gastrointestinali.

Gastrointestinal stromal tumors (GIST) are generally found in the stomach or small intestine and less commonly in the colon or rectum. Complete surgical removal remains the best current therapy for GISTs. The treatment of advanced GIST patients is with imatinib, a selective tyrosine kinase inhibitor. In our series, 23 patients observed between 1994 and 2004 and affected by GIST were treated with complete negative margin resections (three cases by laparoscopy).

Analysis of user-satisfaction with the use of a teleconsultation system in oncology.

There is an increasing interest in assessing telemedicine as alternative method of delivering high quality cancer treatment to patients living in rural areas. In the Province of Trento (north-east Italy) a tele-oncology system was implemented to provide non-surgical oncological consultation to district general hospitals. The aim of this study was to explore user-satisfaction with the system after 6 months of experimentation. During the on-field validation two questionnaires with open and closed-response questions were distributed to 80 physicians and nurses 6 months apart to investigate the users' expected benefits vs. perceived ones. The two questionnaires were compared to assess how perceived benefits differed from expected ones. Significant differences were found regarding improvements in: the standardization of diagnostic-therapeutic procedures using the Electronic Patient Record (EPR)]; information sharing; data updating; consultation speed; and the possibility to diminish patients' travels through the use of teleconsultation (TC). Physicians' responses showed a significant difference regarding the EPR's effects on relationship with patient, the nurses' responses with regards to its effects on care quality. Physicians felt that both modalities of teleconsultation were useful in enhancing communication with colleagues (86% for the synchronous TC, 80% for the asynchronous TC). Responses indicated that the major difficulties encountered were in the introduction of the system into the daily routine. Despite this, user expectations for its future use in clinical field were considerably high.

[Retroperitoneal liposarcoma]. / I liposarcomi retroperitoneali.

Liposarcoma is the most frequent histotype of the rare and malignant retroperitoneal tumours. This neoplasm has a remarkable tendency to recurrence after surgical excision, rarely to metastasize. Recurrence usually shows a more aggressive behaviour than primitive disease with a higher tendency to penetrate into adjacent organs. The symptomatology often appears late and the first sign is frequently a palpable abdominal mass. Preoperative study involves using CT and MRI. The surgical resection is the only tool able to modify natural history with regard to survival and local recurrence. Prognosis is severe, with a survival of 5 years, variable from 12 to 50% in the different series. A very important prognostic factor is the degree of tumour and radical surgical treatment. From 1990 to 2001, 32 operations for malignant retroperitoneal tumors were performed by our surgical unit in 19 patients; in 7 of them the tumor was a liposarcoma (4 male and 3 female). Total operations for retroperitoneal liposarcoma were 15, in 4 patients a second operation was performed for recurrence, in 3 a third operation and in 1 a fourth. Eleven cases out of 15 have undergone exeresis of sarcoma. Average survival consisted in 4 years and 2 months. Intraoperative radiotherapy, performed in 3 patients, perhaps is able to offer some advantages in relation to local control of the disease and of the survival. A possible resection of eventual recurrence justifies a early follow up with CT and MRI.

An evaluation of the use of and user satisfaction with a teleconsultation system in oncology practice.

A three-year oncology teleconsulting project was concluded in November 2000. During a six-month study period, 38 clinical physicians and 47 nurses used the system. A total of 617 electronic patient records were created in the oncology department, 297 in dermatology and 24 in gynaecology. There were 45 synchronous teleconsultations involving various participants, lasting a total of 708 min. We conducted surveys of the attitudes of users to the teleconsulting system both before and after its implementation. There were no significant differences between the two surveys and the results showed that users had a positive reaction to the system and high expectations of its future utilization.

[Multifactorial prognostic analysis in the surgical treatment of well differentiated thyroid neoplasms]. / Analisi prognostica multifattoriale nel trattamento chirurgico dei tumori differenziati della tiroide.

BACKGROUND: Although in recent years our knowledge of pathogenesis and natural history of thyroid cancer has widely increased, there is not accordance among authors in the field of surgical treatment of well-differentiated tumours. In fact the extension of the tumour resection and modality of cervical lymph-nodes dissection show questions not easy to answer. METHODS: From 1985 to 1994, in our Surgical Institute, 128 cases of well-differentiated thyroid cancer, out of 1346 nodular thyreopathies, were operated on. We have considered some factors as anamnestic thyreopathy, familiarity, symptoms, US and scyntigraphic factors, fine-needle aspiration cytology and surgical option. The surgical treatment consisted of 99 total thyroidectomies (with or without cervical lymph-nodes dissection) and 18 lobus-isthmectomies. Surgical morbidity was 0.7% for permanent vocal cords palsy, 9.3% for transient hypoparathyroidism and 1.4% for permanent hypoparathyroidism. RESULTS: The 5.8-year survival rate was 92.9%. Fifty-four patients were in Stage I, 35 patients in Stage II, 27 in stage III and 4 in Stage IV. Histological patterns showed the prevalence of papillary type (63.3%) over follicular type (36.7%). CONCLUSIONS: The aggressive surgical approach in well-differentiated thyroid tumours, supported by complementary postoperative therapies, leads to a good control of the disease

Robotic telepathology for intraoperative remote diagnosis using a still-imaging-based system.

The aim of the present study was to assess whether a telemicroscopy system based on static imaging could provide a remote intraoperative frozen section service. Three pathologists evaluated 70 consecutive frozen section cases (for a total of 210 diagnoses) using a static telemicroscopy system (STeMiSy) and light microscopy (LM). STeMiSy uses a robotic microscope, enabling full remote control by consultant pathologists in a near real-time manner. Clinically important concordance between STeMiSy and LM was 98.6% (95.2% overall concordance), indicating very good agreement. The rates of deferred diagnoses given by STeMiSy and LM were comparable (11.0% and 9.5%, respectively). Compared with the consensus diagnosis, the diagnostic accuracy of STeMiSy and LM was 95.2% and 96.2%. The mean viewing time per slide was 3.6 minutes, and the overall time to make a diagnosis by STeMiSy was 6.2 minutes, conforming to intraoperative practice requirements. Our study demonstrates that a static imaging active telepathology system is comparable to dynamic telepathology systems and can provide a routine frozen section service.

Concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expanders after mastectomy for breast cancer.

BACKGROUND: Immediate breast reconstruction (IBR) by means of skin expander is currently one of the most widely used methods of breast reconstruction in mastectomized patients. However, given that many breast cancer patients usually receive adjuvant chemotherapy, the adoption of IBR raises new questions concerning possible cumulative toxicity. The present study reports our experience in the use of concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expander after mastectomy for breast cancer and the acute cumulative toxicity of the treatments. METHODS: We evaluated a consecutive series of 52 breast cancer patients who have received IBR by skin expander after radical mastectomy and adjuvant chemotherapy concurrently during skin expansion between 1995 and 1998 (IBR/CT group). We identified two series of control patients treated during the same period: 51 consecutive patients undergoing radical mastectomy and IBR without adjuvant chemotherapy (IBR group) and 63 consecutive patients undergoing radical mastectomy and adjuvant chemotherapy without IBR (CT group). For each patient, we evaluated the incidence of surgical complications and chemotherapy's side effects and dose intensity. RESULTS: The interval between surgery and the start of expander inflation was similar in IBR/CT (range 0-19, median 5 days) and IBR groups (range 0-40, median 5 days) and the timing of inflation was not influenced by chemotherapy. The overall incidence of surgical complications in patients undergoing IBR was low: seroma in eight cases, infection in one, skin necrosis in one, expander rupture in two and erythema in three. There were no statistically significant differences in the distribution of complications between the IBR/CT and IBR groups. The dose intensity of chemotherapy was similar between IBR/CT and CT groups, with a median dose intensity of 96% and 95% of the projected dose, respectively. The only statistically significant difference in terms of chemotherapy side effects (p = 0.03) was that stomatitis was more frequent and intense in the CT than in the IBR/CT group. CONCLUSIONS: Concurrent treatment with IBR and adjuvant chemotherapy appears feasible and safe, it does not increase acute surgical complications or chemotherapy side effects, and does not require any changes in dose intensity or the timing of inflation.

Design and initial implementation of a regional tele-oncology project.

Two tele-oncology projects have been in progress since 1997 in the Province of Trento in north-east Italy. The common aim of the projects concerns the design and the implementation of a non-surgical tele-oncology system intended to provide a flexible computing environment for the joint management of oncology patients in a wide-area network. The two projects involve both hospital specialists and general practitioners treating oncological patients. The first phase of the project involves the design and implementation of the oncology teleconsultation service.

[Intraoperative radiotherapy in the combined treatment of pancreatic cancers]. / La radioterapia intraoperatoria nel trattamento integrato del carcinoma pancreatico.

Pancreatic cancer is a highly lethal disease either for the high incidence of distant metastases or for the frequent local recidive also after potentially curative resection. For this reason new multimodality approaches have to be investigated. Intraoperative radiotherapy (IORT) permits to administer a high dose to the tumor or to the retropancreatic tissues and to the regional lymph nodes. Literature data suggest it is possible a better local control and perhaps a better survival than the surgery alone or the palliative treatments by the use of schedules with IORT. Anyway they are retrospective data and IORT is an investigational method which has to be indagate in the combined modality approaches to this disease.

Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up.

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell proliferation, and their immunohistochemical expression may help to identify high-risk breast cancer patients. The authors evaluated p53 and Bcl-2 immunoreactivity in 178 node-negative breast cancers (NNBC) with long-term follow-up (median, 60 months). Bcl-2 was seen in 111 (62%) cases, and was significantly associated with small tumor size, nonductal morphology, low tumor grade, estrogen-receptor (ER) positivity, and p53 negativity. p53 overexpression (ie, > 15% reactive nuclei) was observed in 31 (17%) cases, and was associated with lower age, large tumor size, ductal morphology, high tumor grade, negative ER status, and lack of Bcl-2 immunoreactivity. In univariate analysis, the variables associated with short relapse-free survival (RFS) were large tumor size (P = .002), high histological grade (P = .01), high mitotic count (P = .03), and high Nottingham prognostic index (NPI) (P = .0002). In multivariate analysis (final model), only the NPI was of independent prognostic value concerning RFS.

Grading in superficial papillary bladder carcinoma, with an emphasis on nuclear orientation.

OBJECTIVE: To develop a computerized analysis method that could reflect not only cellular anaplasia but also the orientation (PV) of neoplastic elements and could allow the separation of low (grade G 1 and G 2a) and high (G 2b) grades of superficial papillary bladder tumors (SPBTs). STUDY DESIGN: Cellular anaplasia is based on classic morphometric parameters, such as mean and standard deviation of area, perimeter, roundness and aspect ratio (length/width ratio) of 50 papillary bladder tumors (16 G 1, 10 G 2a and 24 G 2b according to Pauwels). Orientation of the major axis of each nucleus with respect to the true basal membrane was calculated using the SD of valve distribution. RESULTS: No statistically significant differences were found between cases showing contiguous grades (G 1 versus G 2a or G 2a versus G 2b). PV, SD of the area and SD of the perimeter were the parameters that could significantly distinguish between G 1 and G 2b and between G 1 plus G 2a and G 2b (P < .05). When comparing G 1 with G 2a plus G 2b, only PV and SD of the area were statistically significant. CONCLUSION: Quantification of the irregularities in the orientation of nuclei with respect to the basal membrane may improve morphometric classification of low grade SPBTs.

Quantitative growth fraction evaluation with MIB1 and Ki67 antibodies in breast carcinomas.

Ki67 and MIB1 monoclonal antibodies are directed against different epitopes of the same proliferation-related antigen. Whereas Ki67 works only on frozen sections, MIB1 may be used also on fixed sections. The authors immunostained a series of 40 breast carcinomas with MIB1 and Ki67 antibodies on serial frozen sections and on fixed material. The Ki67 labeling index (LI) was 12.9 +/- 8.9 and 12 (mean +/- SD and median, respectively). MIB1 LI was 21.2 +/- 11.9 and 19.5 on frozen sections and 24 +/- 15.2 and 21.5 on fixed sections (mean +/- SD and median, respectively). Ki67 LI and MIB1 LI on frozen and fixed sections were strictly correlated (P < .001). The results are in keeping with the reported coincidental nuclear staining pattern of Ki67 and MIB1, but the mean and median values of MIB1 LI are almost twice the values of Ki67 LI. The cut-off values to define high and low proliferative activity with the two antibodies are therefore different. The differences in immunolabeling may be due to better survival of the MIB1 epitope in freezing and acetone fixation or to differing accessibilities of the MIB1 and Ki67 epitopes during the cell cycle due to molecular conformational modifications. The MIB1 monoclonal antibody is a reasonable substitute for the Ki67 monoclonal antibody. The advantages of MIB1 immunostaining on paraffin sections include the feasibility of retrospective studies and of obtaining clear morphologic specimens that are optimal for use with computer-assisted image analysis systems. Our image-processing system allows automatic nuclear counting, detects positive nuclei and measures their staining intensity.

Long term thyroid function after subtotal thyroidectomy for Graves' disease.

Between 1973 and 1980, 93 patients with Graves' disease underwent subtotal thyroidectomy by the same surgeon (the size of thyroid remnant was 4 g per side). No case of operative mortality, no case of thyroid storm nor of surgical complications occurred. Three months after surgery 40% of patients were euthyroid, 25% had overt hypothyroidism, 35% had subclinical hypothyroidism. In the following yr important variations of thyroid function were observed. The number of patients with subclinical hypothyroidism decreased slowly (22% and 9% at 3 and 6 yr, respectively), and some became euthyroid, some hypothyroid, others relapsed. Seven patients had recurrent hyperthyroidism. In particular at 3 yr 45% of patients were euthyroid, 28% had overt hypothyroidism, 22% had subclinical hypothyroidism, 4% had recurrence; at 6 yr 56% were euthyroid, 32% had overt hypothyroidism, 9% had subclinical hypothyroidism, 3% had recurrence. Four out of the 8 patients operated under 20-yr-old became hypothyroid in comparison with only 2 out of the 15 patients over 50-yr-old. Relapses were present only in patients operated at less than 40-yr and only in females. No correlation was found between thyroid lymphocytic infiltration and thyroid function after surgery, nor between the presence of antithyroid antibodies and hypothyroidism. All cases who relapsed had high TMA titers both before and after operation. This study confirms the need for accurate follow-up after subtotal thyroidectomy for Graves' disease.

[Mediastinal thymoma (presentation of 2 cases)]. / Il timoma mediastinico (presentazione di due casi).

The Authors report on two cases of mediastinal thymoma. Clinical and anatomicopathological aspects are discussed.