Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Diagnostic accuracy of transvaginal sonography for detecting parametrial involvement in women with deep endometriosis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the accuracy of transvaginal sonography (TVS) for detecting parametrial deep endometriosis, using laparoscopy as the reference standard. METHODS: A search was performed in PubMed/MEDLINE and Web of Science for studies evaluating TVS for detecting parametrial involvement in women with suspected deep endometriosis, as compared with laparoscopy, from January 2000 to December 2020. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the quality of the studies. Pooled sensitivity, specificity and positive and negative likelihood ratios for TVS in the detection of parametrial deep endometriosis were calculated, and the post-test probability of parametrial deep endometriosis following a positive or negative test was determined. RESULTS: The search identified 134 citations. Four studies, comprising 560 patients, were included in the analysis. The mean prevalence of parametrial deep endometriosis at surgery was 18%. Overall, the pooled estimated sensitivity, specificity and positive and negative likelihood ratios of TVS in the detection of parametrial deep endometriosis were 31% (95% CI, 10-64%), 98% (95% CI, 95-99%), 18.5 (95% CI, 8.8-38.9) and 0.70 (95% CI, 0.46-1.06), respectively. The diagnostic odds ratio was 26 (95% CI, 10-68). Heterogeneity was high. Visualization of a lesion suspected to be parametrial deep endometriosis on TVS increased significantly the post-test probability of parametrial deep endometriosis. CONCLUSION: TVS has high specificity but low sensitivity for the detection of parametrial deep endometriosis. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The spine instability neoplastic score (SINS) in the assessment of response to radiotherapy for bone metastases

Background. Vertebral metastases are often causing pain and spine instability. Radiotherapy is of significant benefit for painful spine metastases but the response can be very variable. The spine instability neoplastic score (SINS) is a recent classification system for diagnosis of spinal instability caused by vertebral metastases. We analysed the degree of pain relief, the need of drug therapy and the imaging features and the SINS before and after radiotherapy. In particular, we investigated the possible correlation of spine instability defined by pre-treatment SINS with pretreatment pain and with response to radiotherapy. Material/methods. This study included 121 patients with spine metastases treated with palliative 3D conformal radiotherapy. Pain “at rest” and “breakthrough pain”, need for drug therapy in terms of "anti-inflammatory", "weak opioid", "strong opioid", imaging studies and SINS were assessed before and after radiotherapy. Statistical analysis was performed by the correlation coefficient of Spearman and Kruskal-Wallis test. Results. Pain relief after radiotherapy was observed in 50.4 and 57.8% of patients in terms of pain at rest and breakthrough pain, respectively. The correlation between pain before radiotherapy and SINS was not statistically significant for both pain at rest (p = 0.4) and breakthrough pain (p = 0.49). The correlation between pain response after radiotherapy and SINS was statistically significant for both pain at rest (p = 0.007) and breakthrough pain (p = 0.047). Discussion/conclusion. The degree of instability, classified according to SINS, resulted to be predictive factor for pain response after radiotherapy. SINS might become a valid tool to identify those patients who can benefit the most from radiotherapy (AU)

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The spine instability neoplastic score (SINS) in the assessment of response to radiotherapy for bone metastases.

BACKGROUND: Vertebral metastases are often causing pain and spine instability. Radiotherapy is of significant benefit for painful spine metastases but the response can be very variable. The spine instability neoplastic score (SINS) is a recent classification system for diagnosis of spinal instability caused by vertebral metastases. We analysed the degree of pain relief, the need of drug therapy and the imaging features and the SINS before and after radiotherapy. In particular, we investigated the possible correlation of spine instability defined by pre-treatment SINS with pretreatment pain and with response to radiotherapy. MATERIAL/METHODS: This study included 121 patients with spine metastases treated with palliative 3D conformal radiotherapy. Pain "at rest" and "breakthrough pain", need for drug therapy in terms of "anti-inflammatory", "weak opioid", "strong opioid", imaging studies and SINS were assessed before and after radiotherapy. Statistical analysis was performed by the correlation coefficient of Spearman and Kruskal-Wallis test. RESULTS: Pain relief after radiotherapy was observed in 50.4 and 57.8% of patients in terms of pain at rest and breakthrough pain, respectively. The correlation between pain before radiotherapy and SINS was not statistically significant for both pain at rest (p = 0.4) and breakthrough pain (p = 0.49). The correlation between pain response after radiotherapy and SINS was statistically significant for both pain at rest (p = 0.007) and breakthrough pain (p = 0.047). DISCUSSION/CONCLUSION: The degree of instability, classified according to SINS, resulted to be predictive factor for pain response after radiotherapy. SINS might become a valid tool to identify those patients who can benefit the most from radiotherapy.

Concurrent chemo-radiotherapy in elderly patients: tolerance and compliance in a series of 137 patients

Introduction: Aggressive cancer treatment is a challenge in elderly patients. The present study aims to assess tolerance in terms of acute toxicity and compliance of concurrent chemo-radiotherapy (cCRT) in a series of patients aged C70 years. Materials and methods Clinical: records of patients aged C70 years who underwent cCRT between January 2005 and December 2013 were reviewed. Concurrent CRT had curative intent in 134 patients (97.8 %) and palliative intent in 3 patients (2.2 %). Chemotherapy (CT) drugs and schedule were selected according to tumor histology. Radiotherapy median dose was 45.0 Gy (range 11-70 Gy) for curative purposes and 54 Gy (range 40-56 Gy) for palliative purposes. Incidence of acute toxicity and compliance to cCRT were analyzed and correlated with age, Karnofsky Performance Status (KPS), and Charlson Comorbidity Index (CCI). Results: Overall, 137 patients, 82 males (60 %) and 55 females (40 %), median age 74 years (range 70–90 years) were analyzed. Concurrent CRT schedule was completed by 132 patients (96.4 %). Thirty-one of these patients (23.5 %) temporarily interrupted treatment. Hematological toxicity with grade C1 was observed in 25 patients (18.2 %), gastrointestinal toxicity in 55 (40.1 %), and genitourinary in 13 (9.5 %). Mucositis with grade C1 was recorded in 19 patients (13.9 %). No statistical significant correlation between KPS, CCI, and toxicity was found. A correlation trend between mucositis and patient age (p = 0.05) was observed. Conclusion: Concurrent CRT for elderly was feasible and quite well tolerated. Great attention in prescribing CT dose should be paid to limit acute toxicity (AU)

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Concurrent chemo-radiotherapy in elderly patients: tolerance and compliance in a series of 137 patients.

INTRODUCTION: Aggressive cancer treatment is a challenge in elderly patients. The present study aims to assess tolerance in terms of acute toxicity and compliance of concurrent chemo-radiotherapy (cCRT) in a series of patients aged ≥70 years. MATERIALS AND METHODS: Clinical records of patients aged ≥70 years who underwent cCRT between January 2005 and December 2013 were reviewed. Concurrent CRT had curative intent in 134 patients (97.8 %) and palliative intent in 3 patients (2.2 %). Chemotherapy (CT) drugs and schedule were selected according to tumor histology. Radiotherapy median dose was 45.0 Gy (range 11-70 Gy) for curative purposes and 54 Gy (range 40-56 Gy) for palliative purposes. Incidence of acute toxicity and compliance to cCRT were analyzed and correlated with age, Karnofsky Performance Status (KPS), and Charlson Comorbidity Index (CCI). RESULTS: Overall, 137 patients, 82 males (60 %) and 55 females (40 %), median age 74 years (range 70-90 years) were analyzed. Concurrent CRT schedule was completed by 132 patients (96.4 %). Thirty-one of these patients (23.5 %) temporarily interrupted treatment. Hematological toxicity with grade ≥1 was observed in 25 patients (18.2 %), gastrointestinal toxicity in 55 (40.1 %), and genitourinary in 13 (9.5 %). Mucositis with grade ≥1 was recorded in 19 patients (13.9 %). No statistical significant correlation between KPS, CCI, and toxicity was found. A correlation trend between mucositis and patient age (p = 0.05) was observed. CONCLUSION: Concurrent CRT for elderly was feasible and quite well tolerated. Great attention in prescribing CT dose should be paid to limit acute toxicity.

Subjective and objective measures of late genitourinary morbidity following hypofractionated radiotherapy in men with prostate cancer.

To value the late genitourinary (GU) morbidity in men treated with a hypofractionated radiotherapy regimen for prostate cancer. Patients with intermediate risk factors according to D'Amico's criteria were selected. The hypofractionated schedule consisted of 15 fractions of 3.63 Gy delivered three times per week for a total dose of 54.3 Gy. Significant changes in storage-symptoms were not found. A significant transient worsening in the score of late effects of normal tissue late effects normal tissue task force (LENT)-subjective, objective, management, analytic (SOMA) urinary-function domain was observed at 12 months with subsequent improvement at 28 months. The assessment of voiding-symptoms and maximum urinary flow rate (Qmax) showed that no significant difference was measurable at 12 and 28 months. For PVR, a transient increase at 12 months with a subsequent decrease at 28 months was measured. No significant increase in alpha-blockers usage and in the percentage of men with pathological nonintubated uroflowmetry (NIF) was observed at 12 and 28 months. Finally, patients did not perceive any clinical worsening in their quality of life (QoL) as attested by the International Prostate Symptom Score (IPSS)-QoL. Our study seems to suggest that our hypofractionated radiotherapy schedule for the treatment of prostate cancer is safe in terms of late urinary morbidity. Further study will be required to confirm our results.

p53, cyclin-D1, PCNA, AgNOR expression in squamous cell cancer of the lip: a multicenter study.

BACKGROUND: The development of squamous cell carcinoma of the lower lip is an interesting model of photocarcinogenesis because of the structural and topographic characteristics of the lips. The purpose of this study was to evaluate the expression of immunohistochemical markers on the lips of patients with lower lip squamous cell carcinoma (LLSCC), compared with a control population. METHODS: Of the 98 subjects involved in the study, 58 were suffering from squamous cell carcinoma of the lower lip. The remaining 40 acted as a control. The case studies were taken from six university and hospital dermatology and plastic surgery departments. Questionnaires were administered to assess the risk factors for LLSCC. The cases involving squamous cell carcinoma underwent surgical excision and punch biopsy specimens were obtained from 20 control patients. Tissues were prepared in 5-microm-thick sections to carry out the following immunohistochemical study: PCNA, p53, AgNOR, cyclin-D1, bcl-2. RESULTS: The lower lip was the predominant location of squamous cell carcinoma, with the following factors playing important roles: chronic sun exposure, history of smoking, alcohol use and familial risk of cutaneous tumors. The male/female ratio in our survey was 5:1. The p53 protein was positive in approximately 50% of SCC cases and in 20% of controls. This protein is mostly associated with chronically photoexposed skin areas. AgNOR positivity increased with the loss of cellular differentiation; a progressive increase in size and a poorly defined shape were evident in poorly differentiated carcinomas. CONCLUSIONS: The results of this multicenter study showed that there is a noticeable difference in the expression of PCNA, p53, cyclin-D1, and AgNOR in tissues from patients with LLSCC and controls.

Thrombin mutants with altered enzymatic activity have an impaired mitogenic effect on mouse fibroblasts and are inefficient modulators of stellation of rat cortical astrocytes.

We produced recombinant human thrombin mutants to investigate the correlation between the thrombin enzyme and mitogenic activity. Single amino acid substitutions were introduced in the catalytic triad (H43N, D99N, S205A, S205T), in the oxy-anion binding site (G203A) and in the anion binding exosite-1 region (R73E). Proteins were produced as prethrombin-2 mutants secreted in the culture medium of DXB11-derived cell lines. All mutants were activated by ecarin to the corresponding thrombin mutants; the enzymatic activity was assayed on a chromogenic substrate and on the procoagulant substrate fibrinogen. Mutations S205A and G203A completely abolished the enzyme activity. Mutations H43N, D99N and S205T dramatically impaired the enzyme activity toward both substrates. The R73E mutation dissociated the amidolytic activity and the clotting activity of the protein. The ability of thrombin mutants to induce proliferation was investigated in NIH3T3 mouse fibroblasts and rat cortical astrocytes. The ability of the thrombin mutants to revert astrocyte stellation was also studied. The mitogenic activity and the effect on the astrocyte stellation of the thrombin mutants correlated with their enzymatic activity. Furthermore the receptor occupancy by the inactive S205A mutant prevented the thrombin effects providing strong evidence that a proteolytically activated receptor is involved in cellular responses to thrombin.