Glycogen Synthase Kinase-3β Inhibition Attenuates the Development of Bleomycin-Induced Lung Injury:

Glycogen synthase kinase-3 (GSK-3) is an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study is to investigate the effects of TDZD-8, a potent and selective GSK-3β inhibitor, on the development of lung injury caused by administration of bleomycin (BLM). Mice subjected to intra-tracheal administration of BLM developed significant lung injury characterized by marked neutrophil infiltration and tissue edema. An increase in immunoreactivity to nitrotyrosine, iNOS, TNF-α and IL-1β was also observed in the lungs of BLM-treated mice. In contrast, administration of BLM-treated mice with TDZD-8 (1 mg/kg daily) significantly reduced (I) the degree of lung injury, (II) the increase in staining (immunohistochemistry) for myeloperoxidase (MPO), nitrotyrosine, iNOS, TNF-α and IL-1β and (III) the degree of apoptosis, as evaluated by Bax and Bcl-2 immunoreactivity and TUNEL staining. Taken together, these results clearly demonstrate treatment with the GSK-3β inhibitor TDZD-8 reduces the development of lung injury and inflammation induced by BLM in mice

How SARS-CoV-2 Infection Impacts the Management of Patients with Vulvar Cancer: Experience in a Third-Level Hospital of Southern Italy

: Background: Since February 2020, the spread of Coronavirus Disease 2019 (COVID-19) in Italy has induced the government to call for lockdown of any activity apart from primary needs, and changing the lives of each of us. All that has dramatically impacted the management of patients affected by cancer. Patients with vulvar cancer (VC) represent a particularly frail population because they are elderly and affected by multiple comorbidities. The aim of this study is to evaluate the clinical impact of the SARS-CoV-2 infection on VC patients in terms of delay or impossibility of carrying out the scheduled treatment. Methods: The medical records of patients affected by vulvar tumors, referred to "DAI Materno-Infantile" of AOU Federico II of Naples between February 2020 and January 2022 were retrospectively analyzed. The presence of a positive reverse transcription-polymerase chain reaction (RT-PCR) in nasopharyngeal swab defined the positivity to SARS-CoV-2. Results: Twenty-four patients with VC were analyzed and scheduled for treatment. The median age was 70.7 years (range: 59-80). Seven (29.2%) patients were diagnosed with SARS-CoV-2 infection: In three (42.8%) patients, the treatment was delayed with no apparent consequences, in four (57.2%), the treatment was delayed or changed due to cancer progression and, of these four, one died due to respiratory complications of COVID-19, and one died due to oncologic disease progression. Conclusion: COVID-19 caused, in most cases, significant delays in oncologic treatments and high mortality in our series of patients affected by VC

The evolving therapeutic landscape of trastuzumab-drug conjugates: Future perspectives beyond HER2-positive breast cancer

A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents “second generation ADCs” that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed

Systemic treatment of malignant gastrointestinal neuroectodermal tumour after childhood neuroblastoma: chemotherapy in malignant gastrointestinal neuroectodermal tumour

Malignant gastrointestinal neuroectodermal tumour is an extremely rare neoplasm that arises in the wall of the small bowel, stomach or large bowel in youngaged and middle-aged adults. Histologically, it is generally characterized by monomorphic cells with clear cytoplasma, S-100 protein expression, and EWSR1 gene translocation. To the best of our knowledge, we describe for the first time, the case of a young woman with a diagnosis of metastatic gastrointestinal neuroectodermal tumour arising from ileum, who had a childhood adrenal neuroblastoma with liver, bone and lymph nodes metastasis, treated with four cycles of chemotherapy with the schedule CADO-CVP (CADO: cyclophosphamide 300 mg/m2/day on days 1–5, vincristine 1,5 mg/m2/ day on days 1 and 5, and doxorubicin 60 mg/m2/day on day 5; CVP: cisplatin 40 mg/m2/day on days 1–5 and etoposide 100 mg/m2/day on days 1–5) followed by right adrenal, kidney, lymph nodes and liver lesion resection, conditioning chemotherapy (melphalan-carmustineteniposide), stem cells autologous transplantation and consecutively radiotherapy on the spine (T9 to L3) for a total of 30 Gy. For the second diagnosis of gastrointestinal neuroectodermal tumour with liver metastasis, she underwent ileal tumour resection and platinum-anthracycline based chemotherapy with initial shrinkage of liver metastasis. Unfortunately, despite the initial response and the following delivered therapies, she died for rapid progressive disease. Taking into account the late effects of past therapeutic modalities, a long-term surveillance of young child treated for neuroblastoma, is required to appreciate their overall risks of second malignancies

Evolving treatments and outcomes in HER2-Positive metastatic breast cancer: Data from the GIM14/BIOMETA study

Background: Treatment for HER2-positive (+) metastatic breast cancer has improved in the last decade. We analyzed treatment changes over time and their impact on patients outcomes in a real-world dataset. Methods: Data from 637 HER2+ patients with metastatic breast cancer enrolled in the multicenter Italian GIM14/BIOMETA study were retrieved. Progression-free survival (PFS) over time was evaluated according to the type of anti-HER2 therapy, disease onset (de novo vs. relapsing), metastatic site, and year of treatment (2000–2013 vs. 2014–2020). Results: Median follow-up was 64.4 months. Overall, for first-line therapies, mPFS was 16.5 vs 19.5 months for patients treated in 2000–2013 vs 2014–2020 (HR: 0.78, 95% CI:0.65–0.94, P = 0.008). mPFS improved over time in all patients except for those with brain metastasis. Interestingly mPFS was 17.4 vs13.4 months (HR, 1.49; 95% CI, 1.13–1.98, P = 0.005) in 2000–2013 and 24.4 vs 20.9 months (HR 1.04; 95% CI 0.78–1.40 p = 0.77) in 2014–2020 in pts without vs with liver metastases. For second line therapies, the overall median PFS was 9.6 months (95% CI, 8.31–10.97) and did not change over time. Conclusion: Median first-line PFS improved since 2014, mainly due to the introduction of pertuzumab. The outcome of patients with liver metastases appears to have improved in recent years. Patients with brain metastases had the worst PFS, which also did not improve over time

Weekly Docetaxel (Wd) Vs Cmf As Adjuvant Chemotherapy for Elderly Early Breast Cancer (Ebc) Patients (Pts): Final Results from the Randomised Phase 3 Elda Trial

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Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs)

Background: No previous prospective trials have been reported with capecitabine and gemcitabine (CAP-GEM) in patients with metastatic thymic epithelial tumors (TETs). We conducted a multicenter study to determine the activity and tolerability of this regimen in pretreated TETs. Patients and methods: A total of 15 patients were enrolled in the first stage of phase II study. All patients received CAP-GEM every 3 weeks. The primary end point was objective response rate (RR); secondary end points were toxicity, progression-free survival (PFS) and overall survival. Results: Complete responses (CR) and partial responses were observed in three (20%) and three (20%) patients for a 40% RR, respectively. Grade 1-2 neutropenia, anemia and thrombocytopenia were the most common side-effects, noted in seven (46.7%), five (33.3%) and five (33.3%) patients, respectively. The most common grade 3 toxicity was neutropenia in three patients (20%). Median PFS was 11 months (95% confidence interval 4-17). The 1- and 2-year survival rates were 80% and 67%, respectively. Conclusion: We have decided to publish the preliminary results because this regimen was more active than that expected. Although our results are preliminary, CAP-GEM shows activity and safety in pretreated TETs. Furthermore, multicenter trials, also in first-line setting, are necessary to confirm our results

lba14_prthe hoboe 2 multicenter randomized phase iii trial in premenopausal patients with hormone receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole zoledronic acid

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