Non-palpable breast lesions localization techniques - A new priority: Results of a Senonetwork survey among breast centers in Italy.

INTRODUCTION: Non palpable breast tumors are increasingly diagnosed because of screening programs, and their localization during surgery is essential to ensure an adequate resection. Little is known regarding which techniques are used in "real world". MATERIALS AND METHODS: A national web-based survey, with a 21-items questionnaire, was conducted among Breast Centers (BCs) in Italy in 2023. RESULTS: Among 153 BCs, 110 (72 %) participated. Wire-guided localization was reported to be the most used technique, regardless of the volume of malignant tumors treated by each Center (N = 36, 33 %). However, newer techniques such as Radioactive occult lesion localization and magnetic seeds, were reported to be employed in 34 (31 %) BCs, and more often among high-volume BCs (>300 cases/year) (N = 32, 29 % vs. N = 13, 12 %; p = 0.02). Logistic problems of localization were reported to cause delays to the scheduled surgery at least once or in multiple occasions in 26 (24 %) and in 4 (3.5 %) BCs, respectively. Although the majority of BCs declared they were satisfied (N = 48, 44 %) or somewhat satisfied (N = 41, 37 %) with the procedure used in their center, responders stated that they would change their technique, or that they were strongly considering this possibility in 24 (22 %) and in 38 (35 %) cases, respectively. The main barrier to introducing a new technique was associated with procedure costs (90 BCs, 82 %). CONCLUSIONS: There are several critical issues regarding localization techniques at a national level. This should be recognized as a priority because of its impact on both patients and clinical practices.

Multicentric/multifocal breast cancer with a single histotype: is the biological characterization of all individual foci justified?

BACKGROUND: Invasive multiple breast cancers with a single histological feature (MBCSH) are routinely assessed for biological parameters to indicate adjuvant treatments only in the largest invasive carcinomas. However, the heterogeneity of individual foci in multiple carcinomas has not been widely studied. We analyzed whether such biological features are differently expressed in different MBCSH foci. PATIENT AND METHODS: One hundred and thirteen invasive MBCSH were tested over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. RESULTS: Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. CONCLUSIONS: In our experience, invasive MBCSH showed heterogeneity among foci. In our clinical practice, such assessment led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor.

Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA.

PURPOSE: Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center. PATIENTS AND METHODS: Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA. RESULTS: Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1-5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed. CONCLUSIONS: Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.

Mammographic density to predict response to neoadjuvant systemic breast cancer therapy.

BACKGROUND: Mammographic density (MD) is a risk factor for breast cancer (BC) development, and recurrence. However, its predictive value has been less studied. Herein, we challenged MD as a biomarker associated with response in patients treated with neoadjuvant therapy (NAT). METHODS: Data on all NAT treated BC patients prospectively collected in the registry of Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (2009-2019) were identified. Diagnostic mammograms were used to evaluate and score MD as categorized by the Breast Imaging-Reporting and Data System (BI-RADS), which identifies 4 levels of MD in keeping with relative increase of fibro-glandular over fat tissue. Each case was classified according to the following categories a (MD < 25%), b (26-50%), c (51-75%), and d (> 75%). The association between MD and pathological complete response (pCR), i.e., absence of BC cells in surgical specimens, was analyzed in multivariable setting used logistic regression models with adjustment for clinical and pathological variables. RESULTS: A total of 442 patients were analyzed, 120 of which (27.1%) attained a pCR. BI-RADS categories a, b, c, and d accounted for 10.0%, 37.8%, 37.1% and 15.2% of cases. Corresponding pCR were 20.5%, 26.9%, 30.5%, 23.9%, respectively. At multivariable analysis, when compared to cases classified as BI-RADS a, those with denser breast showed an increased likelihood of pCR with odds ratio (OR) of 1.70, 2.79, and 1.47 for b, c and d categories, respectively (p = 0.0996), independently of age, BMI [OR underweight versus (vs) normal = 3.76], clinical nodal and tumor status (OR T1/Tx vs T4 = 3.87), molecular subtype (HER2-positive vs luminal = 10.74; triple-negative vs luminal = 8.19). In subgroup analyses, the association of MD with pCR was remarkable in triple-negative (ORs of b, c and d versus a: 1.85, 2.49 and 1.55, respectively) and HER2-positive BC cases (ORs 2.70, 3.23, and 1.16). CONCLUSION: Patients with dense breast are more likely to attain a pCR at net of other predictive factors. The potential of MD to assist decisions on BC management and as a stratification factor in neoadjuvant clinical trials should be considered.

Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy.

BACKGROUND: As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression. MATERIALS AND METHODS: Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing. RESULTS: ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response. CONCLUSION: ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.

VMAT partial-breast irradiation: acute toxicity of hypofractionated schedules of 30 Gy in five daily fractions.

PURPOSE: To report acute toxicities in breast cancer (BC) patients (pts) recruited in a prospective trial and treated with accelerated partial-breast irradiation (APBI) using Volumetric Modulated Arc Therapy (VMAT) delivered with a hypofractionated schedule. METHODS: From March 2014 to June 2019, pts with early-stage BC (Stage I), who underwent breast conservative surgery (BCS), were recruited in a prospective study started at the National Cancer Institute of Milan. Pts received APBI with a hypofractionated schedule of 30 Gy in five daily fractions. Radiotherapy treatment (RT) was delivered using VMAT. Acute toxicity was assessed according to RTOG/EORTC criteria at the end of RT. RESULTS: Between March 2014 and June 2019, 151 pts were enrolled in this study. 79 Pts had right-side and 72 had left-side breast cancer. Median age was 69 (range 43-92). All pts presented with pathological stage IA BC, molecular classification was Luminal A in 128/151 (85%) and Luminal B in 23/151 (15%) cases. Acute toxicity, assessed at the end of RT, consisted of G1 erythema in 37/151 (24. 5%) pts and skin toxicities higher than G1, did not occur. Fibrosis G1 and G2 were reported in 41/151 (27. 1%) pts and in 2/151 pts (1. 3%), respectively. Edema G1 occurred in 8/151 (5. 3%) pts and asthenia G1 occurred in 1/151 (0. 6%) pts. CONCLUSIONS: APBI with VMAT proved to be feasible and can be a valid alternative treatment option after BCS in selected early breast cancer pts according to ASTRO guidelines. A longer follow-up is needed to assess late toxicity.

Axillary nodal involvement by primary tumor features in early breast cancer: an analysis of 2600 patients.

BACKGROUND: Primary tumor characteristics, which are readily available to all clinicians, may aid in selecting the optimal adjuvant therapy for patients with breast cancer (BC). Herein, we investigated the relationship between tumor size, hormone receptor and HER2 status, Ki67 and age with axillary lymph node metastases (ALNM) in early-BC patients. METHODS: We analyzed data on consecutive 2600 early-BC cases collected in the registry of Fondazione IRCC Istituto Nazionale dei Tumori, Milano, Italy. Correlation between Ki67 and primary tumor size (T-size) was calculated by Spearman's rank correlation coefficient. Association of ALNM with Ki67 and other tumor characteristics was investigated by logistic regression. Adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated in all cases, and separately analyzed according to age, T-size and BC subtype. RESULTS: Large tumor size strongly associated to ALNM, with an adjusted odds ratio (OR) for each 5-mm increase of 1.32 (95% CI 1.24-1.41), except for triple-negative BC (TNBC) cases. In tumors =10 mm, without lymphovascular invasion, representing the strongest predictor of ALNM (OR 6.09, 95% CI 4.93-7.53), Ki67 resulted particularly informative, with a fourfold increased odds of ALNM for values > 30%. CONCLUSIONS: These results raise the question whether axillary node status is redundant in cases with exceptionally good features, i.e., small tumors with low Ki67, or in those candidate to adjuvant systemic treatment/radiotherapy anyway including TNBC, and support the incorporation of primary BC tumor characteristics as stratification factors in ongoing trials aiming at de-escalating axillary surgical procedures.

Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical Oncology (SICO) Breast Oncoteam survey.

The Italian Society of Surgical Oncology (SICO) Breast Oncoteam developed a survey to explore the state of the art of neoadjuvant treatment for breast cancer in Italy, specifically focusing on cases treated during the two-year period 2014-2015. A questionnaire was sent to Italian Breast Units with a minimum of 150 new breast cancer cases treated/year according to the Senonetwork directory and to the SICO Breast Oncoteam Breast Unit network. A total of 23/107 Breast Units submitted the survey, reporting a total amount of 20156 cases of breast carcinoma (17241 invasive, 2915 in situ) treated in the biennium, corresponding approximately to 20% of newly diagnosed breast cancers in Italy. In the United States, medical treatment before surgery for breast cancer is indicated in about 22.7% of newly diagnosed cases according to the National Cancer Database, while a German study reported approximately 20% of cases treated with neoadjuvant therapy. In our survey, a total of 1673/17241 cases (9.7%) were treated with neoadjuvant therapy, ranging from 2.9% to 23.6% according to different centres, showing heterogeneity in neoadjuvant treatment indications, even in multidisciplinary breast units. Better resources should be engaged to achieve a standardised quality indicator for neoadjuvant treatment, and this indicator could be included among the European Society of Breast Cancer Specialists (EUSOMA) quality indicators. In the near future, we plan to develop a second survey to better test improvements in the employment of neoadjuvant therapy after the expiry of the 2016 European Parliament deadline and after the 2017 St. Gallen Conference recommendations.

Sentinel node biopsy after primary chemotherapy in cT2 N0/1 breast cancer patients: Long-term results of a retrospective study.

BACKGROUND: It is controversial whether sentinel node biopsy (SNB) is adequate in breast cancer patients who become cN0 after primary chemotherapy. To address this we retrospectively compared outcomes in T2 cases given primary chemotherapy, comparing those given axillary dissection (AD) with those given SNB but no AD if sentinel nodes were clinically negative post-chemotherapy. METHODS: We examined overall survival (OS), disease-free survival (DFS), and axillary failure in 317 consecutive cT2 cN0/1 patients given primary chemotherapy followed by quadrantectomy/mastectomy, between January 2002 and December 2007. The approach to the axilla changed over time allowing division into three groups: 101 (31.9%) given upfront AD; 139 (43.8%) given SNB + AD; and 77 (24.3%) given SNB only because the SNs were negative. RESULTS: After median follow-ups of 92 (AD), 99 (SNB + AD) and 72 months (SNB-only), OS (p = 0.131) and DFS (p = 0.087) did not differ between the 3 groups, or between SNB-only and the ypN1 and ypN0 subgroups of SNB + AD, or between the cN0 and cN1 subgroups (before chemotherapy) of the SNB-only group. No SNB-only patient had axillary failure. OS (p = 0.004) and DFS (p = 0.002) were better in patients with complete response than those with partial response or stable/progressive disease. CONCLUSIONS: SNB is adequate in T2 patients who are cN0 after primary chemotherapy, irrespective of axillary status before. Better outcomes after complete pathological remission confirm the prognostic importance of response to primary chemotherapy, and suggest that all T2 patients should receive primary chemotherapy.

Atypical ductal hyperplasia of the breast: the controversial management of a borderline lesion: experience of 47 cases diagnosed at vacuum-assisted biopsy.

The present paper describes our experience of 47 cases of atypical ductal hyperplasia (ADH) diagnosed at vacuum-assisted biopsy. From June 1999 to December 2003, 47 consecutive diagnoses of non-palpable ADH of the breast were made by 11-gauge vacuum-assisted biopsy (Mammotome). Of these, 17 were subjected to surgical excision and 11 underwent a second Mammotome at the site of the previous vacuum-assisted biopsy. Diagnostic underestimation occurred in only two cases, with a surgical diagnosis of ductal carcinoma in situ. In both patients, aged between 46 and 55 years, the radiological images showed microcalcifications of >20 mm, and the lesions were not completely removed by Mammotome. Despite the obvious limitations of the present study, it can be concluded that the probability of underestimating ADH diagnosis by Mammotome appears to be related to the radiological features of the lesion (>20 mm) and to the adequacy of specimens.

Antibody-indocyanin conjugates for immunophotodetection of human squamous cell carcinoma in nude mice.

We have recently shown that immunophotodetection of human colon carcinomas in nude mice and in patients is possible by using anti-carcinoembryonic antigen monoclonal antibodies (MAb) coupled to fluorescein. The most common clinical application of photodiagnosis has been for the detection of squamous cell carcinomas (SCC) in the upper respiratory tract, but the free dyes used have a poor tumor selectivity. We selected the known MAb E48 directed against SCC and coupled it to a fluorescent dye: indopentamethinecyanin (indocyanin). This dye has an advantage over fluorescein in that it emits a more penetrating fluorescent red signal at 667 nm after excitation with a laser ray of 640 nm. In vitro, an conjugate with an indocyanin:MAb molar ratio of 2, and an additional trace labeling with 125I, showed more than 80% of binding to cells from the SCC line A431. In vivo, when injected i.v. into nude mice bearing xenografts of the same carcinoma line, the MAb E48-(indocyanin)2 conjugate was almost as efficient as the unconjugated MAb E48 in terms of specific tumor localization: 15% of the injected dose per g of tumor at 24 h after injection and a tumor:overall normal tissue ratio of 6-8. There was no selective tumor localization of an irrelevant IgG1-(indocyanin)2 conjugate. Immunophotodetection of the s.c. SCC xenografts on mice given injections of 100 micrograms of MAb E48-(indocyanin), conjugate (representing 1 microgram of indocyanin) was performed at 24 h. Upon laser irradiation, clearly detectable red fluorescence from the indocyanin-MAb conjugate was observed specifically in the SCC xenografts across the mouse skin. In comparison, injection of 100 micrograms of a MAb E48 coupled to 2 micrograms of fluorescein gave a specific green fluorescence signal in the tumor xenografts, which was detectable, however, only after removing the mouse skin. Injection i.v. of a 15 times higher amount of free indocyanin (15 micrograms) gave a diffuse red fluorescence signal all over the mouse body with no definite increase in intensity in the tumor, indicating a lack of tumor selectivity of the free dye. The results demonstrate the possibility of broadening and improving the efficiency of tumor immunophotodiagnosis by coupling to a MAb directed against SCC, a fluorescent dye absorbing and emitting at higher wavelength than fluorescein, and thus having deeper tissue penetration and lower tissue autofluorescence. Such a demonstration opens the way to a new form of clinical immunophotodiagnosis and possibly to the development of a more specific approach to phototherapy of early bronchial carcinomas.

Cytokine targeting in tumors using a bispecific antibody directed against carcinoembryonic antigen and tumor necrosis factor alpha.

The use of tumor necrosis factor alpha (TNFalpha) in cancer therapy is limited by its short circulatory half-life and its severe systemic side effects. To overcome these limitations, we evaluated the capability of a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and human TNFalpha to target this cytokine in tumors. A BAb was constructed by coupling the Fab' fragments from an anti-CEA monoclonal antibody (MAb) to the Fab' fragments from an anti-TNFalpha MAb via a stable thioether linkage. The double specificity of the BAb for CEA and TNFalpha was demonstrated using a BIAcoreTM two-step analysis. The affinity constants of the BAb for CEA immobilized on a sensor chip and for soluble TNFalpha added to the CEA-BAb complex were as high as those of the parental MAbs (1.7 x 10(9) M-1 and 6.6 x 10(8) M-1, respectively). The radiolabeled 125I-labeled BAb retained high immunoreactivity with both CEA and TNFalpha immobilized on a solid phase. In nude mice xenografted with the human colorectal carcinoma T380, the 125I-labeled BAb showed a tumor localization and biodistribution comparable to that of 131I-labeled anti-CEA parental F(ab')2 with 25-30% of the injected dose (ID)/g tumor at 24 h and 20% ID/g tumor at 48 h. To target TNFalpha to the tumor, a two-step i.v. injection protocol was used first, in which a variable dose of 125I-labeled BAb was injected, followed 24 or 48 h later by a constant dose of 131I-labeled TNFalpha (1 microg). Mice pretreated with 3 microg of BAb and sacrificed 2, 4, 6, or 8 h after the injection of TNFalpha showed a 1.5- to 2-fold increased concentration of 131I-labeled TNFalpha in the tumor as compared to control mice, which received TNFalpha alone. With a higher dose of BAb (25 microg), mice showed a better targeting of TNFalpha with a 3.2-fold increased concentration of 131I-labeled TNFalpha in the tumor: 9.3% versus 2.9% ID/g in control mice 6 h after TNFa injection. In a one-step injection protocol using a premixed BAb-TNFalpha preparation, similar results were obtained 6 h postinjection (3.5-fold increased TNFalpha tumor concentration). A longer retention time of TNFalpha was observed leading to an 8.1-fold increased concentration of TNFalpha in the tumor 14 h postinjection (4.4 versus 0.5% ID/g tumor for BAb-treated and control mice, respectively). These results show that our BAb is able, first, to localize in a human colon carcinoma and, there, to immunoabsorb the i.v.-injected TNFalpha, leading to its increased concentration at the tumor site.

A prognostic score for patients resected for gastric cancer.

This paper describes the construction, validation and use of a simple prognostic score suitable for predicting survival of patients undergoing a curative gastric resection. Using death from all causes as outcome, the prognostic significance of age, sex, tumour site, stage of disease (nodal status and wall invasion), surgical treatment and histological type was investigated in a set of 213 patients recruited in a multi-centre clinical trial. A Weibull multiple regression model was adopted to evaluate the joint effect of these variables on survival. From a full model, containing all the variables, a final parsimonious model was obtained by means of a backward selection procedure. The prognostic score is based on the final model, including four variables which are easily detected in every institution: age, wall invasion, site of tumour, and nodal status. Three groups of patients with different probabilities of surviving 5 years from surgery were identified: group I (survival probability > or = 70%), group II (30%-69%) and group III (< 30%). The prognostic score, obtained from the multicentre trial patients, was tested on a set of 135 consecutive patients in an independent institution, confirming its reliability in predicting survival. The score system presented can supply a simple tool for classifying patients radically operated for gastric cancer into three well discriminated groups from the prognostic point of view.

Early gastric cancer in the province of Forlì: follow-up of 337 patients in a high risk region for gastric cancer.

Long-term clinical outcome was analysed in a series of 337 patients with early gastric cancer (EGC) at a median follow-up of 8 years. Tumours were classified according to the macroscopic and microscopic criteria proposed by the Japanese society of gastroenterological endoscopy (JSGE) and Lauren, respectively. Type of penetration (PEN) was classified according to Kodama. Overall survival rate was 92% at 5 years and 88% at 8 years and was significantly related to depth, type of penetration, lymph node status and tumour size. A significantly lower 5-year survival (p<0.05) was observed for patients with lymph node metastases and PEN A type EGC (55%) or for those with node-positive tumours and submucosal wall penetration (58%) than for the other pathologic subgroups. Therefore, these two subgroups should be considered as advanced gastric cancer patients from the prognostic point of view. Moreover, multivariate analysis by Cox regression model showed the degree of lymph node involvement and Kodama's type PEN A as the only independent prognostic factors.

Identification of occult micrometastases in patients with early gastric cancer using anti-cytokeratin monoclonal antibodies.

The presence of occult micrometastases was evaluated in 1488 lymph nodes removed from 139 patients with node-negative early gastric cancer (EGC). Additional multiple levels of the lymph nodes were examined with haematoxylin-eosin staining and keratin immunostaining. Occult nodal micrometastases were detected in 24 patients (17%) in one or more lymph nodes dissected after a gastrectomy. The cases investigated were a small group from a total of 412 EGC patients who underwent surgical treatment in our hospital between 1976 and 1997; the mean follow-up period was 9 years (range 1-22). We found no significant differences between cytokeratin-negative and positive patients regarding the following clinicopathological parameters: age, gender, tumour size and site, macroscopic and microscopic type, depth of invasion and type of infiltration, according to Kodama's classification. The survival rate at 5 years was 88% and 87% for cytokeratin-negative and positive patients, respectively (log-rank = 0.6; ns). Our data suggest that occult micrometastases do not add useful information and immunohistochemical studies to detect them are probably unnecessary.

Combined radioimmunotherapy and chemotherapy of human colon carcinoma grafted in nude mice, advantages and limitations.

In order to determine if 5-fluorouracil (5FU) could potentiate the effect of radioimmunotherapy (RIT), nude mice bearing subcutaneous human colon carcinoma xenografts were treated by 1 or 2 intravenous injection(s) of subtherapeutic doses of 131I labeled F(ab')2 from anti-carcinoembryonic antigen monoclonal antibodies combined with 5 daily intraperitoneal injections of 5FU. Control mice received either 131I F(ab')2 alone, 5FU alone or no treatment. RIT alone induced significant tumor regression, while 5FU alone gave only minimal tumor growth inhibition. The combined treatment group also resulted in long-term tumor regression with tumors remaining significantly smaller than in the RIT alone group. There was however, no significant difference in tumor recurrence time between the groups treated with RIT alone or with RIT + 5FU. Myelotoxicity, the major side effect of RIT, detected by the decrease of peripheral white blood cells (WBC), was shown to be almost identical between the groups receiving only RIT or only 5FU. Surprisingly, there was no cumulative bone marrow toxicity in animals which received 5FU before RIT. Furthermore, in the latter group, the WBC levels after RIT were significantly higher than in the control group receiving only RIT. Taken together, the results demonstrate the higher therapeutic efficiency of RIT as compared to 5FU in this model. They do not show, however, that the combination of the two forms of treatment can induce longer tumor remission. Interestingly, the WBC results suggest that 5FU given before RIT can have a radioprotective effect on bone marrow, possibly by selecting radioresistant bone marrow stem cells.

[Surgical treatment of adrenal metastases. Personal experience]. / Trattamento chirurgico delle metastasi surrenaliche. Esperienza personale.

The adrenal glands are often the site of metastases. However, there is much discussion as to the benefits of surgical resection. Personal experience of surgical treatment in 4 patients, one of whom died postoperatively after bilateral adrenalectomy for metachronous metastases, is reported. Surgery achieved pain relief in all patients, average survival was 30 months and 1 patient is still alive after 68 months. The present study shows that surgery is advisable in patients who present the following characteristics: 1) the primary tumor has been resected or is radically resectable, 2) there is no evidence of other metastatic lesions, 3) the adrenal metastasis is unilateral and complete resection is possible, 4) the patient's general physical condition is good.

[Radiolabeled monoclonal antibodies as anti-tumor missiles, their diagnostic success and therapeutic potential]. / Les anticorps monoclonaux radiomarqués en tant que missiles anti-tumeurs, leurs succès diagnostiques, leur potentiel thérapeutique.

While it is now well accepted that radiolabeled antibodies can be useful for tumour detection by immunoscintigraphy, the use of larger doses of more aggressive radioisotopes coupled to antibodies for radioimmunotherapy is still in its infancy. At the experimental level, our group has shown that the intravenous injection of large doses of 131I labeled F(ab')2 fragments from monoclonal anti-carcinoembryonic antigen (CEA) antibodies can eradicate well established human colon carcinoma xenografts in nude mice. At the clinical level, in a dosimetry study performed at the Institut Gustave Roussy, the same anti-CEA monoclonal antibodies and fragments, labeled with subtherapeutic doses of 131I, were injected in patients with liver metastases from colorectal carcinomas. Direct measurement of radioactivity in surgically resected liver metastases and normal liver confirmed the specificity of tumour localization of the antibodies, but also showed that the calculated radiation doses which could be delivered by injections of 200 to 300 mCi of 131I labeled antibodies or fragments, remained fairly low, in the range of 1,500 to 3,000 rads. This is obviously insufficient for a single modality treatment. An alternative approach is to inject radiolabeled antibodies intra peritoneally to treat peritoneal carcinomatosis. Several clinical studies using this strategy are presently under evaluation and suggest that positive results can be obtained when the tumour diameters are very small. In systemic radioimmunotherapy, positive results have been obtained in more radiosensitive types of malignancies such as B cell lymphomas by intravenous injection of antibodies directed against B cell differentiation markers or against idiotypic antigens from each lymphoma, and labeled with 131I or 90Y. The major directions of research for improvement of radioimmunotherapy include the design of genetically engineered new forms of humanized antibodies, the synthesis of original chelates for coupling new radioisotopes to antibodies and the development of two step strategies for immunolocalization of radioisotopes.

[Respiratory function tests as a predictive indicator of postoperative course in patients undergoing pneumonectomy because of neoplasms]. / Le prove di funzionalità respiratoria come indice predittivo del decorso postoperatorio nei pazienti pneumonectomizzati per neoplasia.

Postoperative morbidity and mortality were correlated with the preoperative results of three widely used pulmonary function tests (FVC, FEV1, FEV1/FVC) in 100 consecutive patients who underwent pneumonectomy for lung carcinoma. Factor analyzed following operation included thirty-day mortality, incidence of cardiovascular and respiratory complications, number of individuals requiring prolonged mechanical ventilation. Nineteen patients had a forced vital capacity (FVC) of 70% or less of the normal value, seven had a one-second forced expiratory volume (FEV1) of 1.5 liters or less, and thirty-three had a FEV1 of less than 2 liters. Fourteen patients had a FEV1/FVC ratio of 65% or less. There were no differences in morbidity or mortality between these patients and those presenting higher test scores. As a general rule, decisions regarding operability and extent of resection cannot be made solely on the basis of the three spirometry tests reviewed.