Heterogeneous pathogenesis of melanoma: BRAF mutations and beyond.

Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation of melanocyte stem cells. This heterogeneity manifests in diverse biological phenotypes and developmental states, influencing variable responses to treatments. Unveiling the aberrant mechanisms steering melanoma initiation, progression, and metastasis is imperative. Beyond mutations in oncogenic and tumor suppressor genes, the involvement of distinct molecular pathways assumes a pivotal role in melanoma pathogenesis. Ultraviolet (UV) radiations, a principal factor in melanoma etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape of lesions correlates with UV exposure, impacting mutational load and spectrum of mutations. The World Health Organization's 2018 classification underscores the interplay between sun exposure and genomic characteristics, distinguishing melanomas associated with CSD from those unrelated to CSD. The classification elucidates molecular features such as tumor mutational burden and copy number alterations associated with different melanoma subtypes. The significance of the mutated BRAF gene and its pathway, notably BRAFV600 variants, in melanoma is paramount. BRAF mutations, prevalent across diverse cancer types, present therapeutic avenues, with clinical trials validating the efficacy of targeted therapies and immunotherapy. Additional driver mutations in oncogenes further characterize specific melanoma pathways, impacting tumor behavior. While histopathological examination remains pivotal, challenges persist in molecularly classifying melanocytic tumors. In this review, we went through all molecular characterization that aid in discriminating common and ambiguous lesions. Integration of highly sensitive molecular diagnostic tests into the diagnostic workflow becomes indispensable, particularly in instances where histology alone fails to achieve a conclusive diagnosis. A diagnostic algorithm based on different molecular features inferred by the various studies is here proposed.

Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia. METHODS: A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms. RESULTS: Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival. CONCLUSIONS: The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.

Current Trends in Mucosal Melanomas: An Overview.

Primary mucosal melanomas (MMs) are uncommon tumors originating from melanocytes located in the mucous membranes at various anatomic sites within the body. MM significantly differs from cutaneous melanoma (CM) regarding epidemiology, genetic profile, clinical presentation, and response to therapies. Despite these differences, that have important implications for both disease diagnosis and prognosis, MMs are usually treated in the same way as CM but exhibit a lower response rate to immunotherapy leading to a poorer survival rate. Furthermore, a high inter-patient variability can be observed in relation to therapeutic response. Recently, novel "omics" techniques have evidenced that MM lesions have different genomic, molecular, and metabolic landscapes as compared with CM lesions, thus explaining the heterogeneity of the response. Such specific molecular aspects might be useful to identify new biomarkers aimed at improving the diagnosis and selection of MM patients who could benefit from immunotherapy or targeted therapy. In this review, we have focused on relevant molecular and clinical advancements for the different MM subtypes in order to describe the updated knowledge relating to main diagnostic, clinical, and therapeutic implications as well as to provide hints on likely future directions.

High Incidence of Gestational Trophoblastic Disease in a Third-Level University-Hospital, Italy: A Retrospective Cohort Study.

INTRODUCTION: to assess incidence, prognosis and obstetric outcome of patients treated for gestational trophoblastic disease GTD in a twenty-year period. Incidence, prognosis and obstetric outcome of gestational throphoblastic disease. METHODS: retrospective study. RESULTS: Fifty-four cases of GTD: 46 (85.18%) cases of Hydatidiform mole (HM); 8 cases of Persistent Gestational Trophoblastic Neoplasia (GTN) (14.81%): 6/8 cases (75%) GTN not metastatic; 2/8 cases (25%) GTN metastatic. In both cases, the metastases occurred in the lungs. In 3 out of 8 GTN cases (37.5%) a histological picture of choriocarcinoma emerged. The incidence of GTD cases treated from 2000 to 2020 was 1.8 cases per 1000 deliveries and 1.3 cases per 1000 pregnancies. Of the 54 patients, 30 (55.56%) presented showed normal serum hCG levels without the need for chemotherapy. On the other hand, 24 patients (44.44%) developed a persistent trophoblastic disease and underwent adjuvant therapy. The negative prognostic factors that affected the risk of persistence of GTD were: serum hCG levels at diagnosis > 100,000 mUI/ml; characteristic "snow storm" finding at the ultrasound diagnosis; a slow regression of serum hCG levels during follow-up; the persistence of high serum hCG levels (especially if > 1000 mUI/ml one month after suction curettage) that was the main risk factor for resistance to first-line chemotherapy. There were 10 pregnancies in total following treatment. Patients' survival in our study was 100%. DISCUSSION: Although GTD is a rare disease, its incidence was 1.3 cases per 1,000 pregnancies in Sardinia, Italy, higher if compared with mean national and worldwide incidence.

EGFR, KRAS, BRAF, ALK, and cMET genetic alterations in 1440 Sardinian patients with lung adenocarcinoma.

BACKGROUND: Lung cancer is one of the most incident neoplastic diseases, and a leading cause of death for cancer worldwide. Knowledge of the incidence of druggable genetic alterations, their correlation with clinical and pathological features of the disease, and their interplay in cases of co-occurrence is crucial for selecting the best therapeutic strategies of patients with non-small cell lung cancer. In this real-life study, we describe the molecular epidemiology of genetic alterations in five driver genes and their correlations with the demographic and clinical characteristics of Sardinian patients with lung adenocarcinoma. METHODS: Data from 1440 consecutive Sardinian patients with a histologically proven diagnosis of lung adenocarcinoma from January 2011 through July 2016 were prospectively investigated. EGFR mutation analysis was performed for all of them, while KRAS and BRAF mutations were searched in 1047 cases; ALK alterations were determined with fluorescence in situ hybridization in 899 cases, and cMET amplifications in 788 cases. RESULTS: KRAS mutations were the most common genetic alterations involving 22.1% of the cases and being mutually exclusive with the EGFR mutations, which were found in 12.6% of them. BRAF mutations, ALK rearrangements, and cMET amplifications were detected in 3.2, 5.3, and 2.1% of the cases, respectively. Concomitant mutations were detected only in a few cases. CONCLUSIONS: Almost all the genetic alterations studied showed a similar incidence in comparison with other Caucasian populations. Concomitant mutations were rare, and they probably have a scarce impact on the clinical management of Sardinians with lung adenocarcinoma. The low incidence of concomitant cMET amplifications at diagnosis suggests that these alterations are acquired in subsequent phases of the disease, often during treatment with TKIs.

BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas.

Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next-generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may induce immune tolerance into the tumour microenvironment (i.e., by increasing the VEGF production) was poorly associated with mutations in genes that have been related to diminished clinical benefit of the treatment with BRAF inhibitors. Screening for mutations in BRAF and other MAPK genes should be included in the routine diagnostic test for a better classification of SNM patients.

[Breaktrough cancer pain in metastatic prostate adenocarcinoma: a case report.] / Dolore episodico intenso e tumore della prostata metastatico.

The pain associated with frequent secondary bone involvement can negatively affect the quality of life of patients affected by metastatic prostate cancer. Its proper diagnostic framework is important to optimize the treatment. We describe the case of a patient suffering from breaktrough cancer pain treated with sublingual fentanyl.

Complete and Durable Response to Combined Chemo/Radiation Therapy in EGFR Wild-Type Lung Adenocarcinoma with Diffuse Brain Metastases.

Most non-small-cell lung cancer (NSCLC) patients are likely to develop brain metastases during the course of their illness. Currently, no consensus on NSCLC patients' treatment with brain metastasis has been established. Although whole brain radiotherapy prolongs the median survival time of approximately 4 months, a cisplatin-pemetrexed combination may also represent a potential option in the treatment of asymptomatic NSCLC patients with brain metastases. Herein, we report the case of a non-smoker male patient with multiple, large and diffuse brain metastases from an "epidermal growth factor receptor (EGFR) wild-type" lung adenocarcinoma who underwent an overly aggressive chemo/radiation therapy. This approach led to a complete and durable remission of the disease and to a long survival of up to 58 months from diagnosis of primary tumor. The uncommon course of this metastatic disease induced us to describe its oncological management and to investigate the molecular features of the tumor.

The metabolomic scent of cancer disease progression in soft tissue sarcoma: A case report.

BACKGROUND: The purpose of this case report is to describe the potential that metabolomics breath analysis may have in cancer disease monitoring. The advances in mass spectrometry instrumentation allow the accurate real-time analysis of volatile metabolites exhaled in the breath. The application of such non-invasive devices may provide innovative and complementary monitoring of the physio-pathological conditions of cancer patients. CASE PRESENTATION: A 59-year-old Caucasian woman with spindle cell malignant mesenchymal sarcoma of the presacral region started a first-line therapy with non-pegylated liposomal doxorubicin and ifosfamide associated with pelvic radiant treatment. After two cycles of chemotherapy plus radiotherapy, a significant pulmonary disease progression was reported. Thus, a second-line therapy with trabectedin was administered. However, after only two cycles of treatment a re-staging computed tomography scan reported further cancer disease progression of the target pulmonary lesions as well as occurrence of new satellite bilateral nodules. Real-time analysis of breath exhaled volatile organic compounds, performed by select ion flow tube mass spectrometry (SIFT-MS) during the follow-up of the patient, showed a specific metabolic pattern not observed in the breath of other soft tissue sarcoma patients who achieved clinical benefit from the treatments. CONCLUSIONS: This case report revealed the importance of the non-invasive real-time volatile organic compounds breath analysis to distinguish individual specific chemo-resistance phenotypes among soft tissue sarcoma patients. Such observation seems to suggest that breath metabolomics may be particularly useful for monitoring cancer disease progression in soft tissue sarcoma patients where only cost-effective diagnostic tools, such as positron emission tomography and computed tomography, are available.

A new mutation of the CDH1 gene in a patient with an aggressive signet-ring cell carcinoma of the stomach.

Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segregation study in the family detected the same mutation in his healthy 31-year-old brother. The mutation affects one of the extracellular repeat (CAD repeats) domains which is essential for the homophilic binding specificity that directs "E-cadherin" to bind with itself each others. In this case, immunohistochemical analysis showed no expression of E-cadherin in the tumor sample and was a useful prescreening tool to genetic testing. This finding was associated with a poor response to trastuzumab-based treatment.

Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma.

We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m2 given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy.

Grade 4 unclassified renal cell carcinoma with sarcomatoid component expressing S-100 protein. A case report with peculiar diagnostic and therapeutic implications.

Grade 4 unclassified renal cell carcinoma, with a sarcomatoid component (URCCSC) is a rare high grade tumor presumptively derived from all histological subtypes of renal cell carcinoma (RCC). Even though rare, URCCSC generates a great deal of interest, as it is a particularly aggressive variant of RCC, that is poorly responsive to chemo-immunotherapy. Whether it originates from a separate sarcomatoid cell clone within the tumor or from true cell dedifferentiation from RCC has yet to be established. The diagnosis of URCCSC is usually based on morphological and immunohistochemical characteristics of the neoplastic cells which show transitional epithelial/mesenchymal features. In fact, the frequent loss of epithelial markers and gain of mesenchymal phenotypes, can result in difficulties in interpreting diagnostic data. Consequently assigning the optimal therapeutic treatments can be hindered due to this biological "complexity." Here we present the clinicopathological records of a 51 year-old patient who underwent an excision of a periureteral retroperitoneal mass, and whose first pathological diagnosis was malignant peripheral nerve sheath tumor (MPNST). Eleven months after surgery, a CT-scan revealed a local recurrence of the disease. Later on the patient was admitted to our hospital and a systemic, sarcoma-oriented, treatment was initiated. A partial remission was observed but only with a dacarbazine based regimen administered as a third line therapy, after which a second surgery took place. The removed tumor was diagnosed as URCCSC based on the peculiar morphologic and immunohistochemical characteristics of the cells. Pathological assessment of the first intervention was re-evaluated, resulting in a diagnosis of URCCSC. This case-report therefore highlights the implications that an erroneous pathologic diagnosis can have for the clinical management of this disease. Furthermore, the unexpected response to a dacarbazine based regimen, indicates that this drug should be included among the therapeutic options available against this type of renal carcinoma.

Second-line chemotherapy in recurrent clear cell ovarian cancer: results from the multicenter italian trials in ovarian cancer (MITO-9).

BACKGROUND AND AIMS: Ovarian clear cell carcinoma (CCC) has a poorer prognosis than other subtypes of ovarian cancer. In this study, we evaluated the responsiveness to second-line chemotherapy in recurrent ovarian CCC. METHODS: The MITO-9 project investigated a cohort of patients observed between 1991 and 2007 in 20 centers. We identified 72 out of 240 patients with recurrent disease (28% stage I-II and 72% stage III-IV at diagnosis). RESULTS: In 56% of patients, the clear cell histology was pure. Twenty-five patients were platinum-resistant, 18 were platinum-sensitive with a platinum-free interval (PFI) of 6-12 months, and 29 had a PFI >12 months. Upon recurrence, 47% of patients were treated with platinum chemotherapy according to the PFI. The overall response rate (RR) to platinum was 80%, with 55, 100, and 80% RR in patients with PFI of 6-12, >12, and >24 months. The RR to nonplatinum agents in resistant patients was 33%. Among the nonplatinum agents used in primary and secondary resistant cases, gemcitabine, administered in 12 cases, had a higher activity (RR = 66%) compared to topotecan or liposomal doxorubicin (n = 31; RR = 33 and 10%, respectively). CONCLUSIONS: This study showed that the treatment of recurrent ovarian CCC should be based on the PFI as in the other subtypes. Data in platinum-resistant patients suggest gemcitabine as the drug with the highest activity. We recommend that gemcitabine be studied prospectively in a phase 2 trial.

In situ malignant melanoma on nevus spilus in an elderly patient.

Nevus spilus is the term usually given to a pigmented skin lesion, congenital or acquired, that may occur anywhere on the body, consisting of a large light tan patch with numerous superimposed darker scattered maculae or papulae that are flat or slightly raised. For a long time, nevus spilus was believed to be a benign lesion. However, in 1957 Perkinson reported a melanoma appearing on nevus spilus for the first time. Since then other reports about melanomas developing on nevus spilus have been published, sometimes with a fatal outcome. We describe the case of an 80-year-old male patient with a congenital nevus just above his left knee. The lesion had remained unchanged over time, but some months before his checkup the patient noticed a darker area in the lesion that had continued to enlarge. The lesion was removed and histological examination revealed an in situ malignant melanoma. Although nevus spilus is not normally considered a precursor of melanoma, the potentiality of malignant transformation requires regular monitoring, and careful checkups are recommended and justified.

Chemo/tomotherapy stereotactic body radiation therapy (chemo/SBRT) for the salvage treatment of esophageal carcinoma following trimodality therapy: a case report.

BACKGROUND: Esophageal cancer (EC) patients presenting a local recurrence following trimodality therapy (chemoradiaton and surgery) have limited palliative treatment options when the three major modalities of therapy have been exhausted. In addition, some patients experience a local recurrence or develop a metachronous cancer in a previously irradiated site, without evidence of systemic disease. For these patients there is a potential for cure, although the risk of further distant recurrences remains high. CASE REPORT: We report of a successful concomitant chemo/SBRT treatment in a case of locally advanced metachronous squamous cervical EC, which was diagnosed in a patient previously treated with trimodality therapy for a squamous tonsillar carcinoma. RESULT: Chemo/SBRT seems to be a reasonable salvage option for patients without distant metastases who have exhausted standard therapies. CONCLUSIONS: Our experience also suggests that a concomitant chemo/SBRT treatment appears to be either feasible or effective and chemo/SBRT can be considered also in selected patients affected by EC with squamous histology and with neoplastic infiltration of the trachea.

Weekly paclitaxel in heavily pretreated ovarian cancer patients: does this treatment still provide further advantages?

OBJECTIVE: To evaluate the disease control rate (DCR) in heavily pretreated and relapsed ovarian cancer patients re-challenged with a weekly paclitaxel schedule and to establish whether a correlation between dose intensity, progression-free interval (PFI) and overall survival (OS) exists. METHODS: Retrospective data were collected from 30 heavily pretreated metastatic ovarian cancer patients who received 80 mg/m(2)/week paclitaxel regimen. RESULTS: The treatment was well tolerated and showed a DCR in 70% of the patients, with only one case of grade 3 hematological toxicity. One patient (3%) showed a complete response, 15 patients (50%) a partial response and five patients (17%) a stabilization of their disease. The regimen was mostly used as a fourth-line chemotherapy (range 2-7). The median dose intensity in responding patients was 57.5 mg/m(2)/week and in those with progressive disease 49.7 mg/m(2)/week. (p = 0.20). PFI and OS were increased in the responder patient groups with a log-rank test of 25.64 (p < 0.001) and 15.10 (p = 0.0001), respectively. CONCLUSIONS: Weekly administration of paclitaxel was active and well tolerated as a salvage therapy for heavily pretreated ovarian cancer patients.

Fulminant liver failure in a patient affected by polycystic liver disease and liver metastases from breast carcinoma.

BACKGROUND: Polycystic liver disease (PLD) is a rare, congenital, benign condition characterized by the presence of multiple bile-duct-derived epithelial cysts in the liver parenchyma. The disease is usually asymptomatic, but cyst growth can result in complications such as ascites, esophageal varices, jaundice and hepatic failure. The exact mechanism leading to cyst growth is unclear, but estrogenic stimulation and paracrine action of vascular endothelial growth factor (VEGF) are thought to play a role in the growth of cyst epithelium. CASE REPORT: We report a case of acute liver failure in a young woman with PLD and liver metastases from breast carcinoma. RESULTS: No data are available in the literature about metastatic liver involvement in PLD patients affected by breast cancer. The prognosis of patients with liver metastases is generally poor but fulminant liver failure is a very rare occurrence. Estrogen stimulation seems to be a risk factor for breast cancer and severe PLD. In the reported case, the presence of either the cysts or the metastatic lesions may have resulted in more extensive liver damage. CONCLUSIONS: The adoption of drugs selected in relation to their hepatic toxicity together with careful monitoring of liver function is warranted in the management of breast cancer patients affected by PLD, in order to reduce the risk of liver failure.

Successful outcome after combined chemotherapeutic and surgical management in a case of esophageal cancer with breast and brain relapse.

Esophageal cancer (EC) is a highly lethal disease. Approximately 50% of patients present with metastatic EC and most patients with localized EC will have local recurrence or develop metastases, despite potentially curative local therapy. The most common sites of distant recurrence are represented by lung, liver and bone while brain and breast metastases are rare. Usually patients with advanced disease are not treated aggressively and their median survival is six months. We report a woman patient who developed breast and brain metastases after curative surgery. We treated her with a highly aggressive chemotherapeutic and surgical combination resulting in a complete remission of the disease even after 11-year follow-up. We think that in super selected patients with more than one metastasis, when functional status is good and metastases are technically resectable, a surgical excision may be considered as a salvage option and chemotherapy should be delivered to allow a systemic control.