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Simple Summary: Exploring the impact of heat shock protein (HSP) inhibition in cancer may give new insights into the cellular processes that these molecules sustain to promote cancer survival and may accelerate the discovery of more HSP inhibitors to be introduced in clinical trials. In this study, we explored the expression and role of high-molecular-weight HSP110 in the survival of Primary Effusion Lymphoma (PEL) cells. We found that the proper expression of this HSP is required to prevent lysosomal permeabilization, DNA damage, c-Myc downregulation and STAT3 de-phosphorylation. Indeed, HSP silencing strongly reduces PEL cell survival through the dysregulation of these processes that have been found to be interconnected. Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110. [ABSTRACT FROM AUTHOR]

Simple Summary: This Editorial summarizes the findings of the articles submitted in 2020 and 2021 to the Special Issue "The Impact of COVID-19 in Cancer". [ABSTRACT FROM AUTHOR]

Simple Summary: One of the major obstacles to anti-cancer therapy is the development of drug resistance that allows the cancer cell to adapt to the treatments and keep surviving. In this mini-review we attempt to give an overview of the adaptive responses and the cross-talk between them that could be targeted to counteract cancer resistance to stress and improve the outcome of cancer treatment. Different from normal cells, cancer cells must hyperactivate a variety of integrated responses in order to survive their basal stress or its exacerbation caused by exposure to anti-cancer agents. As cancer cells become particularly dependent on these adaptive responses, namely UPR, DDR autophagy, anti-oxidant and heat shock responses, this turns out to be an Achille's heel, which allows them to be selectively killed while sparing normal unstressed cells. Better knowledge of the cross-talk between these adaptive processes and their impact on the immune system is needed to design more effective anti-cancer therapies, as reviewed in this paper. [ABSTRACT FROM AUTHOR]

Simple Summary: The COVID-19 pandemic has had a major impact on the entire healthcare system, resulting in severe restrictions of nonemergency clinical services, as well as in the clinical practice of uro-oncology. We performed a retrospective analysis to evaluate outcomes of the COVID-19 pandemic resulting from delayed diagnosis, staging, and treatment of bladder cancer. We showed that the COVID-19 pandemic led to a deferred oncological diagnosis and treatment of bladder cancer. More attention is required to avoid adverse outcomes, with increased rates of advanced and aggressive tumors in patients with primary bladder cancer. Moreover, timely treatment is compulsory in those patients. Coronavirus-19 (COVID-19)-induced effects on deferred diagnosis and treatment of bladder cancer (BC) patients are currently not clarified. The aim of this study was to evaluate outcomes of the COVID-19 pandemic by considering its effects on tumor stage and grade, and to create feasible clinical triage decisions. A retrospective single-center analysis of all patients who underwent diagnostic and surgical procedures due to BC, during January 2019 and December 2020, was performed. Due to COVID-19 lockdowns, significantly fewer (diagnostic and therapeutic) endoscopic procedures were performed in the first 6 months of 2020 compared to 2019 (p = 0.002). In patients with a primary diagnosis of BC, a significant increase of high-grade tumors (p < 0.001), as well as advanced tumor stages (p = 0.014), were noticed during 2020 in comparison to 2019. On the contrary, patients with recurrent BC undergoing risk-adapted surveillance, depending on previous tumor histology, showed no adverse outcomes regarding tumor stage and grade when comparing the pre COVID-19 era with 2020. Thus, more awareness in clinical urologic practice is mandatory to avoid adverse consequences, with increased rates of advanced and aggressive tumors in patients with primary BC. In recurrent BC, an individual risk stratification in order to avoid worse outcomes during the COVID-19 pandemic seems to be justified. [ABSTRACT FROM AUTHOR]

Simple Summary: Since the beginning of the COVID-19 outbreak, Cancer Centers adopted specific procedures to protect patients as well as to monitor the possible spread of SARS-CoV-2 among healthcare personnel. In April 2020, we implemented a prospective longitudinal study aimed at monitoring the serological response to SARS-Cov-2 in the healthcare personnel of a Comprehensive Cancer Center identified by the Lombardy region (the Italian region most affected by the COVID-19 pandemic) as one of the three oncologic hubs where the Regional Health Authorities referred all the cancer patients in the region. We identified a fraction of healthcare personnel with long-term anti-SARS-CoV-2 antibody response, though negative for viral RNA, who could safely approach fragile cancer patients. Since the beginning of the COVID-19 outbreak, Cancer Centers adopted specific procedures both to protect patients and to monitor the possible spread of SARS-CoV-2 among healthcare personnel (HCP). In April 2020 at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, one of the three oncologic hubs in Lombardy where the Health Regional Authorities referred all the cancer patients of the region, we implemented a prospective longitudinal study aimed at monitoring the serological response to SARS-Cov-2 in HCP. One hundred and ten HCP answered a questionnaire and were screened by nasopharyngeal swabs as well as for IgM/IgG levels; seropositive HCPs were further screened every 40–45 days using SARS-CoV-2-specific serology. We identified a fraction of HCP with long-term anti-SARS-CoV-2 antibody responses, though negative for viral RNA, and thus probably able to safely approach fragile cancer patients. Monitoring asymptomatic HCP might provide useful information to organize the healthcare service in a Cancer Center, while waiting for the effectiveness of the active immunization by SARS-CoV-2 vaccines, which will provide protection from infection. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer patients are vulnerable to the SARS-CoV-2 infection. Their treatment has also been negatively affected by the COVID-19 pandemic. No solid data exist regarding the appropriate management of cancer patients during the pandemic. Our center, a referral oncology/hematology unit, has implemented specific preventive and screening measures. This study aimed to record the epidemiological characteristics of our patients with cancer that were detected positive for SARS-CoV-2 by molecular testing. Since June 2020, 11,618 patient visits were performed in our unit, and only 26 patients were detected positive for SARS-CoV-2, corresponding to a 0.22% positivity ratio. Among asymptomatic patients committed to begin a new line of systemic therapy, only four were found positive. No transmission within the unit was found after detailed tracing of positive patients. These data will help to update guidelines and recommendations in order to improve cancer care during the current pandemic. Cancer patients infected with SARS-CoV-2 have worse outcomes, including higher morbidity and mortality than the general population. Protecting this vulnerable group of patients from COVID-19 is of the utmost importance for the continuous operation of an oncology unit. Preventive strategies have been proposed by various societies, and centers around the world have implemented these or modified measures; however, the efficacy of these measures has not been evaluated. In our center, a referral oncology/hematology unit in Athens, Greece, we implemented strict protective measures from the outset of the pandemic in the country and we have prospectively recorded the epidemiological characteristics of COVID-19. Among 11,618 patient visits performed in our unit, 26 patients (case-to-visit ratio of 0.22%) were found positive for SARS-CoV-2, including 4 (1%) among 392 patients that were screened before starting primary systemic treatment. Among patients tested positive for SARS-CoV-2, 22 were symptomatic at the time of diagnosis; subsequently, 12 required hospitalization and 5 died due to COVID-19. Detailed contact tracing indicated that there was no in-unit transmission of the infection. Thus, strict implementation of multilevel protective strategies along with a modestly intense screening program allowed us to continue cancer care in our unit through the pandemic. [ABSTRACT FROM AUTHOR]

Simple Summary: The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a major global health crisis. Owing to the rising number of cases and limited global resources, being able to predict patients with a severe disease course is crucial for the initial allocation of the limited medical resources. This study aimed to identify whether lymphopenia is a reliable prognostic marker for COVID-19 using Korean nationwide cohort. Lymphopenia and its severity levels may serve as reliable predictive factors for COVID-19 clinical outcomes including mortality, needs for intensive care, and oxygen requirements. Current study suggests that lymphopenia at the initial presentation of COVID-19 is associated with poor prognosis. We aimed to identify whether lymphopenia is a reliable prognostic marker for COVID-19. Using data derived from a Korean nationwide longitudinal cohort of 5628 COVID-19 patients, we identified propensity-matched cohorts (n = 770) with group I of severe lymphopenia (absolute lymphocyte counts [ALC]: <500/mm3, n = 110), group II of mild-to-moderate lymphopenia (ALC: ≥500–<1000/mm3, n = 330), and group III, no lymphopenia (ALC: ≥1000/mm3, n = 330). A significantly higher mortality rate was associated with lymphopenia severity: 40% in group I, 22.7% in group II, and 13.0% in group III (p < 0.001). At 28 days, the estimated inferior overall survival associated with intensified lymphopenia: 62.7% in group I, 79.9% in group II, and 89.0% in group III (p < 0.001). Lymphopenia contributed significantly toward a greater need for interventions in all groups but at varying degrees: requirements of invasive ventilation, intensive oxygen supply, or adequate oxygen supply, respectively (p < 0.001). The lymphopenia intensity was independently associated with higher COVID-19 mortality in multivariable analysis; adjusted odds ratios of 5.63 (95% CI, 3.0–10.72), and 2.47 (95% CI, 1.5–4.13) for group I and group II, respectively. Lymphopenia and its severity levels may serve as reliable predictive factors for COVID-19 clinical outcomes; thus, lymphopenia may provide the prognostic granularity required for clinical use in the management of patients with COVID-19. [ABSTRACT FROM AUTHOR]

Simple Summary: Coronavirus disease 2019 (COVID-19) represents a major challenge for global healthcare systems. Since these healthcare systems have been frequently overwhelmed by the large number of COVID-19 patients, it is conceivable to hypothesize that other diseases such as cancer have been neglected during the pandemic. This study showed that the number of new cancer diagnoses in Germany significantly decreased between March and May 2020 compared with 2019. Given that a sudden decline in the actual incidence of cancer is unlikely, these data suggest that a large proportion of cancer cases have been undiagnosed or diagnosed with some delay in this country, and this may be associated with poor short-term and long-term outcomes. Thus, the present study provides important evidence for the vivid discussion on how healthcare systems should optimally deal with the ongoing COVID-19 pandemic. The aim of this retrospective study was to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on cancer diagnosis in general and specialized practices in Germany. This study included a total of 102,009 patients aged ≥18 years newly diagnosed with cancer in 1660 practices in Germany from January to May 2019 and from January to May 2020. Practices included general, gynecology, ear, nose, and throat (ENT), dermatology, and urology practices. New cancer diagnoses included all types of cancer and corresponded to cancers not previously documented in the database for a given patient. The number of new cancer diagnoses per general practice decreased significantly between March and May 2020 compared with the same period in 2019 (March: −12.0%, April: −27.6%, and May: −23.4%). A similar trend was observed in specialized practices, and this trend was more pronounced in April 2020 (dermatology: −44.4%, gynecology: −32.0%, and ENT: −28.2%). In addition, there was a significant decrease in almost all sex and age groups in April and May 2020 compared with the same period in 2019. Finally, the decrease in the number of new cancer diagnoses was particularly pronounced among cancers of the skin and the respiratory and intrathoracic organs. Together, these data show that the COVID-19 pandemic had a significant negative impact on cancer diagnosis in Germany, highlighting the need for public health measures improving the management of cancer in this country during this ongoing pandemic. [ABSTRACT FROM AUTHOR]

The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies. [ABSTRACT FROM AUTHOR]