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.

Primary pleural epithelioid hemangioendothelioma: case report and review of the literature.

Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with an unpredictable clinical behavior. Pleural EHEs have been associated with poor response to treatment and reduced survival. To date, no standard treatment for EHE is available. Here we report the case of a 53-year-old man who underwent radical surgery for a symptomatic primary pleural EHE. Clinical presentation was characterized by chronic pain in the left hemithorax with transitory flare, anemia, weight loss and progressive worsening of clinical conditions. After surgery, he resumed active life and normal daily activities and, at 8 months, 18F-FDG PET and computed tomography scan showed no radiological evidence of recurrent disease. Clinical signs of this rare disease, histological features, imaging findings and functional imaging are discussed. We also report a summary of other cases with resected pleural EHE and we briefly review the role of chemotherapeutic, immunomodulatory and antiangiogenic drugs for advanced disease.

KRAS Mutations Are Associated with Shortened Survival in Patients with Epithelioid Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleural surface that includes three major histologic subtypes, epitheliod, sarcomatoid and biphasic. Epithelioid mesothelioma is usually associated with better prognosis. The genetic mechanisms driving MPM, the possible target mutations and the correlation with overall survival remain largely unsettled. We performed target exome sequencing in 29 cases of MPM aimed at identifying somatic mutations and, eventually, their correlation with phenotypic traits and prognostic significance. We found that KRAS mutations, occurring in 13.7% of cases, were associated with shortened median survival (7.6 versus 32.6 months in KRAS wild-type; p = 0.005), as it was the occurrence of any ≥3 mutations (7.6 versus 37.6 months; p = 0.049). Conversely, the presence of KDR single nucleotide polymorphism p.V297I (rs2305948) resulted in a favorable variable for survival (NR versus 23.4 months; p = 0.026). With the intrinsic limitations of a small number of cases and patient heterogeneity, results of this study contribute to the characterization of the mutation profile of MPM and the impact of selected somatic mutations, and possibly KDR polymorphism, on prognosis.

Gastric and colonic metastasis from NSCLC: A very unusual case report.

RATIONALE: Lung cancer is the most common cause of cancer-related deaths worldwide. Approximately 50% of patients is metastatic at diagnosis and the most common metastatic sites are bone, lungs, brain, adrenal glands, liver, and extra thoracic lymph nodes. The occurrence of gastrointestinal metastasis from lung carcinoma is rare and seems more commonly related to small cell lung cancer compared to non-small cell lung cancer (NSCLC). PATIENT INFORMATION AND DIAGNOSIS: A 78-year-old man with completely surgically resected NSCLC and no initial evidence of distant metastases developed colon and gastric metastases 7 months after diagnosis, confirmed by serial radiological examinations and endoscopic biopsies. INTERVENTIONS: The patient was subjected to total gastrectomy with D2 lymph node dissection plus partial colectomy for intraoperative detection of a transverse colon neoformation. Subsequent instrumental imaging showed bilateral lung tumor recurrence, treated with gemcitabine monotherapy for 8 months as first line chemotherapy for lung adenocarcinoma. RESULTS: The patient presented complete response to therapy and was disease-free for 4 years. LESSONS: Colonic and gastric metastasis are very infrequent in NSCLC. The resection of gastrointestinal metastasis may provide benefits in terms of both symptom control and survival in patients properly selected.

Absolute eosinophil count predicts clinical outcomes and toxicity in non-small cell lung cancer patients treated with immunotherapy.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in non-small cell lung cancer (NSCLC) treatment. We investigated absolute eosinophil count (AEC) as a predictor of clinical outcomes and toxicity in NSCLC patients receiving ICIs. MATERIALS AND METHODS: AEC was retrospectively collected at baseline and during treatment from 158 advanced NSCLC patients treated with single agent anti-PD1/anti-PDL1 monoclonal antibody in first or subsequent line of therapy at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between January 2016 to October 2020. RESULTS: We found a significant association between high baseline AEC (≥130/µL) and better clinical outcomes. The response rates were 64.4% and 35.6% for patients with high and low AEC, respectively (p = 0.009). The high-AEC group showed a significantly longer PFS and OS than the low-AEC group (mPFS = 7.0 months, 95% CI 5.0-10.0 vs 2.5 months, 95% CI 2.0-4.0, p = 0.007 and mOS = 9.0 months, CI 95% 7.0-15.0 vs 5.5 months, 95% CI 4.0-8.0, p = 0.009, respectively). An increased risk of immune-related adverse events (irAEs) was reported in the high-AEC group (p = 0.133). IrAEs resulted an independent prognostic factor for both better outcomes (mPFS = 8.0 months, 95% CI 7.0-12.0 vs 2.0 months, 95% CI 2.0-3.0, p<0.001; mOS = 13.0 months 95% CI 9.0-19.0 vs 4.0 months 95% CI 3.0-6-0, p<0.001) and response to ICIs (response rate = 33.8% vs 14.9%, disease control rate = 72.0% vs 32.1%, p<0.001). CONCLUSION: High baseline AEC value (≥130/µL) is a predictive biomarker of clinical benefit and irAEs occurrence in NSCLC patients treated with ICIs.

KRAS G12 isoforms exert influence over up-front treatments: A retrospective, multicenter, Italian analysis of the impact of first-line immune checkpoint inhibitors in an NSCLC real-life population.

Background: KRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS "undruggability", and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial. Methods: We retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations. Results: In the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician's choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age (p = 0.007), female gender (p = 0.016), and an ICI-based regimen (p = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS. Conclusions: KRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future.

From clinical trials to clinical practice: predictors of response to erlotinib in advanced non-small cell lung cancer patients pretreated with chemotherapy.

BACKGROUND: Inhibition of the epidermal growth factor receptor pathway with tyrosine kinase inhibitors can improve outcome of patients with advanced non-small cell lung cancer after first-line chemotherapy. The use of clinical characteristics and molecular markers may permit the identification of patients who are more likely to benefit from erlotinib. PATIENTS AND METHODS: Retrospective analysis of unselected patients with metastatic non-small cell lung cancer who had previously failed on at least one line of chemotherapy and treated at our institution with erlotinib (150 mg/day orally) until disease progression. Mutations of epidermal growth factor receptor (exon 19-21) and KRAS (codon 12-13) genes were screened with high-resolution melting analysis and identified with direct sequencing. RESULTS: Fifty-three patients were included in the study. The disease control rate was 38%. Median progression-free survival and median overall survival were 4 and 15 months, respectively. Skin rash, diarrhea and mucositis were the most common toxicities of erlotinib. In 19 patients, erlotinib dose was reduced for toxicity. The disease control rate and progression-free survival were significantly better in non-smokers, responders to chemotherapy and patients with epidermal growth factor receptor mutations. Overall survival was longer in patients with skin toxicity and epidermal growth factor receptor mutations. CONCLUSIONS: In our experience, epidermal growth factor receptor mutations, response to previous chemotherapy and non-smoking status were predictors of higher disease control rate and longer progression-free survival. Overall survival was significantly longer in patients with epidermal growth factor receptor mutations and skin toxicity.

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series.

Microsomal epoxide hydrolase gene (EPHX1) is polymorphic and encodes an enzyme involved in both the activation and detoxification of several tobacco carcinogens. Therefore, a contribution of EPHX1 enzymatic activity on lung cancer risk is possible. A genetic component of early-onset lung cancer has been suggested but variations in enzyme activity and polymorphisms in EPHX1 have seldom been studied in young patients with lung cancer. Primary lung cancer cases of both sexes and under age 45 at diagnosis were considered for this study. Controls fulfilled the following criteria: over 60 years old, smoking history of at least 40 years, no malignancies. Because of these criteria, they are referred to as super controls. The polymorphisms at exons 3 (Tyr113His) and 4 (His139Arg) as well as at the 5'-UTR-290T/G of the EPHX1 gene were genotyped by minisequencing. The association of these three polymorphisms with the development of early-onset lung cancer and the group of the super controls was evaluated by means of 2x2 tables using Yate's X(2) test or Fisher's exact test. Overall, data were obtained from 42 cases and 72 super controls. There was a significant association between early-onset lung cancer and the presence of the EPHX1 exon 4 variant (OR=3.33, 95% CI=1.50-7.41). This was confirmed at the phenotypic level when the data of both patients and super controls were stratified according to the predicted enzymatic activity (X(2) for linear trend=7.23, p=0.007). This analysis of lung cancer in subjects under age 45 supports the hypothesis that EPHX1 polymorphisms may have a role in cancer susceptibility in this age group.

Renal metastasis from pulmonary adenocarcinoma: the pathologist's approach to an uncommon finding: case report and review of the literature.

We herein report an uncommon case of renal metastasis from the lung in a 72-year-old man who 2 years before underwent surgical treatment for a pulmonary adenocarcinoma. During follow-up, a computed tomography scan revealed the presence of a solid mass located in the right kidney. Histopathologic and immunohistochemical examination of the enucleated lesion demonstrated the renal localization of an adenocarcinoma of the lung. Clinically recognized renal metastatic lesions from pulmonary cancer are a rare finding with only 35 cases reported to date in the English literature, and renal localization of adenocarcinoma of the lung is extraordinarily uncommon. Together with suggestive clinical data and negativity for markers of adenocarcinomas of different origin, thyroid transcription factor-1, when positive, is considered to be the most reliable marker for the differential diagnosis.

Isolated chest wall implantation of non-small cell lung cancer after fine-needle aspiration: a case report and review of the literature.

Percutaneous fine-needle aspiration biopsy (FNAB) is a well-established and useful procedure in the diagnosis of lung squamous cell carcinoma (LSCC). Tumor seeding has been shown to be a potential risk. We report the case and management of a 78-year-old patient affected by LSCC who developed a chest wall metastasis in a straight line from the primary lesion along the FNAB needle track. Although tumor seeding after FNAB is a rare but possible complication, we suggest that careful examination for implantation (with periodical CT scans) should be performed for at least three years after FNAB.

Adequacy of lymphadenectomy in laparoscopic colorectal cancer surgery: a single-centre, retrospective study.

PURPOSE: This study aimed at evaluating the lymph node (LN) harvest after both open and laparoscopic colorectal cancer surgery. METHODS: In the period between 1996 and 2009, 404 patients with colorectal cancer underwent open resection, whereas 147 patients underwent laparoscopic surgery. RESULTS: The overall number of harvested LNs was significantly higher in the laparoscopic group than in the open one (16.5 vs. 14.3, P<0.001). A higher number of LNs was found in moderately differentiated tumors of the laparoscopic group when compared with the open surgery group (16.7 vs. 14.2, P<0.01). The numbers of harvested LNs in the proximal tumors and in stage II and III tumors were higher in the laparoscopic group than in the open group (18.9 vs. 15.4, P<0.001; 17.9 vs. 14.2, P=0.002; 17.3 vs. 15.3, P=0.02, respectively). CONCLUSIONS: Laparoscopic surgery for colorectal cancer can achieve LN retrieval similar to that achieved by the open approach.

The impact of histopathologic examination of graft-versus-host disease in the era of reduced-intensity conditioning regimen: a study from the Gruppo Italiano Trapianto di Midollo Osseo.

Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2 (2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24 (27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value by multivariate analysis (P = .01). The present study indicates that pathologists should be aware of the peculiar morphologic changes of cutaneous graft-versus-host disease following reduced-intensity conditioning and further recommends histopathology in the diagnostic workup of graft-versus-host disease in patients undergoing reduced-intensity conditioning regimen.

Pathologic determinants of survival after resection of T3N0 (Stage IIA) colorectal cancer: proposal for a new prognostic model.

PURPOSE: There is an increasing need for accurate prognostic stratification of patients with Stage II colorectal cancer to identify a subgroup of high-risk patients who may benefit from adjuvant therapies. This study was designed to evaluate the prognostic impact of a wide spectrum of pathologic parameters in a consecutive series of homogenously treated and well-characterized patients with Stage IIA (T3N0M0) colorectal cancer. METHODS: The study included 238 patients operated on by a single surgeon for Stage IIA colorectal tumors. The median postoperative follow-up was 110 (range, 96-120) months. At least 12 lymph nodes were harvested and examined in all the resection specimens. The prognostic value of 13 pathologic parameters, including lymph node occult disease (micrometastases) detected by immunohistochemistry, was investigated. RESULTS: Multivariate analysis identified tumor growth pattern (expanding or infiltrating; P = 0.01) and extent of tumor spread beyond muscularis propria (< or =5 mm or >5 mm; P = 0.04) as the only factors having independent prognostic value. The combination of these two easily determined parameters allowed us to identify two groups of patients at low risk or high risk of tumor recurrence. The eight-year survival rates were 83.3 and 53.4 percent for the two groups, respectively. The high-risk group comprised those patients with infiltrating tumors and extramural tumor spread > 5 mm. CONCLUSIONS: We propose a new and simple prognostic model to identify patients with high-risk Stage IIA colorectal cancer for whom adjuvant therapies may be justified and effective.