Cancers

12 pages, 4682 KiB

Open AccessArticle

Irinotecan- vs. Oxaliplatin-Based Doublets in KRAS^G12C-Mutated Metastatic Colorectal Cancer—A Multicentre Propensity-Score-Matched Retrospective Analysis

by Vincenzo Formica, Cristina Morelli, Veronica Conca, Maria Alessandra Calegari, Jessica Lucchetti, Emanuela Dell’Aquila, Marta Schirripa, Marco Messina, Lisa Salvatore, Federica Lo Prinzi, Giovanni Dima, Giovanni Trovato, Silvia Riondino, Mario Roselli, Ferdinandos Skoulidis, Hendrik-Tobias Arkenau and Chiara Cremolini

Cancers 2023, 15(11), 3064; https://doi.org/10.3390/cancers15113064 - 5 Jun 2023

Viewed by 2540

Abstract

Background: KRAS^G12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS^G12C-inhibitor might [...] Read more.

Background: KRAS^G12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS^G12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. Methods: A multicentre retrospective analysis was conducted including KRAS^G12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/− bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment–effect interactions. KRAS^G12D-mutated patients were analysed as control. Results: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRAS^G12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRAS^G12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations. Full article

(This article belongs to the Special Issue Cetuximab and Cancer)

► Show Figures

Figure 1

23 pages, 5614 KiB

Open AccessArticle

Resistance of Leukemia Cells to 5-Azacytidine: Different Responses to the Same Induction Protocol

by Kristína Šimoničová, Lubos Janotka, Helena Kavcova, Zdena Sulova, Lucia Messingerova and Albert Breier

Cancers 2023, 15(11), 3063; https://doi.org/10.3390/cancers15113063 - 5 Jun 2023

Cited by 2 | Viewed by 2384

Abstract

Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2′-deoxycytidine (DAC), as [...] Read more.

Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2′-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2. Full article

(This article belongs to the Special Issue Advances in Cancer Epigenetics)

► Show Figures

Figure 1

25 pages, 6877 KiB

Open AccessArticle

Investigating the Role of Heparanase in Breast Cancer Development Utilising the MMTV-PyMT Murine Model of Mammary Carcinoma

by Krishnath M. Jayatilleke, Hendrika M. Duivenvoorden, Gemma F. Ryan, Belinda S. Parker and Mark D. Hulett

Cancers 2023, 15(11), 3062; https://doi.org/10.3390/cancers15113062 - 5 Jun 2023

Cited by 1 | Viewed by 2132

Abstract

Breast cancer is the second most common human malignancy and is a major global health burden. Heparanase (HPSE) has been widely implicated in enhancing the development and progression of solid tumours, including breast cancer. In this study, the well-established spontaneous mammary tumour-developing MMTV-PyMT [...] Read more.

Breast cancer is the second most common human malignancy and is a major global health burden. Heparanase (HPSE) has been widely implicated in enhancing the development and progression of solid tumours, including breast cancer. In this study, the well-established spontaneous mammary tumour-developing MMTV-PyMT murine model was utilised to examine the role of HPSE in breast cancer establishment, progression, and metastasis. The use of HPSE-deficient MMTV-PyMT (MMTV-PyMTxHPSE^−/−) mice addressed the lack of genetic ablation models to investigate the role of HPSE in mammary tumours. It was demonstrated that even though HPSE regulated mammary tumour angiogenesis, mammary tumour progression and metastasis were HPSE-independent. Furthermore, there was no evidence of compensatory action by matrix metalloproteinases (MMPs) in response to the lack of HPSE expression in the mammary tumours. These findings suggest that HPSE may not play a significant role in the mammary tumour development of MMTV-PyMT animals. Collectively, these observations may have implications in the clinical setting of breast cancer and therapy using HPSE inhibitors. Full article

(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)

► Show Figures

Figure 1

17 pages, 5649 KiB

Open AccessEditor’s ChoiceArticle

deepPERFECT: Novel Deep Learning CT Synthesis Method for Expeditious Pancreatic Cancer Radiotherapy

by Hamed Hooshangnejad, Quan Chen, Xue Feng, Rui Zhang and Kai Ding

Cancers 2023, 15(11), 3061; https://doi.org/10.3390/cancers15113061 - 5 Jun 2023

Cited by 10 | Viewed by 2238

Abstract

Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This [...] Read more.

Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This idea is based on the theory that diagnostic CT can be used for RT planning, but in practice, due to the differences in patient setup and acquisition techniques, separate planning CT is required. We developed a generative deep learning model, deepPERFECT, that is trained to capture these differences and generate deformation vector fields to transform diagnostic CT into preliminary planning CT. We performed detailed analysis both from an image quality and a dosimetric point of view, and showed that deepPERFECT enabled the preliminary RT planning to be used for preliminary and early plan dosimetric assessment and evaluation. Full article

(This article belongs to the Special Issue Radiation Therapy for Pancreatic Cancer)

► Show Figures

Figure 1

9 pages, 263 KiB

Open AccessArticle

Arterial Thrombosis in Patients with Acute Myeloid Leukemia: Incidence and Risk Factors

by Mirjana Mitrovic, Nikola Pantic, Nikica Sabljic, Zoran Bukumiric, Marijana Virijevic, Zlatko Pravdic, Mirjana Cvetkovic, Jovan Rajic, Jelena Bodrozic, Violeta Milosevic, Milena Todorovic-Balint, Ana Vidovic, Nada Suvajdzic-Vukovic and Darko Antic

Cancers 2023, 15(11), 3060; https://doi.org/10.3390/cancers15113060 - 5 Jun 2023

Cited by 3 | Viewed by 1451

Abstract

Background: Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. Aim: The [...] Read more.

Background: Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. Aim: The objectives of this study were to determine the incidence of ATE in non-promyelocytic-AML patients and to define the potential risk factors for ATE development. Methods: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. The primary outcome was the occurrence of confirmed ATE, defined as myocardial infarction, stroke or critical limb ischemia. Results: Out of 626 eligible AML patients, 18 (2.9%) patients developed ATE in the median time of 3 (range: 0.23–6) months. Half of these patients died due to ATE complications. Five parameters were predictors of ATE: BMI > 30 (p = 0.000, odds ratio [OR] 20.488, 95% CI: 6.581–63.780), prior history of TE (p = 0.041, OR 4.233, 95% CI: 1.329–13.486), presence of comorbidities (p = 0.027, OR 5.318, 95% CI: 1.212–23.342), presence of cardiovascular comorbidities (p < 0.0001, OR 8.0168, 95% CI: 2.948–21.800) and cytogenetic risk score (p = 0.002, OR 2.113, 95% CI: 1.092–5.007). Conclusions: Our study showed that patients with AML are at increased risk of ATE. The risk was increased in patients with cardiovascular comorbidities, previous thrombosis, adverse cytogenetic risk as well as BMI > 30. Full article

(This article belongs to the Special Issue Advance Research in Thrombosis and Hematologic Malignancies)

12 pages, 631 KiB

Open AccessReview

The Role of Anesthetic Drugs and Statins in Prostate Cancer Recurrence: Starting at the Actual Knowledge and Walking through a New Paradigm

by Aida Raigon Ponferrada, Juan Carlos Molina Ruiz, Salvador Romero Molina, Verónica Rodriguez Garcia and Jose Luis Guerrero Orriach

Cancers 2023, 15(11), 3059; https://doi.org/10.3390/cancers15113059 - 5 Jun 2023

Viewed by 1554

Abstract

Prostate cancer has become a major health problem in men. Its incidence is increasing as the average age of the affected population tends to be higher. Of all the possible treatments, surgery is the gold standard in its treatment. Surgery produces a deregulation [...] Read more.

Prostate cancer has become a major health problem in men. Its incidence is increasing as the average age of the affected population tends to be higher. Of all the possible treatments, surgery is the gold standard in its treatment. Surgery produces a deregulation in the immune system that can favour the development of distant metastases. Different anesthetic techniques have raised the hypothesis that different anesthetic drugs influence tumor recurrence and prognosis. Some mechanisms are beginning to be understood by which halogenated agents in cancer patients and the use of opioids may negatively affect patients. In this document, we group together all the available evidence on how the different anesthetic drugs affect tumor recurrence in prostate cancer. Full article

(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)

► Show Figures

Figure 1

13 pages, 1825 KiB

Open AccessArticle

Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy

by Katja Seipel, Mariesol Abbühl, Ulrike Bacher, Henning Nilius, Michael Daskalakis and Thomas Pabst

Cancers 2023, 15(11), 3058; https://doi.org/10.3390/cancers15113058 - 5 Jun 2023

Cited by 3 | Viewed by 2271

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63–84% and complete response observed in 43–54%. Common germline variants of the target antigen CD19 may elicit different responses [...] Read more.

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63–84% and complete response observed in 43–54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome. Full article

(This article belongs to the Special Issue Advances in the Diagnosis, Prognosis and Treatment of Diffuse Large B-cell Lymphoma)

► Show Figures

Graphical abstract

13 pages, 3868 KiB

Open AccessEditor’s ChoiceArticle

Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer

by Elizabeth B. Jeans, Daniel K. Ebner, Hirotoshi Takiyama, Kaitlin Qualls, Danielle A. Cunningham, Mark R. Waddle, Krishan R. Jethwa, William S. Harmsen, Joleen M. Hubbard, Eric J. Dozois, Kellie L. Mathis, Hiroshi Tsuji, Kenneth W. Merrell, Christopher L. Hallemeier, Anita Mahajan, Shigeru Yamada, Robert L. Foote and Michael G. Haddock

Cancers 2023, 15(11), 3057; https://doi.org/10.3390/cancers15113057 - 5 Jun 2023

Cited by 5 | Viewed by 1733

Abstract

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six [...] Read more.

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

12 pages, 1233 KiB

Open AccessArticle

Risk of Second Primary Malignancies in Melanoma Survivors: A Population-Based Study

by Javier Antoñanzas, Ana Morello-Vicente, Gloria Maria Garnacho-Saucedo, Pedro Redondo, Leyre Aguado-Gil and Rafael Salido-Vallejo

Cancers 2023, 15(11), 3056; https://doi.org/10.3390/cancers15113056 - 5 Jun 2023

Viewed by 1423

Abstract

(1) Introduction: The association between melanoma (MM) and the occurrence of second primary neoplasms (SPNs) has been extensively studied, with reported incidence rates ranging from 1.5% to 20%. This study aims to evaluate the occurrence of SPNs in patients with a history of [...] Read more.

(1) Introduction: The association between melanoma (MM) and the occurrence of second primary neoplasms (SPNs) has been extensively studied, with reported incidence rates ranging from 1.5% to 20%. This study aims to evaluate the occurrence of SPNs in patients with a history of primary MM and to describe the factors that make the risk higher in our population. (2) Material and Methods: We conducted a prospective cohort study and calculated the incidence rates and relative risks (RR) for the development of different SPNs in 529 MM survivors from 1 January 2005 to 1 August 2021. Survival and mortality rates were obtained, and the Cox proportional hazards model was used to determine the demographic and MM-related factors that influence the overall risk. (3) Results: Among the 529 patients included, 89 were diagnosed with SPNs (29 prior to MM diagnosis, 11 synchronous, and 49 after MM), resulting in 62 skin tumors and 37 solid organ tumors. The estimated probability of developing SPNs after MM diagnosis was 4.1% at 1 year, 11% at 5 years, and 19% at 10 years. Older age, primary MM location on the face or neck, and histologic subtype of lentigo maligna mm were significantly associated with a higher risk of SPNs. (4) Conclusions: In our population, the risk of developing SPNs was higher in patients with primary MM located on the face and neck and with the histological subtype of lentigo maligna-MM. Age also independently influences the risk. Understanding these hazard factors can aid in the development of MM guidelines with specific follow-up recommendations for individuals with the highest risk. Full article

(This article belongs to the Special Issue New Concepts and Recent Advances in the Management of Skin Cancer)

► Show Figures

Figure 1

23 pages, 1092 KiB

Open AccessReview

Cardiovascular Complications of Pan-Cancer Therapies: The Need for Cardio-Oncology

by Mengjia Chen, Jianing Xue, Maoling Wang, Junyao Yang and Ting Chen

Cancers 2023, 15(11), 3055; https://doi.org/10.3390/cancers15113055 - 5 Jun 2023

Cited by 5 | Viewed by 1957

Abstract

It is more likely that a long-term survivor will have both cardiovascular disease and cancer on account of the progress in cancer therapy. Cardiotoxicity is a well-recognized and highly concerning adverse effect of cancer therapies. This side effect can manifest in a proportion [...] Read more.

It is more likely that a long-term survivor will have both cardiovascular disease and cancer on account of the progress in cancer therapy. Cardiotoxicity is a well-recognized and highly concerning adverse effect of cancer therapies. This side effect can manifest in a proportion of cancer patients and may lead to the discontinuation of potentially life-saving anticancer treatment regimens. Consequently, this discontinuation may adversely affect the patient’s survival prognosis. There are various underlying mechanisms by which each anticancer treatment affects the cardiovascular system. Similarly, the incidence of cardiovascular events varies with different protocols for malignant tumors. In the future, comprehensive cardiovascular risk assessment and clinical monitoring should be considered for cancer treatments. Baseline cardiovascular evaluation risk should be emphasized prior to initiating clinical therapy in patients. Additionally, we highlight that there is a need for cardio-oncology to avoid or prevent cardiovascular side effects. Cardio-oncology service is based on identifying cardiotoxicity, developing strategies to reduce these toxicities, and minimizing long-term cardiotoxic effects. Full article

► Show Figures

Figure 1

17 pages, 675 KiB

Open AccessReview

A Panorama of Immune Fighters Armored with CARs in Acute Myeloid Leukemia

by Ilias Christodoulou and Elena E. Solomou

Cancers 2023, 15(11), 3054; https://doi.org/10.3390/cancers15113054 - 5 Jun 2023

Cited by 1 | Viewed by 2796

Abstract

Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging [...] Read more.

Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML. Full article

(This article belongs to the Special Issue Targeted Immunotherapies for Cancers)

► Show Figures

Figure 1

13 pages, 2161 KiB

Open AccessReview

The Emerging, Multifaceted Role of WTAP in Cancer and Cancer Therapeutics

by Guomin Ju, Jiangchu Lei, Shuqi Cai, Siyuan Liu, Xinjia Yin and Chuanhui Peng

Cancers 2023, 15(11), 3053; https://doi.org/10.3390/cancers15113053 - 4 Jun 2023

Cited by 8 | Viewed by 2978

Abstract

Cancer is a grave and persistent illness, with the rates of both its occurrence and death toll increasing at an alarming pace. N6-methyladenosine (m⁶A), the most prevalent mRNA modification in eukaryotic organisms, is catalyzed by methyltransferases and has a significant impact [...] Read more.

Cancer is a grave and persistent illness, with the rates of both its occurrence and death toll increasing at an alarming pace. N6-methyladenosine (m⁶A), the most prevalent mRNA modification in eukaryotic organisms, is catalyzed by methyltransferases and has a significant impact on various aspects of cancer progression. WT1-associated protein (WTAP) is a crucial component of the m⁶A methyltransferase complex, catalyzing m⁶A methylation on RNA. It has been demonstrated to participate in numerous cellular pathophysiological processes, including X chromosome inactivation, cell proliferation, cell cycle regulation, and alternative splicing. A better understanding of the role of WTAP in cancer may render it a reliable factor for early diagnosis and prognosis, as well as a key therapeutic target for cancer treatment. It has been found that WTAP is closely related to tumor cell cycle regulation, metabolic regulation, autophagy, tumor immunity, ferroptosis, epithelial mesenchymal transformation (EMT), and drug resistance. In this review, we will focus on the latest advances in the biological functions of WTAP in cancer, and explore the prospects of its application in clinical diagnosis and therapy. Full article

► Show Figures

Figure 1

17 pages, 1467 KiB

Open AccessEditor’s ChoiceArticle

Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy

by Marin Golčić, Luka Simetić, Davorin Herceg, Krešimir Blažičević, Gordana Kenđel Jovanović, Ivan Dražić, Andrej Belančić, Nataša Skočibušić, Dora Palčevski, Igor Rubinić, Vera Vlahović-Palčevski, Tea Majnarić, Renata Dobrila-Dintinjana and Stjepko Pleština

Cancers 2023, 15(11), 3052; https://doi.org/10.3390/cancers15113052 - 4 Jun 2023

Cited by 4 | Viewed by 2575

Abstract

Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients [...] Read more.

Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors or Targeted Therapy in the Treatment of Patients with Melanoma Volume II)

► Show Figures

Figure 1

13 pages, 937 KiB

Open AccessArticle

Utility of Patient-Reported Symptom and Functional Outcomes to Indicate Recovery after First 90 Days of Radical Cystectomy: A Longitudinal Study

by Xin Shelley Wang, Kelly K. Bree, Neema Navai, Mona Kamal, Shu-En Shen, Elizabeth Letona, Charles S. Cleeland, Qiuling Shi and Vijaya Gottumukkala

Cancers 2023, 15(11), 3051; https://doi.org/10.3390/cancers15113051 - 4 Jun 2023

Cited by 2 | Viewed by 1652

Abstract

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the [...] Read more.

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the MD Anderson Symptom Inventory (the MDASI-PeriOp-BLC). The feasibility of collecting an objective measure for physical functioning, using “Timed Up & Go test” (TUGT) and PRO scores at baseline, discharge and end of study, was tested. Patients (n = 52) received care under an ERAS pathway. The more severe scores of fatigue, sleep disturbance, distress, drowsiness, frequent urination and urinary urgency at baseline predicted poor functional recovery postoperatively (OR = 1.661, 1.039–2.655, p = 0.034); other more severe symptoms at discharge (pain, fatigue, sleep disturbance, lack of appetite, drowsiness, bloating/abdominal tightness) predicted poor functional recovery (OR = 1.697, 1.114–2.584, p = 0.014) postoperatively. Compliance rates at preoperative, discharge and end of study were 100%, 79% and 77%, while TUGT completion rates were 88%, 54% and 13%, respectively. This prospective study found that more severe symptom burden at baseline and discharge is associated with poor functional recovery post-radical cystectomy for BLC. The collection of PROs is more feasible than using performance measures (TUGT) of function following radical cystectomy. Full article

(This article belongs to the Collection Urological Cancer)

► Show Figures

Figure 1

9 pages, 251 KiB

Open AccessArticle

The BETTY Score to Predict Perioperative Outcomes in Surgical Patients

by Michael Baboudjian, Rawad Abou-Zahr, Bogdan Buhas, Alae Touzani, Jean-Baptiste Beauval and Guillaume Ploussard

Cancers 2023, 15(11), 3050; https://doi.org/10.3390/cancers15113050 - 4 Jun 2023

Cited by 2 | Viewed by 1259

Abstract

The aim of this study is to evaluate a new user-friendly scoring system, namely the BETTY score, that aims to predict 30-day patient outcomes after surgery. In this first description, we rely on a population of prostate cancer patients undergoing robot-assisted radical prostatectomy. [...] Read more.

The aim of this study is to evaluate a new user-friendly scoring system, namely the BETTY score, that aims to predict 30-day patient outcomes after surgery. In this first description, we rely on a population of prostate cancer patients undergoing robot-assisted radical prostatectomy. The BETTY score includes the patient’s American Society of Anesthesiologists score, the body mass index, and intraoperative data, including operative time, estimated blood loss, any major intraoperative complications, hemodynamic, and/or respiratory instability. There is an inverse relationship between the score and severity. Three clusters assessing the risk of postoperative events were defined: low, intermediate, and high risk of postoperative events. A total of 297 patients was included. The median length of hospital stay was 1 day (IQR1-2). Unplanned visits, readmissions, any complications, and serious complications occurred in 17.2%, 11.8%, 28.3%, and 5% of cases, respectively. We found a statistically significant correlation between the BETTY score and all endpoints analyzed (all p ≤ 0.01). A total of 275, 20, and 2 patients were classified as low-, intermediate-, and high-risk according to the BETTY scoring system, respectively. Compared with low-risk patients, patients at intermediate-risk were associated with worse outcomes for all endpoints analyzed (all p ≤ 0.04). Future studies, in various surgical subspecialties, are ongoing to confirm the usefulness of this easy-to-use score in routine. Full article

(This article belongs to the Special Issue Prognostic Factors in Urologic Cancers—Assessment and Integration into Clinical Care)

9 pages, 1259 KiB

Open AccessArticle

Adjuvant FOLFIRINOX in Patients with Resectable Pancreatic Cancer Is Effective but Rarely Feasible in Real Life: Is Neoadjuvant FOLFIRINOX a Better Option?

by Yossi Maman, Yaacov Goykhman, Oz Yakir, Alex Barenboim, Ravit Geva, Sharon Peles-Avraham, Ido Wolf, Joseph M. Klausner, Guy Lahat and Nir Lubezky

Cancers 2023, 15(11), 3049; https://doi.org/10.3390/cancers15113049 - 3 Jun 2023

Cited by 2 | Viewed by 2025

Abstract

Background: The recommended treatment for resectable pancreatic cancer (PC) is resection followed by adjuvant FOLFIRINOX. We assessed the proportion of patients that managed to complete the 12 courses of adjuvant FOLFIRINOX and compared their outcome with that of patients with borderline resectable pancreatic [...] Read more.

Background: The recommended treatment for resectable pancreatic cancer (PC) is resection followed by adjuvant FOLFIRINOX. We assessed the proportion of patients that managed to complete the 12 courses of adjuvant FOLFIRINOX and compared their outcome with that of patients with borderline resectable pancreatic cancer (BRPC) who underwent resection after neoadjuvant FOLFIRINOX. Methods: A retrospective analysis was performed on a prospectively maintained database of all PC patients who underwent resection with (2/2015–12/2021) or without (1/2018–12/2021) neoadjuvant therapy. Results: A total of 100 patients underwent upfront resection, and 51 patients with BRPC received neoadjuvant treatment. Only 46 resection patients started adjuvant FOLFIRINOX, and only 23 completed 12 courses. The main reasons for not starting/completing adjuvant therapy were poor tolerance and rapid recurrence. Significantly more patients in the neoadjuvant group received at least six FOLFIRINOX courses (80.4% vs. 31%, p < 0.001). Patients who completed at least 6 courses, either pre- or postoperatively, had better overall survival (p = 0.025) than those who did not. In spite of having more advanced disease, the neoadjuvant group had comparable overall survival (p = 0.062) regardless of the number of treatment courses. Conclusion: Only a minority of patients (23%) undergoing upfront pancreatic resection completed the planned 12 courses of FOLFIRINOX. Patients who received neoadjuvant treatment were significantly more likely to receive at least six treatment courses. Patients receiving at least six courses had better overall survival than those who received fewer than six courses, regardless of the timing of treatment relative to surgery. Potential ways to increase chemotherapy adherence, such as administering treatment before surgery, should be considered. Full article

(This article belongs to the Special Issue Neoadjuvant Therapy of Pancreatic Cancer)

► Show Figures

Figure 1

13 pages, 657 KiB

Open AccessSystematic Review

Minimally Invasive Surgery for Perihilar Cholangiocarcinoma: A Systematic Review of the Short- and Long-Term Results

by Giammauro Berardi, Alessio Lucarini, Marco Colasanti, Germano Mariano, Stefano Ferretti, Roberto Luca Meniconi, Nicola Guglielmo, Marco Angrisani, Sofia Usai, Maria Carola Borcea, Giulia Canali, Giovanni Moschetta and Giuseppe Maria Ettorre

Cancers 2023, 15(11), 3048; https://doi.org/10.3390/cancers15113048 - 3 Jun 2023

Cited by 5 | Viewed by 2545

Abstract

Surgery and postoperative systemic chemotherapy represent the standard treatment for patients with perihilar cholangiocarcinoma (PHC). Minimally Invasive Surgery (MIS) for hepatobiliary procedures has spread worldwide in the last two decades. Since resections for PHC are technically demanding, the role of MIS in this [...] Read more.

Surgery and postoperative systemic chemotherapy represent the standard treatment for patients with perihilar cholangiocarcinoma (PHC). Minimally Invasive Surgery (MIS) for hepatobiliary procedures has spread worldwide in the last two decades. Since resections for PHC are technically demanding, the role of MIS in this field is yet to be established. This study aimed to systematically review the existing literature on MIS for PHC, to evaluate its safety and its surgical and oncological outcomes. A systematic literature review on PubMed and SCOPUS was performed according to the PRISMA guidelines. Overall, a total of 18 studies reporting 372 MIS procedures for PHC were included in our analysis. A progressive increase in the available literature was observed over the years. A total of 310 laparoscopic and 62 robotic resections were performed. A pooled analysis showed an operative time ranging from 205.3 ± 23.9 and 840 (770–890) minutes, and intraoperative bleeding between 101.1 ± 13.6 and 1360 ± 809 mL. Minor and major morbidity rates were 43.9% and 12.7%, respectively, with a 5.6% mortality rate. R0 resections were achieved in 80.6% of patients and the number of retrieved lymph nodes ranged between 4 (3–12) and 12 (8–16). This systematic review shows that MIS for PHC is feasible, with safe postoperative and oncological outcomes. Recent data has shown encouraging results and more reports are being published. Future studies should address differences between robotic and laparoscopic approaches. Given the management and technical challenges, MIS for PHC should be performed by experienced surgeons, in high-volume centers, on selected patients. Full article

(This article belongs to the Special Issue New Insights in Biliary Tract Cancers Therapy)

► Show Figures

Figure 1

14 pages, 1291 KiB

Open AccessArticle

Third-Line Palliative Systemic Therapy for Advanced Biliary Tract Cancer: Multicentre Review of Patterns of Care and Outcomes

by Simon Gray, Octave Letissier, Constance d’Abrigeon, Dinakshi Shah, Stephen Wardell, Olusola Faluyi, Angela Lamarca, Richard A. Hubner, Julien Edeline, Juan W. Valle and Mairéad G. McNamara

Cancers 2023, 15(11), 3047; https://doi.org/10.3390/cancers15113047 - 3 Jun 2023

Cited by 1 | Viewed by 2380

Abstract

Phase 3 trials have established standard first-line (1L) and 2L systemic therapy options for patients with advanced biliary cancer (ABC). However, a standard 3L treatment remains undefined. Clinical practice and outcomes for 3L systemic therapy in patients with ABC were therefore evaluated from [...] Read more.

Phase 3 trials have established standard first-line (1L) and 2L systemic therapy options for patients with advanced biliary cancer (ABC). However, a standard 3L treatment remains undefined. Clinical practice and outcomes for 3L systemic therapy in patients with ABC were therefore evaluated from three academic centres. Included patients were identified using institutional registries; demographics, staging, treatment history, and clinical outcomes were collected. Kaplan–Meier methods were used to assess progression-free survival (PFS) and overall survival (OS). Ninety-seven patients, treated between 2006 and 2022, were included; 61.9% had intrahepatic cholangiocarcinoma. At the time of analysis, there had been 91 deaths. Median PFS from initiating 3L palliative systemic therapy (mPFS3) was 3.1 months (95%CI 2.0–4.1), while mOS3 was 6.4 months (95%CI 5.5–7.3); mOS1 was 26.9 months (95%CI 23.6–30.2). Among patients with a therapy-targeted molecular aberration (10.3%; n = 10; all received in 3L), mOS3 was significantly improved versus all other included patients (12.5 vs. 5.9 months; p = 0.02). No differences in OS1 were demonstrated between anatomical subtypes. Fourth-line systemic therapy was received by 19.6% of patients (n = 19). This international multicentre analysis documents systemic therapy use in this select patient group, and provides a benchmark of outcomes for future trial design. Full article

► Show Figures

Figure 1

18 pages, 4551 KiB

Open AccessEditor’s ChoiceArticle

Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder

by Elshafa Hassan Ahmed, Mark Lustberg, Claire Hale, Shelby Sloan, Charlene Mao, Xiaoli Zhang, Hatice Gulcin Ozer, Sarah Schlotter, Porsha L. Smith, Frankie Jeney, Wing Keung Chan, Bonnie K. Harrington, Christoph Weigel, Eric Brooks, Haley L. Klimaszewski, Christopher C. Oakes, Tamrat Abebe, Muntaser E. Ibrahim, Lapo Alinari, Gregory K. Behbehani, Polina Shindiapina, Michael A. Caligiuri and Robert A. Baiocchi Show full author list Hide full author list

Cancers 2023, 15(11), 3046; https://doi.org/10.3390/cancers15113046 - 3 Jun 2023

Cited by 2 | Viewed by 3200

Abstract

Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a [...] Read more.

Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention. Full article

(This article belongs to the Special Issue Epstein-Barr Virus-Associated Cancers: From Pathogenesis to Treatment)

► Show Figures

Figure 1

14 pages, 1782 KiB

Open AccessArticle

The Role of Adhesion Molecules and Extracellular Vesicles in an In Vitro Model of the Blood–Brain Barrier for Metastatic Disease

by Chiara Vasco, Ambra Rizzo, Chiara Cordiglieri, Elena Corsini, Emanuela Maderna, Emilio Ciusani and Andrea Salmaggi

Cancers 2023, 15(11), 3045; https://doi.org/10.3390/cancers15113045 - 3 Jun 2023

Cited by 6 | Viewed by 2157

Abstract

Metastatic brain disease (MBD) has seen major advances in clinical management, focal radiation therapy approaches and knowledge of biological factors leading to improved prognosis. Extracellular vesicles (EVs) have been found to play a role in tumor cross-talk with the target organ, contributing to [...] Read more.

Metastatic brain disease (MBD) has seen major advances in clinical management, focal radiation therapy approaches and knowledge of biological factors leading to improved prognosis. Extracellular vesicles (EVs) have been found to play a role in tumor cross-talk with the target organ, contributing to the formation of a premetastatic niche. Human lung and breast cancer cell lines were characterized for adhesion molecule expression and used to evaluate their migration ability in an in vitro model. Conditioned culture media and isolated EVs, characterized by super resolution and electron microscopy, were tested to evaluate their pro-apoptotic properties on human umbilical vein endothelial cells (HUVECs) and human cerebral microvascular endothelial cells (HCMEC/D3) by annexin V binding assay. Our data showed a direct correlation between expression of ICAM1, ICAM2, β3-integrin and α2-integrin and the ability to firmly adhere to the blood–brain barrier (BBB) model, whereas the same molecules were down-regulated at a later step. Extracellular vesicles released by tumor cell lines were shown to be able to induce apoptosis in HUVEC while brain endothelial cells showed to be more resistant. Full article

(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)

► Show Figures

Figure 1

17 pages, 9697 KiB

Open AccessArticle

Long-Chain Acyl Coenzyme A Dehydrogenase, a Key Player in Metabolic Rewiring/Invasiveness in Experimental Tumors and Human Mesothelioma Cell Lines

by Daniel L. Pouliquen, Giacomo Ortone, Letizia Rumiano, Alice Boissard, Cécile Henry, Stéphanie Blandin, Catherine Guette, Chiara Riganti and Joanna Kopecka

Cancers 2023, 15(11), 3044; https://doi.org/10.3390/cancers15113044 - 3 Jun 2023

Cited by 3 | Viewed by 1943

Abstract

Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant [...] Read more.

Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant mesothelioma (MM) tumors with analysis of ten patient-derived cell lines to identify common features associated with mitochondrial proteome rewiring. A comparison of significant abundance changes between invasive and non-invasive rat tumors gave a list of 433 proteins, including 26 proteins reported to be exclusively located in mitochondria. Next, we analyzed the differential expression of genes encoding the mitochondrial proteins of interest in five primary epithelioid and five primary sarcomatoid human MM cell lines; the most impressive increase was observed in the expression of the long-chain acyl coenzyme A dehydrogenase (ACADL). To evaluate the role of this enzyme in migration/invasiveness, two epithelioid and two sarcomatoid human MM cell lines derived from patients with the highest and lowest overall survival were studied. Interestingly, sarcomatoid vs. epithelioid cell lines were characterized by higher migration and fatty oxidation rates, in agreement with ACADL findings. These results suggest that evaluating mitochondrial proteins in MM specimens might identify tumors with higher invasiveness. Data are available via ProteomeXchange with the dataset identifier PXD042942. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)

► Show Figures

Figure 1

19 pages, 2192 KiB

Open AccessArticle

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters

by Elisabeth Groß, Ralf-Axel Hilger, Franziska Lea Schümann, Marcus Bauer, Alyssa Bouska, Christian Rohde, Edith Willscher, Jana Lützkendorf, Lutz Peter Müller, Bayram Edemir, Thomas Mueller, Marco Herling, Mascha Binder, Claudia Wickenhauser, Javeed Iqbal, Guido Posern and Thomas Weber

Cancers 2023, 15(11), 3043; https://doi.org/10.3390/cancers15113043 - 3 Jun 2023

Viewed by 2385

Abstract

T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. [...] Read more.

T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. EZH2 is overexpressed in several tumor entities including T-cell neoplasms leading to epigenetic and consecutive oncogenic dysregulation. Thus, pharmacological EZH2 inhibition is a promising target and its clinical evaluation in T-cell lymphomas shows favorable results. We have investigated EZH2 expression in two cohorts of T-cell lymphomas by mRNA-profiling and immunohistochemistry, both revealing overexpression to have a negative impact on patients’ prognosis. Furthermore, we have evaluated EZH2 inhibition in a panel of leukemia and lymphoma cell lines with a focus on T-cell lymphomas characterized for canonical EZH2 signaling components. The cell lines were treated with the inhibitors GSK126 or EPZ6438 that inhibit EZH2 specifically by competitive binding at the S-adenosylmethionine (SAM) binding site in combination with the common second-line chemotherapeutic oxaliplatin. The change in cytotoxic effects under pharmacological EZH2 inhibition was evaluated revealing a drastic increase in oxaliplatin resistance after 72 h and longer periods of combinational incubation. This outcome was independent of cell type but associated to reduced intracellular platinum. Pharmacological EZH2 inhibition revealed increased expression in SRE binding proteins, SREBP1/2 and ATP binding cassette subfamily G transporters ABCG1/2. The latter are associated with chemotherapy resistance due to increased platinum efflux. Knockdown experiments revealed that this was independent of the EZH2 functional state. The EZH2 inhibition effect on oxaliplatin resistance and efflux was reduced by additional inhibition of the regulated target proteins. In conclusion, pharmacological EZH2 inhibition is not suitable in combination with the common chemotherapeutic oxaliplatin in T-cell lymphomas revealing an EZH2-independent off-target effect. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

► Show Figures

Figure 1

19 pages, 6599 KiB

Open AccessArticle

Analyses of Genes Critical to Tumor Survival Reveal Potential ‘Supertargets’: Focus on Transcription

by Darya Chetverina, Nadezhda E. Vorobyeva, Balazs Gyorffy, Alexander A. Shtil and Maksim Erokhin

Cancers 2023, 15(11), 3042; https://doi.org/10.3390/cancers15113042 - 3 Jun 2023

Cited by 3 | Viewed by 2680

Abstract

The identification of mechanisms that underlie the biology of individual tumors is aimed at the development of personalized treatment strategies. Herein, we performed a comprehensive search of genes (termed Supertargets) vital for tumors of particular tissue origin. In so doing, we used the [...] Read more.

The identification of mechanisms that underlie the biology of individual tumors is aimed at the development of personalized treatment strategies. Herein, we performed a comprehensive search of genes (termed Supertargets) vital for tumors of particular tissue origin. In so doing, we used the DepMap database portal that encompasses a broad panel of cell lines with individual genes knocked out by CRISPR/Cas9 technology. For each of the 27 tumor types, we revealed the top five genes whose deletion was lethal in the particular case, indicating both known and unknown Supertargets. Most importantly, the majority of Supertargets (41%) were represented by DNA-binding transcription factors. RNAseq data analysis demonstrated that a subset of Supertargets was deregulated in clinical tumor samples but not in the respective non-malignant tissues. These results point to transcriptional mechanisms as key regulators of cell survival in specific tumors. Targeted inactivation of these factors emerges as a straightforward approach to optimize therapeutic regimens. Full article

(This article belongs to the Special Issue Bioinformatics in Cancer Diagnostics and Screening)

► Show Figures

Figure 1

13 pages, 729 KiB

Open AccessArticle

Better Late Than Never: The Impact of Steroidal Treatment on the Outcome of Melanoma Patients Treated with Immunotherapy

by Neta Bar-Hai, Guy Ben-Betzalel, Ronen Stoff, Shirly Grynberg, Jacob Schachter, Ronnie Shapira-Frommer and Nethanel Asher

Cancers 2023, 15(11), 3041; https://doi.org/10.3390/cancers15113041 - 3 Jun 2023

Cited by 10 | Viewed by 3735

Abstract

Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients [...] Read more.

Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. Methods: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014–2020 was conducted. Results: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Conclusions: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors or Targeted Therapy in the Treatment of Patients with Melanoma Volume II)

► Show Figures

Figure 1

14 pages, 12859 KiB

Open AccessArticle

Clinical Outcomes Depending on Sympathetic Innervation in Pancreatic Cancer

by Elena-Anca Târtea, Mihai Petrescu, Ion Udriștoiu, Victor Gheorman, Viorel Biciușcă, Alexandra-Roxana Petrescu, Ana-Maria Ciurea and Cristin Constantin Vere

Cancers 2023, 15(11), 3040; https://doi.org/10.3390/cancers15113040 - 2 Jun 2023

Cited by 1 | Viewed by 1514

Abstract

Background: The aim of our study was to evaluate sympathetic neuronal remodeling in patients with pancreatic cancer, together with its correlation with clinical outcomes. Methods: In this descriptive, retrospective study, we analyzed pancreatic cancer specimens and peritumoral pancreatic tissue from 122 patients. We [...] Read more.

Background: The aim of our study was to evaluate sympathetic neuronal remodeling in patients with pancreatic cancer, together with its correlation with clinical outcomes. Methods: In this descriptive, retrospective study, we analyzed pancreatic cancer specimens and peritumoral pancreatic tissue from 122 patients. We also investigated tyrosine hydroxylase immunoreactivity for the analysis of sympathetic nerve fibers and beta 2 adrenoreceptors immunoreactivity. To investigate the potential interaction between tyrosine hydroxylase (TH), beta 2 adrenoreceptors (B2A) immunoreactivity, and clinicopathological outcomes, we used the median to classify each case as TH+, respectively, B2A+ (if it presented a value higher than the median). Results: Firstly, the overall survival was analyzed according to TH and B2A immunoreactivity, in both intratumoral and peritumoral tissue. Only B2A immunoreactivity in the peritumoral pancreatic tissue influenced overall survival at 5 years of follow-up; thus, B2A+ patients recorded a 5-year survival of only 3% compared to B2A− patients who recorded an overall survival at 5 years of follow-up of 14% (HR = 1.758, 95% CI of ratio 1.297 to 2.938, p = 0.0004). Additionally, the increased immunoreactivity of B2A in the peritumoral tissue was also associated with other factors of poor prognosis, such as moderately or poorly differentiated tumors, the absence of response to first-line chemotherapy, or metastatic disease. Conclusions: The increased immunoreactivity of beta 2 adrenoreceptors in pancreatic peritumoral tissue represents a poor prognostic factor in pancreatic cancer. Full article

► Show Figures

Figure 1

16 pages, 1062 KiB

Open AccessEditor’s ChoiceArticle

Cytogenetic Assessment and Risk Stratification in Myelofibrosis with Optical Genome Mapping

by Álvaro Díaz-González, Elvira Mora, Gayane Avetisyan, Santiago Furió, Rosalía De la Puerta, José Vicente Gil, Alessandro Liquori, Eva Villamón, Carmen García-Hernández, Marta Santiago, Cristian García-Ruiz, Marta Llop, Blanca Ferrer-Lores, Eva Barragán, Silvia García-Palomares, Empar Mayordomo, Irene Luna, Ana Vicente, Lourdes Cordón, Leonor Senent, Alberto Álvarez-Larrán, José Cervera, Javier De la Rubia, Juan Carlos Hernández-Boluda and Esperanza Such Show full author list Hide full author list

Cancers 2023, 15(11), 3039; https://doi.org/10.3390/cancers15113039 - 2 Jun 2023

Viewed by 2658

Abstract

Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, [...] Read more.

Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, copy number variants, and loss of heterozygosity) in a single workflow. In this study, peripheral blood samples from a series of 21 myelofibrosis patients were analyzed via OGM. We assessed the clinical impact of the application of OGM for disease risk stratification using the DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores compared with the standard-of-care approach. OGM, in combination with NGS, allowed for risk classification in all cases, compared to only 52% when conventional techniques were used. Cases with unsuccessful karyotypes (n = 10) using conventional techniques were fully characterized using OGM. In total, 19 additional cryptic aberrations were identified in 9 out of 21 patients (43%). No alterations were found via OGM in 4/21 patients with previously normal karyotypes. OGM upgraded the risk category for three patients with available karyotypes. This is the first study using OGM in myelofibrosis. Our data support that OGM is a valuable tool that can greatly contribute to improve disease risk stratification in myelofibrosis patients. Full article

(This article belongs to the Special Issue Diagnosis of Hematologic Malignancies)

► Show Figures

Figure 1

18 pages, 759 KiB

Open AccessReview

Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies

by Alyssa L. Becker and Arup K. Indra

Cancers 2023, 15(11), 3038; https://doi.org/10.3390/cancers15113038 - 2 Jun 2023

Cited by 9 | Viewed by 3119

Abstract

Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV [...] Read more.

Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival. Full article

(This article belongs to the Special Issue Oxidative Stress and Cancer: Possible Beneficial and Antioxidant Strategies)

► Show Figures

Figure 1

22 pages, 1060 KiB

Open AccessReview

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer

by Giovanni Tossetta, Sonia Fantone, Daniela Marzioni and Roberta Mazzucchelli

Cancers 2023, 15(11), 3037; https://doi.org/10.3390/cancers15113037 - 2 Jun 2023

Cited by 31 | Viewed by 2585

Abstract

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer [...] Read more.

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

► Show Figures

Figure 1

11 pages, 1347 KiB

Open AccessArticle

Creation of EGD-Derived Gastric Cancer Organoids to Predict Treatment Responses

by Hannah G. McDonald, Megan M. Harper, Kristen Hill, Anqi Gao, Angelica L. Solomon, Charles J. Bailey, Miranda Lin, Mautin Barry-Hundeyin, Michael J. Cavnar, Samuel H. Mardini, Prakash J. Pandalai, Reema A. Patel, Jill M. Kolesar, Justin A. Rueckert, Lawrence Hookey, Mark Ropeleski, Shaila J. Merchant, Joseph Kim and Mei Gao

Cancers 2023, 15(11), 3036; https://doi.org/10.3390/cancers15113036 - 2 Jun 2023

Cited by 2 | Viewed by 2181

Abstract

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using [...] Read more.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods: Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results: Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions: The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies. Full article

(This article belongs to the Special Issue Unravelling Gastric Cancer Pathobiology: From Correa Cascade to Patchwork Vision)

► Show Figures

Figure 1

21 pages, 1577 KiB

Open AccessArticle

A Novel Gene List Identifies Tumors with a Stromal-Mesenchymal Phenotype and Worse Prognosis in Gastric Cancer

by Secil Demirkol Canli, Meral Uner, Baris Kucukkaraduman, Diren Arda Karaoglu, Aynur Isik, Nesrin Turhan, Aytekin Akyol, Ismail Gomceli and Ali Osmay Gure

Cancers 2023, 15(11), 3035; https://doi.org/10.3390/cancers15113035 - 2 Jun 2023

Cited by 2 | Viewed by 2061

Abstract

Background: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors. Methods: Microarray, RNA sequencing, [...] Read more.

Background: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors. Methods: Microarray, RNA sequencing, and single-cell RNA sequencing-based gene expression data from gastric tumors were obtained from public databases. Freshly frozen gastric tumors (n = 42) and matched FFPE (formalin-fixed, paraffin-embedded) (n = 40) tissues from a Turkish gastric cancer cohort were used for quantitative real-time PCR and immunohistochemistry-based assessments of gene expression, respectively. Results: A novel list of 20 prognostic genes was identified and used for the classification of gastric tumors into two major tumor subgroups with differential stromal gene expression (“Stromal-UP” (SU) and “Stromal-DOWN” (SD)). The SU group had a more mesenchymal profile with an enrichment of extracellular matrix-related gene sets and a poor prognosis compared to the SD group. Expression of the genes within the signature correlated with the expression of mesenchymal markers ex vivo. A higher stromal content in FFPE tissues was associated with shorter overall survival. Conclusions: A stroma-rich, mesenchymal subgroup among gastric tumors identifies an unfavorable clinical outcome in all cohorts tested. Full article

(This article belongs to the Special Issue New Biomarkers in Cancers 2nd Edition)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cancers, Volume 15, Issue 11 (June-1 2023) – 195 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI