Neoadjuvant Systemic Therapy in Early Breast Cancer: Results of a Prospective Observational Multicenter BRIDE Study.

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study.

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

PURPOSE: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. METHODS: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. RESULTS: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. CONCLUSION: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Effect Modifiers of Low-Dose Tamoxifen in a Randomized Trial in Breast Noninvasive Disease.

PURPOSE: Low-dose tamoxifen halved recurrence after surgery in a phase III trial in breast noninvasive disease without increasing adverse events. We explored the effect of low-dose tamoxifen in clinically relevant subgroups, including menopausal status, estradiol levels, smoking, body mass index, and proliferation of baseline lesion. PATIENTS AND METHODS: Incidence of invasive breast cancer or ductal carcinoma in situ was the primary endpoint. HRs and interaction terms were estimated using Cox models. RESULTS: A favorable HR and 95% confidence interval (CI) could be demonstrated for postmenopausal status (HR = 0.30; 95% CI, 0.11-0.82 vs. HR = 0.73; 95% CI, 0.30-1.76 in premenopausal women; P interaction = 0.13), women with estradiol less than 15.8 pg/mL, presence of menopausal symptoms at baseline, and never smoking (P interaction = 0.07), although the interaction P value was >0.05 for all characteristics. Efficacy was similar in all body mass index categories. Tumors with Ki-67 above the median level of 10% had a greater benefit (HR = 0.27; 95% CI, 0.09-0.81) than those with Ki-67 ≤10% (HR = 1.58; 95% CI, 0.45-5.60; P interaction = 0.04). CONCLUSIONS: The efficacy of low-dose tamoxifen seems to be greater in postmenopausal women and in women with lower estradiol levels. Benefits appear to be larger also in women with menopausal symptoms, never smokers, and tumors with Ki-67 >10%. Our results by menopausal status provide important insight into low-dose tamoxifen personalized treatment, although caution is necessary given their exploratory nature. Observation of an improved response in tumors with Ki-67 >10% is consistent but the use of the marker in this setting is investigational.See related commentary by Fabian, p. 3510.

Predictors of longitudinal depression trajectories after traumatic brain injury in Latin America: A multi-site study.

BACKGROUND: Latin America has exceptionally high rates of traumatic brain injury (TBI), but very little research has been conducted on longitudinal TBI outcomes in this global region. OBJECTIVE: This study examined whether cognitive dysfunction and social disadaptation in individuals with TBI in Latin America at hospital discharge predict longitudinal trajectories of depression at baseline, 2 months, and 4 months. METHODS: A sample of 109 people with a new TBI was recruited from three hospitals: Mexico City, Mexico, Cali, Colombia and Neiva, Colombia. Participants completed measures of cognitive dysfunction and social disadaptation before hospital discharge and measures of depression at baseline, 2 months, and 4 months. RESULTS: Results suggested that depression scores were found to decrease over time in a quadratic (or U-shaped) fashion, and more significant cognitive dysfunction at hospital discharge was associated with higher longitudinal depression trajectories. Social disadaptation did not exert a unique effect on depression trajectories after controlling for cognitive dysfunction. Depression trajectories changed differentially over time as a function of baseline cognitive dysfunction, such that for those with high cognitive impairment, depression scores started high and then dropped to a moderated range and plateaued, but for individuals with low cognitive dysfunction, depression scores started lower and decreased linearly but moderately. CONCLUSIONS: The results suggest a strong need for neuropsychological assessments and evidence-based cognitive rehabilitation strategies to be implemented immediately after TBI in Latin America, which could exert salubrious effects on depression trajectories over time.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia.

PURPOSE: Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose. PATIENTS AND METHODS: We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. RESULTS: Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen (P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo. CONCLUSION: Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.

Gemcitabine and paclitaxel combination as second-line chemotherapy in patients with small-cell lung cancer: a phase II study.

BACKGROUND: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. PATIENTS AND METHODS: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. RESULTS: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. CONCLUSIONS: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

The use of the orbital septum in inferior palpebral reconstruction: the pocket technique.

BACKGROUND: Surgery involving massive inferior palpebral demolition often imposes the use of free flaps for the reconstruction of the anterior and posterior lamellae. PURPOSE: We describe a surgical technique which provides for the use of a homologous pedunculated elastic flap on which we wrap the free flap as in a pocket, in order to guarantee that the free flap itself takes root better. METHODS: A study of 10 patients admitted to our hospitals for massive inferior palpebral demolition surgery between March 2002 and November 2004 was undertaken, and clinical records (age, sex, involved site of lesions, surgery technique) were accurately noted: in all patients we performed the 'pocket technique'. RESULTS: The pocket technique has encouraged optimal attachment of the implanted free tissue, in absence of necrotic phenomena or tissue extrusion. CONCLUSIONS: Reconstructive surgery of the inferior eyelid avails itself of consolidated techniques. In case of extreme tissue reduction, the variation we wish to suggest is simple to understand and easy to perform, significantly reducing inflammatory reaction and/or post-surgical rejection, allowing excellent aesthetic results.

Mucosal damage: a major risk factor for severe complications after cytotoxic therapy.

The oral and gastrointestinal mucosa is frequently damaged during chemotherapy and radiotherapy in patients with cancer, leading to a high incidence of mucositis (ie, oral, esophageal, lower gastrointestinal tract mucositis). Patients with mucositis often experience considerable pain and discomfort. Furthermore, neutropenic patients with mucositis have an increased risk of potentially life-threatening infections as well as prolonged hospital stays. Mucositis may also require that subsequent chemotherapy or radiotherapy doses be reduced, thereby potentially compromising the efficacy of cancer therapy. Standard care for oral mucositis is based on effective oral hygiene, appropriate analgesia, infection management, and parenteral nutrition when needed; few other approaches have been shown to be effective. The evaluation of new options to treat and prevent mucositis rather than control the symptoms is therefore an urgent priority. A comprehensive understanding of the complex pathobiology of mucositis will help to identify potential targets for new drugs. Promising investigational approaches have recently emerged. These include fibroblast growth factor-20, which is effective in animal models of chemotherapy/radiation-induced mucosal toxicity, and is being investigated in clinical studies. The candidate that is most advanced in terms of drug development is recombinant human keratinocyte growth factor (rHuKGF; palifermin), which in phase III clinical trials was shown to reduce the severity and duration of oral mucositis and improve clinical sequelae.

Prevention and therapy of neutropenia in elderly patients.

Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin's lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors.

A high cytosol value of urokinase-type plasminogen activator (uPA) may be predictive of early relapse in primary breast cancer.

BACKGROUND: There is now much data that suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is a multistep process resulting from an ordered set of events and regulated by positive and negative modulators of microvessels growth and by the expression of various proteolytic enzymes. MATERIALS AND METHODS: We prospectively evaluated VEGF and microvessels density on tumor specimen and cytosolic levels of uPA and PAI-1. RESULTS: We enrolled 81 primary breast cancer patients. The median follow-up was 38 months. Using the median value as cutoff for the statistical analysis, we found significant correlation between cytosolic levels of uPA and PAI-1 (r = 0.61; p < .0001), between VEGF and steroid hormone receptor status (p = .01), between PAI-1 and tumor grading (p = .009), and between uPA and tumor size greater than 1 cm (p = .04). With respect to the prognosis, we observed a significant correlation between low uPA levels and RFS and an unforeseen, direct correlation between high VEGF values and better RFS. CONCLUSIONS: Our preliminary results indicate that the cytosolic level of uPA at diagnosis may be predictive of early relapse in primary breast cancer.

Stenosis of the lachrymal system in Rubinstein-Taybi syndrome.

In this article the authors describe a case of atypical stenosis of the lachrymal excretory system in Rubinstein-Taybi syndrome (RTS) characterised by morphologic anomalies of the lachrymal bag and by alterations of the osseous structure of the nose. A 9-year-old girl, with typical findings of RTS, was affected by recurrent acute dacryocystitis and tearing. Ocular examination revealed bilateral reflux with mucous and purulent material flowing back after digital pressing: low and bilateral nose-lachrymal duct obstruction was the main cause of the reflux as confirmed by orifice probing, lachrymal drainage system irrigation and spiral CT examination using hydrosoluble contrast medium. The multiplanar reconstruction obtained from CT scanning shows that the right lachrymal sac has an abnormal shape ('grape-bunch' image) and that the left one has various bulgings, or swellings, in its shape. The 'grape-bunch' lachrymal bags are the most unusual features of our patient's lachrymal system and it is important to consider the difficulties that could occur during surgery because of the abnormal bag shape and because of the increased bone thickness in RTS patients. The 'grape-bunch' lachrymal sac is a truly unusual anatomical feature and, most probably, it could be distinctive of this syndrome.

High-dose chemotherapy for solid tumors: results of the EBMT.

The European Group for Blood and Marrow Transplantation (EBMT), formerly known as European Group for Bone Marrow Transplantation, was established in 1974 in the Netherlands to share experiences, to promote research and clinical studies and to set up registries in the field of hematopoietic tissue transplantation. At the present time more 400 European and non-European centers are members of the EBMT group. In 1984 a new Working Party was created (Solid Tumors) with the aim to investigate the role of high-dose chemotherapy and stem cell support in the fields of adult and pediatric solid tumors. By January 2000 more than 14000 patients were registered, and at the present time this Registry is the world largest database on this subject. Several phase III randomized clinical trials have recently started on behalf of the Group in different diseases (breast carcinoma, small cell lung cancer, ovarian carcinoma, germ cell tumors and Ewing's family sarcoma). Hundreds of randomized patients will finally produce clearer information on this still experimental therapeutic modality. This paper will describe the EBMT Solid Tumors Working Party Registry updated results as well as the main ongoing studies.