Management of the axilla in breast cancer patients: critical review, regional modified Delphi consensus and implementation in the Tuscan breast network.

PURPOSE: Data from recently trials have provided practice-changing recommendations in management of the axilla in early breast cancer (eBC). However, further controversies have been raised, resulting in heterogeneous diffusion of these recommendations. Our purpose was to obtain a better homogeneity. MATERIAL AND METHODS: In 2021, the Tuscan Breast Network (TBN) established a consensus with the aim to update recommendations in this area. We performed a literature review on axillary management in eBC patients which led to an expert Delphi consensus aiming to explore the gray areas, build consensus and propose evidence-based suggestions for an appropriate management. Thereafter, we investigate their implementation in clinical practice. RESULTS: (1) DCIS patients should have SLN biopsy only in case of mastectomy or in conservative surgery if tumor is in a location that would preclude future nodal sampling or in case of a mass; (2) ALND may be omitted for 1-2 positive SLN patients undergoing BCS in T1-2 tumors with 1-2 SLN positive, eligible for whole-breast irradiation and adjuvant systemic therapies; (3) consider the option of RNI in patients with 1-3 positive lymph nodes and one or more high-risk characteristics; (4) the population identified in 2) should NOT undergo lymph node irradiation as an alternative to axillary surgery and (5) patients with clinically (pre-operatively) positive axilla, or undergoing primary systemic therapy, or outside the criteria reported in 2) must receive additional ALND and/or RT as per local policy. CONCLUSION: This consensus provided a practical tool to stimulate local and national breast surgical and radiotherapy protocols.

Assessing psychological needs in female cancer patients: a tailored model.

BACKGROUND AND AIM OF THE WORK: Psychosocial needs in cancer patients seem to be underestimated and undertreated. The present research was designed to explore under-considered psychosocial needs (e.g., stressful life events, perceived social support, sense of mastery and depressive/anxious symptoms) of a female cancer group. The aim of the study was to test an assessment psycho-oncological model for female cancer patients. An assessment model of psychosocial needs and Stressful Life Events was operationalized and tests its predictive power. METHODS: We used Discriminant Analysis to test predictive power of the model and of the single variables included in it. 236 oncological patients (mean age 55.50 ± 13.09) were matched with 232 healthy control groups in the study. The following instruments were chosen: the Florence Psychiatric Interview, Hospital Anxiety Depression Scale, Multidimensional Scale of Perceived Social Support, Beck Depression Inventory I, and Sense of Mastery. RESULTS: The model satisfied the assumption criteria and was significant (Ʌ= .680, X2 = 109.73, p< .001). CONCLUSIONS: Stressful events, depression and anxiety were adequate markers of the assessment psycho-oncological model proposed for female cancer patients. The present study provides contributions in a clinical perspective: the results support the relevance of considering an assessment psychosocial model to use in female oncology for an accurate estimation of the women's needs. Women affected by female cancer with an history of Stressful Early and Recent life events and high level of anxiety and depression could positively benefit from a psychotherapy treatment.

Identification of a Gene Panel for Endometrioid Endometrial Cancer: a Possible Prognostic Value?

The incidence of endometrial cancer (EC) is increasing in developed countries. The most frequent is the endometrioid subtype with usually good prognosis; nevertheless, some cases escape this paradigm and may have recurrence. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. The present preliminary study was performed on 15 G3 endometrioid endometrial cancers (G3 EEC) for the identification of somatic mutations in a panel of specific exons in selected genes as ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, and TP53. The combined procedure, based on the Sanger sequencing and PCR-high-resolution melting analysis, allowed the identification of variations of the selected gene panel in most of patients (93%) of our cohort. The overall evaluation of mutational load exhibited that the most frequent mutated genes were PTEN (93%), followed by PIK3CA (47%) suggesting a deep involvement of PI3K pathway alteration in G3 EEC. Mutations in TP53 (27%), ARID1A (27%), POLE (13%), and at the lower level in KRAS and CTNNB1 (7%) were also observed (exclusively in FIGO III stage patients). The evaluation of the mutations of our proposed panel (ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, TP53) is suitable to improve the characterization of G3 EEC and could suggest targetable pathways for development of personalized treatments.

Use of Electronic Administrative Databases to Measure Quality Indicators of Breast Cancer Care: Experience of Five Regional Oncology Networks in Italy.

PURPOSE: Assuring quality of care, while maintaining sustainability, in complex conditions such as breast cancer (BC) is an important challenge for health systems. Here, we describe a methodology to define a set of quality indicators, assess their computability from administrative data, and apply them to a large cohort of BC cases. MATERIALS AND METHODS: Clinical professionals from the Italian Regional Oncology Networks identified 46 clinically relevant indicators of BC care; 22 were potentially computable using administrative data. Incident cases of BC diagnosed in 2016 in five Italian regions were identified using administrative databases from regional repositories. Each indicator was calculated through record linkage of anonymized individual data. RESULTS: A total of 15,342 incident BC cases were identified. Nine indicators were actually computable from administrative data (two structure and seven process indicators). Although most indicators were consistent with guidelines, for one indicator (blood tumor markers in the year after surgery, 44.2% to 64.5%; benchmark ≤ 20%), deviation was evident throughout the five regions, highlighting systematic overlooking of clinical recommendations. Two indicators (radiotherapy within 4 months after surgery if no adjuvant chemotherapy; 42% to 83.8%; benchmark ≥ 90%; and mammography 6 to 18 months after surgery, 55.1% to 72.6%; benchmark ≥ 90%) showed great regional variability and were lower than expected, possibly as result of an underestimation in indicator calculation by administrative data. CONCLUSION: Despite highlighting some limitations in the use of administrative data to measure health care performance, this study shows that evaluating the quality of BC care at a population level is possible and potentially useful for guiding quality improvement interventions.

Trabectedin in combination with pegylated liposomal doxorubicin in patients with ovarian tumors.

The majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity.

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin.

Leiomyosarcomas represent the most common variant of uterine sarcomas, and are also considered to be the least chemosensitive. To date, adriamycin and ifosfamide are believed to be the most effective drugs for its treatment, in addition to docetaxel and gemcitabine. Recently, the introduction of trabectedin has provided clinicians with another treatment option, and the drug may have some benefits for patients as it may allow for long-term treatment. We present the case of a patient who previously failed multiple cycles of chemotherapy and who was subsequently treated with 30 cycles of trabectedin as third-line therapy for multiple metastases of uterine leiomyosarcoma. During the treatment period, the dosage and dose interval of trabectedin were optimized because of the appearance of grade 4 hematological and gastrointestinal toxicity. Dose adjustments led to acceptable tolerability. Trabectedin was associated with a very good partial response, especially at the pulmonary and pancreatic levels, and stable disease was achieved at all metastatic sites. The patient is currently continuing treatment with trabectedin and has clinically stable disease after 2 years of therapy. This case report provides further evidence that trabectedin is a valid and well-tolerated therapeutic option that can be used in the long term in uterine leiomyosarcoma.

Participation and risk of high grade cytological lesions among immigrants and Italian-born women in an organized cervical cancer screening program in Central Italy.

Few studies analyzed the risk for high-grade squamous intraepithelial lesions or worse (HSIL+) among immigrants and natives attending organized cervical cancer (CC) screening programs (SP). We evaluated participation and diagnosis of HSIL+ by country of birth with logistic models. Overall 540,779 invitation letters were delivered to target women of Florence SP in three screening rounds (years 2000-2002, 2003-2005, 2006-2008). The probability of attending screening was lower for immigrants than natives, but the difference decreased from 35% (1st round) to 20% (2nd-3rd round) for women born in high migration pressure (HMP) countries. The risk of HSIL+ was double than natives for HMP-born women from countries with high prevalence of human papillomavirus, even adjusting for age and previous history of Pap test. This is an important public health problem due to an increasing proportion over time of immigrant women with a lower attendance and greater risk for CC.

Indicators of the standard of care for melanoma: Tuscany data.

Formal indicators for the evaluation of the quality of melanoma care are needed. We identified 13 process indicators, which encompassed early diagnosis, pathology reporting and surgical treatment. We evaluated the adherence to these indicators using a population-based series on incident skin melanomas (only primary melanomas) for the year 2004 (687 cases) and for the first semester of 2008 (539 cases). We compared the indicators for these 2 years. The melanoma incidence increased between 2004 and 2008. There were statistically significant increases in the percentage of thin (≤1 mm) melanomas (from 50.7 to 61.3%) and in the number of pathology reports that mentioned ulceration (from 61.4 to 84.6%) and margin status (from 76.8 to 84.3%). The percentage of patients staged by sentinel lymph node biopsy was stable (63%) and was higher for patients younger than 75 years of age (74%). The number of nodes almost invariably exceeded the proposed site-specific cutoff reference and, in 2008, the number of nodes removed was always reported for lymphadenectomy. From 2004 to 2008, surgical and pathological waiting times increased. Collection and analysis of these indicators would enable continuous evaluation of the quality of melanoma care in Tuscany and provide sources for a comparative study between Italy and elsewhere.

Feasibility of evaluating quality cancer care using registry data and electronic health records: a population-based study.

OBJECTIVE: To evaluate the quality of patients care, a set of indicators of the standards of cancer care were defined. PARTICIPANTS: We developed a set of indicators to assess the implementation in daily practice of recommendation produced by a regional network (Istituto Toscano Tumori). This set was tested in a retrospective study in the resident population of the Tuscany Region; the regional health system is organized on 12 local health authorities which refer to three macro areas (Area Vasta). The study included incident colorectal, lung and breast cancer cases listed in 2004 for the Tuscan Cancer Registry, a population-based registry which collected tumor cases diagnosed in all residents in Tuscany. Electronic data from registry database were used to determine the compliance with each indicator for patients in 2004. To validate the results, an ad hoc clinical survey including the same geographical area for the year 2006 was performed. INTERVENTION: None. MAIN OUTCOME MEASURES: The proportion of patients who fulfilled each of the indicators. RESULTS: Our study showed the feasibility of the evaluation of the quality of cancer care using cancer registry population-based data and major computerized information systems. The estimation of the selected indicators confirmed a good homogeneity among areas, and globally revealed a good intraregional performance. CONCLUSIONS: Further work is needed to develop specific quality measures, particularly about structural data and to continually revise indicators of quality of care. Data from a cancer registry, however, can be useful to evaluate quality of cancer care.

DNA ploidy is stronger than lymph node metastasis as prognostic factor in cervical carcinoma: 10-year results of a prospective study.

INTRODUCTION: To improve the outcome of patients with cervical cancer, a more accurate prognostic assessment is essential. The aim of this study was to evaluate the role of tumor DNA ploidy as an independent prognostic factor in cervical carcinoma. Furthermore, we investigated whether the presence of lymph node metastasis may have a different clinical impact according to ploidy status. METHODS: In a long-term prospective study, DNA ploidy was evaluated by flow cytometry from fresh tumor samples from 136 patients with cervical cancer who underwent surgery. Ploidy, lymph node metastasis, and other classical parameters were analyzed in relation to the length of disease-specific survival. Treatment modalities did not differ between patients with diploid tumors and patients with aneuploid tumors. RESULTS: DNA aneuploidy was found in 52 patients (38.2%). Patients with DNA-aneuploid tumors had a significantly reduced disease-specific survival (P = 0.003). Overall, the 10-year survival probability was 54% for patients with DNA-aneuploid tumors and 80% for patients with DNA-diploid tumors. Among 64 patients with International Federation of Gynecologists and Obstetricians stage I disease, the 10-year survival rates were 38.7% for the patients with DNA-aneuploid tumors and 86.3% for those with DNA-diploid tumors (P = 0.003). Overall, diploid tumors with lymph node metastasis did significantly better than aneuploid tumors with lymph node metastasis (P = 0.05). Among the patients with International Federation of Gynecologists and Obstetricians stage I disease, there was a highly significant difference between patients with diploid node-positive tumors and patients with aneuploid node-positive tumors, with no deaths from the disease in the former group in contrast with the worst outcome in the latter group (P = 0.005). By multivariate analysis, pathologic tumor stage, lymph vascular invasion, and tumor ploidy were significant and independent parameters, whereas lymph node metastasis yielded no independent information. CONCLUSIONS: DNA ploidy was an independent prognostic factor in cervical carcinoma. Presence of lymph node metastasis may not always have the same impact on survival but may vary according to DNA ploidy of the primary tumor.

Ten-year results of a prospective study on the prognostic role of ploidy in endometrial carcinoma: dNA aneuploidy identifies high-risk cases among the so-called 'low-risk' patients with well and moderately differentiated tumors.

BACKGROUND: To improve the outcome of endometrial cancer patients, a more accurate prognostic assessment is mandatory. The aims of the study were to evaluate the role of flow cytometric DNA ploidy as an independent prognostic factor in patients with endometrial cancer and to verify if ploidy was able to distinguish patients with different prognosis into homogeneous subgroups for grade of differentiation and stage. METHODS: In a prospective study, DNA ploidy was evaluated from fresh tumor samples in 174 endometrial cancer patients who underwent surgery as the first treatment. Ploidy, as well as classical parameters, were analyzed in relation to the length of disease-free survival and disease-specific survival. RESULTS: DNA aneuploidy was found in 49 patients (28.2%). Patients with DNA-aneuploid tumors had a significantly reduced disease-free interval and disease-specific survival (P < .0001). The 10-year survival probability was 53.2% for DNA-aneuploid patients and 91.0% for patients with DNA-diploid tumors. By multivariate analysis DNA-aneuploid type was the strongest independent predictor of poor outcome, followed by age and stage. Patients with DNA-aneuploid tumor had a significantly higher risk ratio for recurrence (5.03) and death due to disease (6.50) than patients with DNA-diploid tumors. Stratification by DNA-ploidy within each group by grade of differentiation allowed identification of patients with significantly different outcome. In grade 2 tumors, 10-year survival was 45.0% in aneuploid cases and 91.9% in diploid cases (P < .0001). Patients with advanced-stage (>I) diploid tumor did significantly better than patients with stage I aneuploid tumor (P = .04). CONCLUSIONS: The presence of DNA-aneuploid type in endometrial cancer identifies high-risk cases among the patients considered 'low risk' according to stage and grade of differentiation.

HER-2/neu and bcl-2 in ovarian carcinoma: clinicopathologic, immunohistochemical, and molecular study in patients with shorter and longer survival.

The bcl-2 protein is a membrane protein involved in prolonging cell survival by inhibiting apoptosis. The HER-2 oncogene, which is located on chromosome 17 and encodes for a tyrosine-kinase growth factor receptor, is amplified and HER-2/neu is overexpressed in 25% to 30% of breast carcinomas. The authors analyzed the bcl-2 expression and the bcl-2 gene and HER-2/neu overexpression and amplification in FIGO stage IIIC, serous, G3, ovarian carcinomas obtained from living patients who had no evident disease 5 years after primary treatment compared with ovarian carcinomas obtained from patients, matched for stage, grade of differentiation, and treatment, who had died of progression of disease no later than 2 years after primary treatment. bcl-2 overexpression was statistically correlated with progression of disease during first-line chemotherapy (P=0.021). The HER-2/neu status was found not to correlate with progression of disease during first-line chemotherapy. Both bcl-2 and HER-2/neu expression were not statistically associated with the clinical outcome of ovarian cancer patients. Gene amplification of the HER-2/neu chromosome 17 was found in all the HER-2/neu, 3+ score, positive-staining ovarian carcinomas. None of the analyzed samples revealed a translocation t(14;18)(q32;q21) in the bcl-2 gene. The knowledge of additional prognostic or even predictive factors, such as bcl-2 expression, in patients with advanced ovarian carcinoma before the primary chemotherapeutic treatment may help in the management of patients who require a more tailored treatment. In addition, the gene amplification of the HER-2/neu suggests that HER-2 is a potential target for treatment in ovarian cancer.

COX-2 and preoperative CA-125 level are strongly correlated with survival and clinical responsiveness to chemotherapy in ovarian cancer.

BACKGROUND: CA-125 is elevated in the serum of the majority of ovarian carcinoma patients. Cyclooxygenase-2 is an enzyme whose synthesis is upgraded by several cytokines, growth factors, and tumor promoters. METHODS: We analyzed cyclooxygenase-2, preoperative CA-125 levels, and CA-125 levels during chemotherapy in 41 FIGO stage III, grade 3, ovarian serous carcinoma patients in relation to survival with a logistic regression. The correlation of cyclooxygenase-2 expression and CA-125 preoperative level with clinical responsiveness to chemotherapy was studied according to Fisher's exact test. We compared 23 patients living with no evident disease five years after primary treatment to 18 patients who had died of progression of disease no later than two years after primary treatment. RESULTS: Cyclooxygenase-2 overexpression (p = 0.014 and p = 0.036) and preoperative CA-125 level (p = 0.012 and p = 0.029) were found to be independent predictors of survival in univariate and multivariate analyses. Cyclooxygenase-2 and CA-125 level were correlated to responsiveness to chemotherapy (p = 0.003 and p = 0.036, respectively; Fisher's exact test). The patients with a CA-125 level <35 U/ml after two cycles of chemotherapy showed a longer survival (p = 0.008). The median preoperative CA-125 was 195 in high survival patients and 650 in low survival patients (p= 0.004, Wilcoxon Mann-Whitney test). CONCLUSIONS: Cyclooxygenase-2 overexpression and CA-125 levels may help the management of ovarian cancer patients, permitting the selection of more aggressive and tailored first-line therapy.

Treatment of uterine sarcoma at the University of Florence from 1980-2001.

PURPOSE: To correlate the treatment used in uterine sarcoma with outcome. The prognostic importance of pathology, clinical parameters and treatment are analyzed. PATIENTS AND METHODS: Forty patients (median age, 59 years; range, 37-85) with histologically verified uterine sarcoma were identified from a database compiled at the University of Florence from 1980 to 2001. Patients were followed for a median of 54 months (range, 3 months to 10 years). Twenty-four patients had leiomyosarcoma, 12 patients had mixed mullerian tumors, and 3 patients had endometrial stromal sarcoma. Stage I, II, III and IV tumors were identified in 22, 2, 9 and 7 patients, respectively. High, intermediate, low and unspecified grade sarcoma occurred in 9, 4, 5 and 22 patients, respectively. RESULTS: At the time of analysis, 58% of patients had died and 42% were alive, with a median survival of 2 years from the initial diagnosis. Cause-specific survival for the entire group was 81%, 41% and 25% at 1, 3 and 5 years, respectively. In our series, univariate analysis for cause-specific survival did not demonstrate statistical significance for histology, grade, stage or age. There appeared to be a significant impact for postoperative radiotherapy in reducing local recurrence with a total dose higher than 50 Gy. CONCLUSIONS: Our data favor treatment for uterine sarcoma with radical surgery plus irradiation, even in elderly patients.

Correlation of epidermal growth factor receptor expression with tumor microdensity vessels and with vascular endothelial growth factor expression in ovarian carcinoma.

We analyzed in advanced ovarian serous G3 carcinoma the correlation between epidermal growth factor receptor (EGFR) overexpression and tumor angiogenesis and their relation with clinical outcome. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were statistically correlated with disease-free interval and death from disease both in univariate and multivariate analyses while EGFR expression was not correlated with clinical outcome. MVD was significantly associated with progression of disease during chemotherapy while VEGF and EGFR expression were not correlated with responsiveness to chemotherapy (Fisher's exact test). VEGF expression was correlated with MVD (Fisher's exact test). EGFR showed a trend to correlation with MVD. Further studies focusing on the use of angiogenesis inhibitors in addition to EGFR inhibitors on ovarian carcinoma cells may produce therapeutic strategies in the selection of tailored therapies in ovarian cancer patients.

Vaginal hysterectomy and abdominal hysterectomy for treatment of endometrial cancer in the elderly.

OBJECTIVE: The purpose of this study was to analyze the outcome of vaginal and abdominal hysterectomy for treatment of endometrial cancer in elderly patients. METHODS: In a retrospective series of 171 patients with age > or =70 years and at stages I-III, we evaluated operative and hospitalization data, as well as morbidity, mortality, and long-term survival associated with vaginal and abdominal hysterectomy. A total of 128 patients were operated on with vaginal hysterectomy and 43 cases underwent abdominal hysterectomy. RESULTS: Medically compromised patients were significantly more frequent in the vaginal surgery group (P = 0.01). Overall, the 10-year disease-specific survival rates after vaginal and abdominal hysterectomy were 80% and 78%, respectively (P = n.s.). Limiting the analysis to stage I (130 patients), 10-year disease-specific survival was 83% in 95 women operated on by the vaginal route and 84% in 35 patients operated by the abdominal approach (P = n.s.). Patients in the vaginal surgery group had a significantly shorter operative time (P = 0.01), less blood loss (P < 0.05), and were discharged earlier (P < 0.05). Severe complications occurred in 5.4% of the vaginal and in 7.0% of the abdominal procedures. Perioperative mortality was zero after vaginal hysterectomy and 2.3% after abdominal hysterectomy, respectively. CONCLUSIONS: Vaginal hysterectomy showed a high cure rate, shorter operative time, less blood loss, reduced morbidity, and no mortality and therefore may be considered the elective approach for treatment of elderly patients with endometrial cancer.

COX-2, c-KIT and HER-2/neu expression in uterine carcinosarcomas: prognostic factors or potential markers for targeted therapies?

OBJECTIVES: Uterine carcinosarcomas are uncommon, highly aggressive neoplasms that frequently recur after surgical treatment and adjuvant chemo-radiotherapy. Patients with recurrent disease respond poorly to salvage chemotherapy and irradiation. New therapeutic options are required for patients with metastatic disease. Clinical evidences showing the effect of a tyrosine kinase inhibitor, STI571, in c-KIT-positive gastrointestinal tumors, the role of COX-inhibitors chemotherapy-associated in colorectal cancer patients and the successful therapeutic possibility of anti-HER2 therapy in metastatic breast carcinoma, have encouraged us to study the expression of c-KIT, COX-2 and HER-2/neu in uterine carcinosarcomas. METHODS: We analyzed the expression of COX-2, c-KIT and HER-2/neu in 24 uterine carcinosarcomas and their correlation with clinical outcome. Disease-free interval and actuarial survival rates were the end points of the study. RESULTS: High staining intensity for COX-2 was observed in 8 cases (33.3%). C-KIT was expressed in 4 cases (16.7%) and HER-2/neu in 7 cases (29.2%). Patients with COX-2-positive tumors had a significantly poorer disease-free interval and survival (P = 0.01 and P = 0.05, respectively). All patients with c-KIT-positive tumors had early stage disease. In spite of this, their survival was not significantly better than that of c-KIT-negative cases. HER-2/neu expression did not show any correlation with clinical outcome. CONCLUSION: c-KIT, COX-2, and HER-2/neu were expressed in different proportions of uterine carcinosarcomas. COX-2 expression was a strong indicator of unfavorable prognosis. These results warrant further study to evaluate the possible role of a new molecularly targeted cancer therapy with COX-2 inhibitors in patients with uterine carcinosarcomas. The role of c-KIT expression and consequently the hypothetical use of STI571 should be tested in a larger series.