Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is ...exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.
Highlights
CHK-1 and CHK2 have an important role in DNA damage response.
Inhibition of CHK1 may be an attractive therapeutic strategy to improve outcomes for patients with solid tumors
Prexasertib is a CHK-1/2 inhibitor.
Prexasertib demonstrated efficacy in early clinical trials when combined with other drugs.
There is a potential role in combining prexasertib with chemotherapy and immunotherapy.
The safety of combination therapy needs to be better investigated.
In February 2020, Italy became one of the first countries to be plagued by the SARS-CoV-2 pandemic, COVID-19. In March 2020, the Italian government decreed a lockdown for the whole country, which ...overturned communication systems, hospital organization, and access to patients and their relatives and carers. This issue had a particular regard for cancer patients. Our Thoracic Oncology Division therefore reorganized patient access in order to reduce the risk of contagion and, at the same time, encourage the continuation of treatment. Our staff contacted all patients to inform them of any changes in treatment planning, check that they were taking safety measures, and ascertain their feelings and whether they had any COVID-19 symptoms. To better understand patients’ fears and expectations of during the pandemic period, we created a nine-question interview, administered from April to May 2020 to 156 patients with lung cancer. Patients were classified by age, sex, comorbidity, disease stage, prior treatment, and treatment type. The survey showed that during the pandemic period some patients experienced fear of COVID-19, in particular: women (55% vs. 33%), patients with comorbidities (24% vs. 9%), and patients who had already received prior insult (radiotherapy or surgery) on the lung (30% vs. 11%). In addition, the patients who received oral treatment at home or for whom intravenous treatment was delayed, experienced a sense of relief (90% and 72% respectively). However, only 21% of the patients were more afraid of COVID-19 than of their cancer, in particular patients with long-term (> 12 months) vs. short-term cancer diagnosis (28% vs. 12.5%, respectively). Furthermore, the quarantine period or even just the lockdown period alone, worsened the quality of life of some patients (40%), especially those in oral treatment (47%). Our data demonstrate how lung cancer patients are more afraid of their disease than of a world pandemic. Also this interview indirectly highlights the clinician’s major guiding principle in correctly and appropriately managing not just the patient’s expectations of their illness and its treatment, but also and especially of the patient’s fears.
Thyroidectomy followed by radioactive iodine therapy (RAI) is the treatment of choice for differentiated thyroid carcinoma (DTC). Serum thyroglobulin (Tg) measurement has proved to be useful for ...predicting persistent and/or recurrent disease during follow-up of DTC patients. In our study, we evaluated the risk of disease recurrence in patients with papillary thyroid carcinoma (PTC), who were treated with thyroidectomy and RAI, by measuring serum Tg at different time-points: at least 40 days after surgery, in euthyroidism with TSH < 1.5 and usually 30 days before RAI (Tg
), on the day of RAI (Tg
), and seven days after RAI (Tg
).
One hundred and twenty-nine patients with PTC were enrolled in this retrospective study. All patients were treated with
I for thyroid remnant ablation. Disease relapse (nodal disease or distant disease) during at least 36 months follow-up was evaluated by serum measurements of Tg, TSH, AbTg at different time points and by imaging techniques (neck ultrasonography,
I-whole body scan (WBS) after Thyrogen
stimulation). Typically, patients were assessed at 3, 6, 12, 18, 24, and 36 months after RAI. We classified patients in five groups: (i) those who developed nodal disease (ND), (ii) those who developed distant disease (DD), (iii) those with biochemical indeterminate response and minimal residual thyroid tissue (R), (iv) those with no evidence of structural or biochemical disease + intermediate ATA risk (NED-I), and (v) those with no evidence of structural or biochemical disease + low ATA risk (NED-L). ROC curves for Tg were generated to find potential discriminating cutoffs of Tg values in all patients' groups.
A total of 15 out of 129 patients (11.63%) developed nodal disease and 5 (3.88%) distant metastases, during the follow-up. We found that Tg
(with suppressed TSH) has the same sensitivity and specificity than Tg
(with stimulated TSH), and it is slightly better than Tg
, which can be influenced by the size of the residual thyroid tissue.
Serum Tg
value, measured in euthyroidism 30 days before RAI, is a reliable prognostic factor to predict future nodal or distant disease, thus allowing to plan the most appropriate therapy and follow-up.
A novel coronavirus causing severe acute respiratory syndrome (SARS), named SARS-CoV-2, was identified at the end of 2019. The spread of coronavirus disease 2019 (COVID-19) has progressively expanded ...from China, involving several countries throughout the world, leading to the classification of the disease as a pandemic by the World Health Organization (WHO). According to published reports, COVID-19 severity and mortality are higher in elderly patients and those with active comorbidities. In particular, lung cancer patients were reported to be at high risk of pulmonary complications related to SARS-CoV2 infection. Therefore, the management of cancer care during the COVID-19 pandemic is a crucial issue, to which national and international oncology organizations have replied with recommendations concerning patients receiving anticancer treatments, delaying follow-up visits and limiting caregiver admission to the hospitals. In this historical moment, medical oncologists are required to consider the possibility to delay active treatment administration based on a case-by-case risk/benefit evaluation. Potential risks associated with COVID-19 infection should be considered, considering tumor histology and natural course, disease setting, clinical conditions, and disease burden, together with the expected benefit, toxicities (e.g., myelosuppression or interstitial lung disease), and response obtained from the planned or ongoing treatment. In this study, we report the results of proactive measures including social media, telemedicine, and telephone triage for screening patients with lung cancer during the COVID-19 outbreak in the European Institute of Oncology (Milan, Italy). Proactive management and containment measures, applied in a structured and daily way, has significantly aided the identification of advance patients with suspected symptoms related to COVID-19, limiting their admission to our cancer center; we have thus been more able to protect other patients from possible contamination and at the same time guarantee to the suspected patients the immediate treatment and evaluation in referral hospitals for COVID-19.
Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about ...one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored.
We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model.
Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9-4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0-13, with three-risk group stratification: 0-2 (good prognosis), 3-6 (intermediate prognosis), and 7-13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70-0.81).
We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.
Metastases to the pituitary gland are rare events, and usually indicate widespread malignant disease. The lung and the breast are the most common sites of primary tumors that metastasize to the ...pituitary gland.Metastases are more frequent in older patients and the most common symptoms at presentation are diabetes insipidus and visual alterations.
72-year-old white woman was treated for a breast carcinoma with right superoexternal quadrantectomy, radiotherapy, and hormone therapy. Twelve years later, the patient presented with bone pain, bilateral progressive visual decline, and onset of hypopituitarism. A diagnosis of secondary bone involvement and pituitary metastasis was made.
This was an unusual disease course, and stresses the importance of intensive follow-up in patients with breast cancer even many years after the initial diagnosis This case emphasizes that diagnosis can be difficult and controversial when relapse occurs at uncommon sites.
In this coronavirus 2019 (COVID-19) era, when pneumonitis occurs in patients with lung cancer receiving immune checkpoint inhibitors (ICIs), a major challenge is to make a rapid and correct ...differential diagnosis among drug-induced pulmonary toxicity, tumour progression, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced pneumonitis. While waiting for polymerase chain reaction (PCR) testing results, an accurate evaluation of the symptoms and serologic features can help us make a first diagnostic hypothesis and quickly start correct treatment. Physicians need a collaborative effort to develop and share a common database reporting clinical (anosmia, dysgeusia), serologic, and radiologic data in ICI-treated patients with lung cancer developing interstitial disease to create an evidence-based clinical diagnostic algorithm. This tool will continue to be helpful when we emerge from the pandemic crisis into a world in which COVID-19 may not have been eradicated to better select the target population requiring the most resource-consuming PCR tests.
Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of ...gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer.
•Resistance to ICIs is mediated by tumor intrinsic and tumor extrinsic mechanisms.•Targeting co-inhibitory or co-stimulatory signals raises antitumour immune response.•Tumour microenvironment ...conditions the immune infiltrate composition and activity.•Defining an immune profile of tumour, TME and host may help in selecting I–O therapy.
The adoption of Immune checkpoint inhibitors (ICIs) allowed the achievement of impressive long-term survival results in non-small cell lung cancer (NSCLC), but most patients develop resistance to ICI treatment over time. Resistance to ICIs is mediated by several complex mechanisms affecting, but not limited to, tumour cell-intrinsic alterations and the tumour microenvironment. The possibility of modulating the immune response by interfering with specific alternative immune receptors, pathways and mediators might provide additional strategies to delay or prevent the development of resistance. Therefore, a greater in-depth investigation and understanding of these mechanisms aims to identify novel classes of immune targets and subsequently to evaluate potential new strategies for overcoming resistance, which will be assessed in this review.
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