Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study.

BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

Risk Factors and Innovations in Risk Assessment for Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma.

Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral components, and intrinsic factors, especially involving genetic predisposition. However, the specific risk factors vary among the skin cancer types, highlighting the importance of precise knowledge to facilitate appropriate early diagnosis and treatment for at-risk individuals. Better understanding of the individual risk factors has led to the development of risk scores, allowing the identification of individuals at particularly high risk. These advances contribute to improved prevention strategies, emphasizing the commitment to mitigating the impact of skin cancer.

Benefit of adjuvant chemotherapy in patients with lobular breast cancer: A systematic review of the literature and metanalysis.

The role of adjuvant chemotherapy (aCT) for patients with localized lobular breast cancer (ILC) is still controversial. It is unclear what is the magnitude of benefit of the CT in this setting. In this systematic review of the literature and metanalysis, we aimed to estimate the benefit of aCT in addition to the standard treatments in the early ILC setting. We identified the records by searching Medline, CENTRAL, Web of Science, SCOPUS, and Google Scholar, and the meeting proceeding of the principal oncology meetings of the last 10 years, with no language or time restriction. A research strategy was developed with mapped and MeSH terms. Studies on the clinical use of aCT reporting survival outcomes in the ILC setting were double-screened and tabulated. PRISMA methodology was used for data extraction and synthesis. We extracted information on the study design and setting, eligible population and population size, histology variants, menopausal status, treatment regimens, follow-up duration. Hazard ratios (HR) and 95% confidence interval (CI) were extracted and transformed into logHR and corresponding standard error to obtain the Summary HR (SHR). Heterogeneity (I2 statistics) and publication bias (Macaskill test) were tested; a random effect models provided by SAS Proc Mixed was used for data analysis. Sensitivity analysis was conducted to examine the impact of inclusion criteria on the summary results. Disease-free (DFS), overall (OS) and cancer-specific survival (BCSS) were the primary endpoints of the investigation. The systematic review and metanalysis included 38,387 patients across 8 clinical studies. aCT was not associated with an improvement of OS (SHR 0.99; 95%CI 0.86-1.14), with low heterogeneity (I2 = 28%) and no publication bias (p = 0.43). Sensitivity analysis resulted in unchanged conclusions. We did not perform a metanalysis of the DFS estimates, as only reported in 3 studies. The value of aCT in improving DFS was unconfirmed, consistently with the OS results. Our research did not confirm a certain role of aCT for patients with ILC. Research gaps were identified, warranting the development of prospective, controlled ad hoc investigations.

Oligo metastatic renal cell carcinoma: stereotactic body radiation therapy, if, when and how?

BACKGROUND AND PURPOSE: Renal cell carcinoma (RCC) has traditionally been considered radioresistant with a limited role for conventional fractionation as a local approach. Nevertheless, since the appearance of stereotactic body radiation therapy (SBRT), radiotherapy (RT) has been increasingly employed in the management of metastatic RCC (mRCC). The aim of this study was to evaluate the role of SBRT for synchronous and metachronous oligo metastatic RCC patients in terms of local control, delay of systemic treatment, overall survival and toxicity. PATIENTS AND METHODS: A Monocentric single institution retrospective data collection was performed. Inclusion criteria were: (1) oligo-recurrent or oligo-progressive disease (less than 5 metastases) in mRCC patients after radical/partial nephrectomy or during systemic therapy, (2) metastasectomy or other metastasis-directed, rather than SBRT not feasible, (3) any contraindication to receive systemic therapy (such as comorbidities), (4) all the histologies were included, (5) available signed informed consent form for treatment. Tumor response and toxicity were evaluated using the response evaluation criteria in solid tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. Progression-free survival in-field and out-field (in-field and out-field PFS) and overall survival (OS) were calculated via the Kaplan-Meier method. The drug treatment-free interval was calculated from the start of SBRT to the beginning of any systemic therapy. RESULTS: From 2010 to December 2018, 61 patients with extracranial and intracranial metastatic RCC underwent SBRT on 83 lesions. Intracranial and extracranial lesions were included. Forty-five (74%) patients were treated for a solitary metastatic lesion. Median RT dose was 25 Gy (range 10-52) in 5-10 fractions. With a median follow-up of 2.3 years (range 0-7.15), 1-year in-field PFS was 70%, 2-year in-field PFS was 55%. One year out-field PFS was 39% and 1-year OS was 78%. Concomitant systemic therapy was employed for only 11 (18%) patients, for the others 50 (82%) the drug treatment-free rate was 70% and 50% at 1 and 2 years, respectively. No > G1 acute and late toxicities were reported. CONCLUSION: The pattern of failure was pre-dominantly out-of-field, even if the population was negatively selected and the used RT dose could be considered palliative. Therefore, SBRT appears to be a well-tolerated, feasible and safe approach in oligo metastatic RCC patients with an excellent in-field PFS. SBRT might play a role in the management of selected RCC patients allowing for a delay systemic therapy begin (one out of two patients were free from new systemic therapy at 2 years after SBRT). Further research on SBRT dose escalation is warranted.

Erratum: Why vitamin D for cancer patients?

[This corrects the article on p. 1 in vol. 3.].

Seroconversion in patients with cancer and oncology health care workers infected by SARS-CoV-2.

BACKGROUND: Patients with cancer have high risk for severe complications and poor outcome to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease [coronavirus disease 2019 (COVID-19)]. Almost all subjects with COVID-19 develop anti-SARS-CoV-2 immunoglobulin G (IgG) within 3 weeks after infection. No data are available on the seroconversion rates of cancer patients and COVID-19. PATIENTS AND METHODS: We conducted a multicenter, observational, prospective study that enrolled (i) patients and oncology health professionals with SARS-CoV-2 infection confirmed by real-time RT-PCR assays on nasal/pharyngeal swab specimens; (ii) patients and oncology health professionals with clinical or radiological suspicious of infection by SARS-CoV-2; and (iii) patients with cancer who are considered at high risk for infection and eligible for active therapy and/or major surgery. All enrolled subjects were tested with the 2019-nCoV IgG/IgM Rapid Test Cassette, which is a qualitative membrane-based immunoassay for the detection of IgG and IgM antibodies to SARS-CoV-2. The aim of the study was to evaluate anti-SARS-CoV-2 seroconversion rate in patients with cancer and oncology health care professionals with confirmed or clinically suspected COVID-19. RESULTS: From 30 March 2020 to 11 May 2020, 166 subjects were enrolled in the study. Among them, cancer patients and health workers were 61 (36.7%) and 105 (63.3%), respectively. Overall, 86 subjects (51.8%) had confirmed SARS-CoV-2 diagnosis by RT-PCR testing on nasopharyngeal swab specimen, and 60 (36.2%) had a clinical suspicious of COVID-19. Median time from symptom onset (for cases not confirmed by RT-PCR) or RT-PCR confirmation to serum antibody test was 17 days (interquartile range 26). In the population with confirmed RT-PCR, 83.8% of cases were IgG positive. No difference in IgG positivity was observed between cancer patients and health workers (87.9% versus 80.5%; P = 0.39). CONCLUSIONS: Our data indicate that SARS-CoV-2-specific IgG antibody detection do not differ between cancer patients and healthy subjects.

The evolving field of Dermato-oncology and the role of dermatologists: Position Paper of the EADO, EADV and Task Forces, EDF, IDS, EBDV-UEMS and EORTC Cutaneous Lymphoma Task Force.

BACKGROUND: The incidence of skin cancers has been increasing steadily over the last decades. Although there have been significant breakthroughs in the management of skin cancers with the introduction of novel diagnostic tools and innovative therapies, skin cancer mortality, morbidity and costs heavily burden the society. OBJECTIVE: Members of the European Association of Dermato-Oncology, European Academy of Dermatology and Venereology, International Dermoscopy Society, European Dermatology Forum, European Board of Dermatovenereology of the European Union of Medical Specialists and EORTC Cutaneous Lymphoma Task Force have joined this effort to emphasize the fundamental role that the specialist in Dermatology-Venereology has in the diagnosis and management of different types of skin cancer. We review the role of dermatologists in the prevention, diagnosis, treatment and follow-up of patients with melanoma, non-melanoma skin cancers and cutaneous lymphomas, and discuss approaches to optimize their involvement in effectively addressing the current needs and priorities of dermato-oncology. DISCUSSION: Dermatologists play a crucial role in virtually all aspects of skin cancer management including the implementation of primary and secondary prevention, the formation of standardized pathways of care for patients, the establishment of specialized skin cancer treatment centres, the coordination of an efficient multidisciplinary team and the setting up of specific follow-up plans for patients. CONCLUSION: Skin cancers represent an important health issue for modern societies. The role of dermatologists is central to improving patient care and outcomes. In view of the emerging diagnostic methods and treatments for early and advanced skin cancer, and considering the increasingly diverse skills, knowledge and expertise needed for managing this heterogeneous group of diseases, dermato-oncology should be considered as a specific subspecialty of Dermatology-Venereology.

Adjuvant radiotherapy treatment for soft tissue sarcoma of extremities and trunk. A retrospective mono-institutional analysis.

Soft tissue sarcomas (STS) are uncommon, heterogeneous malignant tumors of mesodermal origin. Other than conservative surgery (CS), neoadjuvant or adjuvant radiotherapy (RT) is recommended when the risk of local recurrence is high. The aim of this study is to present our Institutional experience in adjuvant RT for treatment of STS of extremities and trunk (with either brachytherapy (BRT), external beam RT (EBRT), or both) and to provide an insight of toxicity and oncological outcomes for each RT modality. According to the RT treatment approach, patients were divided into three categories: 1) BRT alone; 2) EBRT alone; 3) combined BRT+EBRT. Differences among the three groups were assessed by the Chi-squared test. Patients' follow-up was performed every 6 months for the first two years after the end of RT and then once a year. Data from 90 patients were analyzed. The overall 3-year distant relapse-free survival (DRFS), progression-free survival (PFS), and overall survival (OS) were 84%, 80%, and 97%, respectively. Acute erythema was the most frequent side effect, although severe grade 3 toxicity was present in 5 patients. Chronic toxicity of any grade was reported in 14 patients. The incidence of chronic toxicity did not show any association with treatment modality. Multivariate analysis suggested a significant correlation between acute toxicity and tumor size, RT modality, and RT dose. In conclusion, good local control and toxicity profile were observed, despite negative patients' selection at baseline. Further investigation on wider series is warranted in order to define the optimal combination with systemic therapy.

Lung optimized treatment with CyberKnife® in inoperable lung cancer patients: feasibility analysis of a mono-institutional 115 patient series.

CyberKnife® Lung Optimized Treatment (LOT) allows the treatment of lung cancer without invasive fiducial implantation. The aim of this retrospective analysis was to evaluate the feasibility, toxicity and clinical outcome. One hundred fifteen patients (124 lesions) were treated with CyberKnife® using LOT. The median age was 72.6 years (range 31.8-90.3). From 124 treated lesions, 52 were with histopathological confirmation (41 primitive pulmonary cancers, 8 pulmonary metastases) and 72 as untyped tumors. For 5 patients (6 lesions) treatment was an in-field re-irradiation. Concomitant therapy was administered in 7 patients. Zero-View tracking was applied in 69 patients, 1-View in 33 patients, 2-View in 22 patients. The median total dose was 45 Gy (range 18-54), median dose/fraction was 15 Gy (range 4-18) with a median prescription isodose of 80% (range 68-85). The median planning target volume (PTV) was 25 cm3 (range 3-195). The median follow-up was 20 months (range 7-47). Thirty-seven patients (32%) were alive with no evidence of disease, 39 patients (34%) were alive with clinically evident disease, and 38 patients (33%) died of the disease. The 1- and 2-year overall survival (OS) rate was 83% and 61%. The median time to progression was 19 months (95% confidence interval: 11-19 months), 1- and 2-year progression-free survival (PFS) rates were 62% and 41%, respectively. Smaller PTV was significantly associated with better OS, PFS and in-field PFS in univariate and multivariate analyses. Acute toxicity was observed in 36 patients (41%). Late toxicity was registered in 25 patients (29%). G3 late toxicity was observed in one patient (1.1%). Our data suggest that fiducial less-stereotactic body radiation therapy (SBRT) is a feasible, well-tolerated and potentially effective treatment with high compliance in the setting of inoperable patients due to concomitant disease or previous treatments.

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors.

PURPOSE: The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. RESULTS: The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001). CONCLUSIONS: These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.

The association between pesticide use and cutaneous melanoma: a systematic review and meta-analysis.

BACKGROUND: The incidence of cutaneous melanoma (CM), the deadliest form of skin cancer, has gradually increased in the last decades among populations of European origin. Epidemiological studies suggested that farmers and agricultural workers are at an increased risk of CM because they were exposed to pesticides. However, little is known about the relationship between pesticides and CM. OBJECTIVES: To investigate the association between exposure to pesticides and CM by systematically reviewing the literature. Secondary aim was to determine the categories of pesticides mainly involved in CM development. METHODS: A systematic review of the literature was performed up to September 2018 using MEDLINE, Embase and Web of Science. Studies assessing CM risk in licensed pesticide applicators were considered. Strict criteria were established to select independent studies and risk estimates; random effect models, taking into account heterogeneity, were applied. A pooled risk estimate for CM was calculated for the use of each type of pesticide and type of exposure. Between-study and estimate heterogeneity was assessed and publication bias investigated. RESULTS: A total of nine studies (two case-controls and seven cohorts) comprising 184 389 unique subjects were included. The summary relative risks for the categories 'herbicides - ever exposure', 'insecticides - ever exposure', 'any pesticide - ever exposure' and 'any pesticide - high exposure' resulted 1.85 [95% confidence interval (CI): 1.01, 3.36], 1.57 (95% CI: 0.58, 4.25), 1.31 (95% CI: 0.85, 2.04) and 2.17 (95% CI: 0.45, 10.36), respectively. Herbicides and insecticides had no between-study heterogeneity (I2  = 0%), while a significant heterogeneity (I2  > 50%) was detected for the high exposure to any pesticide. No indication for publication bias was found. CONCLUSIONS: Individuals exposed to herbicides are at an increased risk of CM. Future properly designed observational studies are required to confirm this finding.

Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

PURPOSE: Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer. METHODS: Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression. RESULTS: Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/µl), low absolute neutrophil count (< 5840/µl), high eosinophil count (> 90 /µl), and NLR < 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group. CONCLUSION: The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.

Correction to: Gr-MDSC-linked asset as a potential immune biomarker in pretreated NSCLC receiving nivolumab as second-line therapy.

Acknowledgements section was missing.

Stereotactic radiation therapy in oligometastatic colorectal cancer: outcome of 102 patients and 150 lesions.

To evaluate the local control (LC), progression free survival (PFS), out-field PFS, overall survival (OS), toxicity and failure predictors of SRT in a series of various sites oligometastatic CRC patients. Patients with oligometastatic CRC disease were analyzed retrospectively. The SRT prescribed dose was dependent on the lesion volume and its location. 102 consecutive oligometastatic CRC patients (150 lesions) were included. They underwent SRT between 2012 and 2015. Median prescription dose was 45 Gy (median dose/fraction was 15 Gy/3 fractions biological equivalent dose (BED10) 112.5 Gy). Median follow-up was 11.4 months. No patients experienced G3 and G4 toxicity. No progression was found in 82% (radiological response at 3 months) and 85% (best radiological response) out of 150 evaluable lesions. At 1 and 2 years: LC was 70% and 55%; OS was 90% and 90%; PFS was 37% and 27%; out-field PFS was 37% and 23% respectively. Progressive disease was correlated with BED10 (better LC when BED10 was ≥ 75 Gy (p < 0.0001)). In multivariate analysis, LC was higher in lesions with a Plpnning target volume (PTV) volume < 42 cm3 and BED10 ≥ 75 Gy. Patients with Karnofsky performance status < 90 showed higher out-field progression. SRT is an effective treatment for patients with oligometastases from CRC. Its low treatment-associated morbidity and acceptable LC make of SRT an option not only in selected cases. Further studies should be focused to clarify which patient subgroup will benefit most from this treatment modality and to define the optimal dose to improve LC while maintaining low toxicity profile.

The risk of extra-ovarian malignancies among women with endometriosis: A systematic literature review and meta-analysis.

We conducted a meta-analysis of studies reporting on the risk of extra-ovarian malignancies among women with endometriosis. Summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We explored causes of between-studies heterogeneity and assessed the presence of publication bias. We included 32 studies published between 1989 and 2018. We found an increased risk of endometrial (SRR 1.38, 95%CI 1.10-1.74) and thyroid cancer (SRR 1.38, 95%CI 1.17-1.63), and inverse association with cervical cancer (SRR 0.78, 95%CI 0.60-0.95). No association emerged for breast cancer (SRR 1.04, 95%CI 0.99-1.09) and melanoma (SRR 1.31, 95%CI 0.86-1.96). Between-study heterogeneity was large for breast and endometrial cancer and melanoma. Associations were generally stronger in case-control, cross-sectional, and cohort studies with internal control group, compared to cohort studies with external control group. No indication for publication bias was found. Our conclusions need to be confirmed in properly designed cohort studies with clinical confirmation of endometriosis.