A case report of a lung cancer patient with two uncommon EGFR mutations and a review of the literature: two sides of the same coin.

Lung cancer is the malignancy with the highest morbidity and mortality worldwide. Approximately 60% of non-small cell lung cancer (NSCLC) presents driver alterations most of which are targetable. Nowadays, limited clinical data are available regarding the efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with NSCLC harboring uncommon EGFR mutations, considering their heterogeneity. Herein, we report a rare case of EGFR-mutated lung adenocarcinoma which has developed into squamous cell carcinoma with uncommon EGFR (Ex18) compound mutations and phosphatidylinositol 3-kinase mutation receiving afatinib at the forefront.

Long-term response of more than 9 years to regorafenib in a heavily pretreated patient with metastatic colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1.9 million new diagnoses and 935 000 deaths annually. Overall, there is accumulating evidence that receiving all available treatments leads to a survival advantage and, although tailored treatments might be appropriate for selected patients, the one-size-fits-all approach is still widely used in chemo-refractory patients. Currently, different antiangiogenics and multitarget agents are indicated in treatment of metastatic CRC (mCRC) whereas the identification of useful predictive factors for the treatment response is lacking. Analysis of potential predictive biomarkers of efficacy of regorafenib is still ongoing but may prove to be difficult because of its nonspecific activity across a wide range of angiogenic, oncogenic, stromal, and intracellular signaling kinases. We present a case of a 57-year-old Caucasian woman diagnosed with recurrence after curative surgery for rectal adenocarcinoma stage III (ypT3N2). Despite undergoing multiple lines of standard chemotherapy, disease control could not be maintained. Consequently, regorafenib, a multikinase inhibitor with antiangiogenic proprieties, was started as a late-line treatment and a dose reduction strategy allowed a long-term response of more than 9 years with good tolerability.

Adjuvant Therapy for Renal Cell Carcinoma: Hype or Hope?

Renal cell carcinoma (RCC) is the third most common genitourinary cancer accounting for approximately 180,000 deaths worldwide in 2020. Although over two-thirds of patients initially present localized disease, up to 50% of them may progress to metastatic disease. Adjuvant therapy aims to reduce the recurrence risk and improve outcomes in several types of cancers but is currently an unmet need in RCC. The results achieved with tyrosine kinase inhibitors in metastatic RCC led to the evaluation of these target therapies in an early setting with conflicting results for disease-free survival and no overall survival (OS) benefit. Likewise, the results of immune checkpoint inhibitors (ICIs) in an adjuvant setting are conflicting. Available data did not show an improvement in OS with ICIs in the early phase, although a positive trend for pembrolizumab has been recorded, receiving the Food and Drug Administration's approval in this setting. However, the disappointing results of several ICIs and the heterogeneous pattern of RCC warrant biomarker identification and subgroup analyses to evaluate which patients could benefit from adjuvant therapy. In this review, we will discuss the rationale for adjuvant treatment in RCC, summarizing the results of the most important adjuvant therapy trials and current applications, to outline possible future directions.

Dermoscopy as a Tool for Identifying Potentially Metastatic Thin Melanoma: A Clinical-Dermoscopic and Histopathological Case-Control Study.

Despite being early-stage tumors, thin cutaneous melanomas contribute significantly to mortality and have a rising incidence. A retrospective case-control study was performed to identify clinical-dermoscopic and histopathological variables linked to local and distant metastases in melanomas ≤0.8 mm. Data from 1 January 2000 to 22 June 2022 were analyzed from two Italian skin cancer referral centers. Sixteen patients with ≤0.8 mm melanomas developing metastases were studied compared to controls without metastases over 5 years. Statistical analysis involved Pearson's chi-squared test or Fisher's exact test. Of the 1396 cases, 1.1% progressed. The median diagnosis age was 49 (range 28-83), with 56.3% men and 43.7% women. The torso was the primary tumor site (43.7%). Clinically, lesions were pigmented (>10 mm diameter: 73.3%, ≥3 colors: 80%). Dermoscopically, the common features were white patches (73.3%), atypical vascular patterns (66.5%), blue-gray areas (60%) and absent pigment networks (60%). Histopathologically, all cases had adverse features like regression (87.4%), dermal mitoses (50%), a vertical growth phase (62.5%) and ulceration (12.5%). These findings were statistically significant compared to controls (p < 0.05). In ≤0.8 mm melanomas, specific clinical-dermoscopic traits might indicate higher metastatic potential when paired with adverse histopathological features.

Challenges in the treatment of small cell lung cancer in the era of immunotherapy and molecular classification.

For many years the standard of care for small cell lung cancer (SCLC) has remained unchanged. Despite decades of active research, current treatment options are limited and the prognosis of patients with extended disease (ED) SCLC remains poor. The introduction of immune checkpoint inhibitors (ICIs) represents an exception and the only recent approval for ED-SCLC. However, the magnitude of benefit obtained with immunotherapy in SCLC is much more modest than that observed in other malignancies. Different pro-immunogenic or immunosuppressive features within the tumor microenvironment of SCLC may either modulate the sensitivity to immunotherapy or conversely dampen the efficacy of ICIs. Beside immunotherapy, a deeper understanding of the molecular biology of SCLC has led to the identification of new therapeutic targets for this lethal malignancy. Recent epigenetic and gene expression studies have resulted into a new molecular classification of four distinct subtypes of SCLC, defined by the relative expression of key transcription regulators and each characterized by specific therapeutic vulnerabilities. This review discusses the rationale for immunotherapy in SCLC and summarizes the main ICIs-trials in this tumor. We provide also an overview of new potential therapeutic opportunities and their integration with the new molecular classification of SCLC.

Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment.

INTRODUCTION: Genomic instability resulting from the inability of cells to repair DNA damage is a breeding ground for immune checkpoint inhibitors (ICIs) and targeted treatments. Poly (ADP-ribose) polymerase inhibitors (PARPi) interfere with the efficient repair of DNA single-strand break damage inducing, mainly in tumors with existing defects in double strand DNA repair system, synthetic lethality. AREAS COVERED: By amplifying the DNA damage and inducing immunogenic cell death PARPi leads tumor neoantigens to increase, upregulation of programmed death-ligand 1, and modulation of the tumor microenvironment facilitating a more intense antitumor immune response. In this review, we reported the immunological role of PARPi and the rational use of the combination with ICIs, evaluating data from combination clinical trials and discussing perspectives. EXPERT OPINION: Several prospective combination studies to overcome existing limitations to PARPi and ICI single agents are currently ongoing. The identification of the different resistance mechanisms to PARPi and ICI as well as the development of accurate and predictive biomarkers of response should be a priority to identify the patients who may most benefit from this combination. Similarly, clarifying the role and interaction between the DNA damage repair pathways and the tumor immune microenvironment would increase success of the combination.