An Italian real-world multicenter study of patients with advanced mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) of the gastro-entero-pancreatic system treated with chemotherapy.

PURPOSE: The aim of this study is to describe the clinical management of an Italian series of patients with advanced gastro-entero-pancreatic (GEP) MiNENs treated in clinical practice. METHODS: Clinical records of patients from four Italian referral Centers were retrospectively analyzed to correlate clinical/biological data with clinical outcomes. All the surgical specimens were centrally reviewed. RESULTS: Clinical data and surgical samples of 51 patients during 1995-2015 were analyzed. Sites of origin were: 32 colorectal, 14 gastro-esophageal, and 5 pancreatobiliary. Twenty-one out of fifty-one (42.2%) developed metachronous distant metastases. Only 5/51 (9.8%) patients received peri-operative therapy, and 23/51 (45.1%) first-line chemotherapy, mostly fluoropyrimidines/oxaliplatin. The NEN component was poorly differentiated in the whole population. Patients with Ki67 index < 55% in the NEC component had a significantly longer median overall survival (OS) (35.3 months; 95% CI 27.1-41.0) than those with Ki67 ≥ 55% (11.9 months; 95% CI 9.1-14.0) P = 0.0005. The median OS was 14 months (95% CI 10.1-19.1) in the whole cohort, with 11.4 months (95% CI 6.2-20.2) in patients who received a first-line therapy. CONCLUSION: This study confirms that GEP-MiNENs represent a complex disease and that over the past years the clinical management has been predominantly guided by the subjective judgment of the clinicians. Although, in this series, the NEC component appeared mostly responsible for the systemic spread and prognosis on the whole neoplasm, the lack of strong prognostic and predictive factors universally recognized seems to condition their management so far. Future prospective clinical and biomolecular studies could help clinicians to improve clinical management of GEP-MiNENs.

Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

Tumor Antigenicity and a Pre-Existing Adaptive Immune Response in Advanced BRAF Mutant Colorectal Cancers.

The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8- tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade.

Prognostic role of hematologic parameters of metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Hemochrome parameters at the diagnosis of metastatic renal cell carcinoma (mRCC) and the development of macrocytosis during sunitinib therapy are considered prognostic. OBJECTIVE: To evaluate the prognostic role of hematologic parameters and macrocytosis in mRCC treated with sunitinib. METHODS: We analyzed clinical data of 100 patients with mRCC treated with sunitinib as first-line therapy in a retrospective multicenter study. We calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) at baseline and erythrocyte mean corpuscular volume (MCV) during therapy. We considered the following cutoffs: NLR >3, PLR >150, LMR <3, and MCV >100 fl. Clinical data histology, prior nephrectomy, Fuhrman grading, metastatic sites, Memorial Sloan-Kettering Cancer Center score, and Heng score were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariate and multivariate analysis using Cox regression model with time-dependent (macrocytosis) covariate were applied. RESULTS: At the univariate analysis, low LMR was associated with shorter PFS and OS (p = 0.02 and p = 0.06, respectively). High PLR was associated with worse PFS (p = 0.005); median OS was 23 vs 28 months (p = 0.13). At the multivariate analysis, poor risk (Heng score), low LMR, and high PLR were associated with shorter PFS (hazard ratio 7.1, 1.5, and 2, respectively); poor PS and poor risk (Heng score) were related to worst OS. Macrocytosis was observed in 26 patients and was not prognostic of survival. CONCLUSIONS: In our cohort of patients with mRCC treated with sunitinib, low LMR (>3) and high PLR (>150) were associated with shorter PFS. Macrocytosis was not prognostic.

Risk of venous and arterial thromboembolic events in women with advanced breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta-analysis.

BACKGROUND: Cyclin-dependent kinase inhibitors (CDKIs) may increase the risk of thrombotic events of endocrine therapy (ET) in women with hormone-sensitive, HER2-negative advanced breast cancer (BC). Aim of our systematic review is the estimate of the risk of venous and arterial thromboembolism in women with advanced BC treated with CDKIs in phase III randomized controlled trials (RCTs). METHODS: Studies were identified by electronic search of MEDLINE, EMBASE and CENTRAL database until October 2021. Risk of bias was assessed according to Cochrane criteria. Differences in thrombotic outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI), which were calculated using both a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I2 statistic. RESULTS: We included 7 phase III RCTs (4415 patients) for a total of 15 papers (7 were the first published paper and 8 the follow-up papers). Reporting of thrombotic events was at high risk of bias. Women with advanced BC treated with CDKIs and ET had a two to threefold increased risk of venous thromboembolic event (VTE) compared to ET plus placebo arm [OR 2.90 (95% CI 1.32, 6.37; I2 = 0%) in the main papers and OR 2.20 (95% CI 0.93, 5.20; I2 = 49%) in the follow-up papers]. Women with advanced BC treated with CDKIs and ET had a non-significant mild increased risk of arterial thromboembolic event compared to ET plus placebo arm [OR 1.22 (95% CI 0.47, 3.18 I2 = 0%)]. CONCLUSIONS: CDKIs in combination with endocrine therapy are associated with a two to threefold higher risk of VTE in comparison to endocrine therapy alone in women with advanced breast cancer, while the risk of arterial events is still to be defined.

Intestinal metastasis from breast cancer: Presentation, treatment and survival from a systematic literature review.

BACKGROUND: Intestinal metastases from breast cancer (BC) arerare; available data depend mainly on case reports and case series. AIM: To conduct a review of the literature regarding presentation, diagnosis, treatment and survival of patients with intestinal metastasis from BC. METHODS: We identified all articles that described patients with intestinal metastasis (from duodenum to anum) from BC using MEDLINE (1975 to 2020) and EMBASE (1975 to 2020) electronic databases. RESULTS: We found 96 cases of intestinal metastasis of BC. Metastasization involved large bowel (cecum, colon, sigmoid, rectum) (51%), small bowel (duodenum, jejunum, ileum) (49%), and anum (< 1%). Median age of patients was 61-years. The most frequent histology was infiltrating lobular carcinoma followed by infiltrating ductal carcinoma. In more than half of patients, the diagnosis was made after the diagnosis of BC (median: 7.2 years) and in many cases of emergency, for bowel obstruction, bleeding or perforation. Diagnosis was achieved through endoscopy, radiological examination or both. In most of the cases, patients underwent surgery with or without systemic therapies. Survival of patients included in this review was available in less than 50% of patients and showed an overall median of 12 mo since diagnosis of the intestinal metastasis. CONCLUSION: Although, intestinal metastases of BC are considered a rare condition, clinicians should consider the possibility of intestinal involvement in case of abdominal symptoms even in acute setting and many years after the diagnosis of BC, especially in patients with a histology of lobular carcinoma.

Abiraterone acetate and acute leukemia: a casual association?

We present the case of a 70-year-old patient affected by metastatic castration-resistant prostate cancer. He underwent radical prostatectomy in 2007 and subsequent adjuvant radiotherapy and hormonal therapy for 2 years. In 2011, he developed bilateral lung metastases, and therefore he received chemotherapy (eight cycles of docetaxel 75 mg/sqm every 3 weeks) with partial remission; rechallenge with the same drug was performed 7 months later due to recurrence of lung metastases. In August 2013, abiraterone acetate was started for progression of lung metastases. The patient received abiraterone for almost 5 years with stability of disease. During the 60th cycle of abiraterone, a diagnosis of acute myeloid leukemia was made.

Baseline PET as prognostic index in diffuse large B-cell lymphoma and grade IIIb follicular lymphoma: a retrospective study of a single-center experience.

BACKGROUND: International guidelines support performing baseline positron emission tomography (PET) in lymphoma. Metabolic tumor volume (MTV) measurement has been proposed as a good measurement of disease burden. We investigated if MTV at baseline PET can be predictive of complete response (CR) to first line standard chemotherapy in diffuse large B-cell lymphoma (DLBCL) and in follicular lymphoma (FL) grade IIIb. METHODS: We retrospectively analyzed data on 54 consecutive patients with DLBCL and FL grade IIIb treated in our institution. Dedicated software automatically estimated the SUVmax of the most active lesion and the MTV of the entire lesion burden using an isocontour threshold method set at 42% (MTV42) and 28% (MTV28) of the SUVmax. In addition, the ratio value (MTV28/MTV42) was calculated. Every group of lesions was evaluated separately. All patients were treated with R-CHOP-21. We performed a univariate and a multivariate logistic regression analysis to explore any possible association between PET parameters and CR. RESULTS: At the univariate logistic regression analysis, patients with a MTV28 lower than the median value (173.1) had an odds ratio (OR) of 4 (95% CI: 0.94-16.9) of obtaining a CR in comparison to patients with a MTV 28 higher than the median value; patients with a MTV42 lower than the median value (i.e. 85.6) had an OR of 3.63 (95% CI: 0.85-15.34) of obtaining a CR in comparison to patients with a MTV 42 equal or higher than the median value. Using MTV28/MTV42 value with median as cut-off instead of MTV28, patients with a MTV28/MTV42 lower than the median value (i.e. 1.81) had an OR of 4.26 (95% CI: 0.72-25.07) and of 7.54 (95% CI: 0.70-80.91) of obtaining a CR in comparison to patients with a MTV28/MTV42 equal or higher than the median value in the two models, respectively. CONCLUSIONS: The results of our study suggest that MTV could be a useful tool to predict response to R-CHOP in patients affected with DLBCL and FL grade IIIb and that a multi-parameters evaluation should be considered.

Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study.

BACKGROUND: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking. METHODS: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months). RESULTS: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences. CONCLUSION: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study.

BACKGROUND: Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis. PATIENTS AND METHODS: From January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed. RESULTS: We evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively). CONCLUSIONS: Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.

BRAF Mutation in Colorectal Rhabdoid and Poorly Differentiated Medullary Carcinomas.

Colorectal rhabdoid carcinomas (CRbCs) are very rare and aggressive cancers. The BRAFmutation and CpG island methylator phenotype have been reported to be common features ofCRbCs. This study reviews the literature about CRbCs and analyzes the clinicopathological andmolecular profiles of seven CRbCs characterized by large discohesive cells with abundanteosinophilic cytoplasm, showing hyaline inclusions and large rounded to bean-shaped nuclei. Forcomparison, we included four poorly differentiated medullary carcinomas (PDMCs) with focalaspects mimicking rhabdoid features. Overall survival was poor in both subsets, with 78% ofpatients dying of disease within 2-11 months. The main features of CRbCs were: Loss of/reduced SMARCB1/INI expression, intense vimentin immunostaining, and dense neutrophilic infiltration. The PDMCs were positive for pancytokeratin but negative for vimentin and showed moderate peritumoral/intratumoral CD8+ lymphocytes. All PDMCs showed SMARCB1(INI-1) expression. The coexistence of BRAF and TP53 mutations was observed in 80% of CRbCs and PDMCs. PDMCs always showed microsatellite instability and CpG island methylator phenotype (CIMP), while CRbCs were CIMP negative and exhibited microsatellite instability (MSI) in two out of seven cases. CRbCs are characterized by BRAF and TP53 mutations. Loss/reduced expression of nuclear SMARCB1/INI, intense vimentin immunostaining, dense neutrophilic infiltration, and low frequency of CIMP are useful markers to recognize these rare aggressive tumors.

Neuroendocrine Differentiation, Microsatellite Instability, and Tumor-infiltrating Lymphocytes in Advanced Colorectal Cancer With BRAF Mutation.

BACKGROUND: Approximately 10% of metastatic colorectal cancer (mCRC) cases will harbor the BRAF p.V600E mutation (BRAF-mCRC) and have been associated with a poor prognosis. Although they are usually considered a unique clinical entity, biologic heterogeneity has been described. We performed an extensive clinicopathologic study of a multicenter series of BRAF-mCRC to highlight differences between tumors with microsatellite instability (MSI) and microsatellite stable tumors, focusing on both inflammatory profiles and neuroendocrine differentiation. METHODS: We included 59 BRAF-mCRC cases and collected the clinical data (ie, surgery, treatment, and follow-up). We evaluated MSI status, budding, lympho-angioinvasion, neuroinvasion, extent of active stroma, CD3+ and CD8+ intratumoral and peritumoral lymphocytes, programmed cell death ligand 1, p53, Ki-67, synaptophysin, and CDX2 expression. RESULTS: The 22 MSI BRAF-mCRC cases were associated with the right side (P < .0001), an expansive grown pattern (P < .01), programmed cell death ligand 1 expression (P < .0001), high CD8 T-cell content (P = .0001), and lymph node metastases (P < .029). The 37 MSS BRAF-mCRC cases were characterized by a greater stromal component (P = .0002), pulmonary metastases (P = .095), and p53 and synaptophysin immunoreactivity (P = .004 and P = .001, respectively). Univariate analysis demonstrated that MSI and a high CD8 T-cell content were associated with a 34% (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.34-1.28; P = .2) and 33% (HR, 0.67; 95% CI, 0.45-0.99; P = .04) reduction in the risk of death, respectively. The combined presence of MSI and CD8 T-cell content decreased the hazard of mortality ≤ 63% (HR, 0.37; 95% CI, 0.14-0.97; P = .2), which was slightly reduced after multivariate analysis. CONCLUSION: A simultaneous evaluation of MSI, CD8 T-cell content, and neuroendocrine markers could allow for the identification of subsets of BRAF-mCRC with a different prognosis and potential eligibility for specific treatments.

Rectovaginal fistula during treatment with axitinib in a patient with renal cell carcinoma: a case report and review of the literature.

Renal cell carcinoma (RCC) is one of the most frequent malignancies of the adults. Its incidence has been increasing steadily by 2-4% each year. Up to 30% of patients present with metastases at diagnosis. It is a highly vascularized cancer because of the hypoxia-induced factor stabilization as a consequence of von Hippel-Lindau inactivation. Hypoxia-induced factor accumulation leads to transactivation of molecules involved in angiogenesis including vascular endothelial growth factor (VEGF) and platelet-derived growth factor. Sunitinib is an oral tyrosine kinase inhibitor that interacts with several angiogenesis receptors including platelet-derived growth factor receptors and VEGF receptors, and is approved for the first-line treatment in metastatic RCC. In terms of tolerability, patients treated with sunitinib showed a higher incidence of diarrhea, vomiting, hypertension, hand-foot syndrome, and neutropenia, a safety profile consistent with what had been observed in earlier phase studies. Axitnib is a potent and selective tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3, and is approved in the second-line setting for patients with metastatic RCC. The tolerability profile of axitinib is favorable. The most commonly reported treatment-related adverse events are diarrhea, hypertension, fatigue, nausea, and dysphonia. Bowel toxicity, especially pneumatosis intestinalis and bowel perforation, is very uncommon. In particular, the incidence of intestinal perforation or fistulae is not well known for sunitinib or axitinib. Here, for the first time, we report the incidence of rectovaginal fistula in a 57-year-old White woman, with RCC, following treatment with sunitinib and axitinib.

Poorly Differentiated Neuroendocrine Carcinoma of the Sigmoid Tract in Long-Standing Ulcerative Colitis: Report of a Case and Review of the Literature.

A 37-year-old male with long-standing and extensive ulcerative pancolitis developed a rapidly lethal poorly differentiated neuroendocrine carcinoma (NEC) in the sigmoid colon. Prior biopsies obtained from multiple sites of the colon during endoscopic surveillance showed minimal inflammatory changes and no sign of dysplasia. Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies, and adenocarcinoma is the most common type of colorectal neoplasm associated with ulcerative colitis and Crohn's disease, but other types of epithelial and nonepithelial tumors have also been described in IBD. NECs arising in the setting of ulcerative colitis are very rare and are reported as anecdotic findings. We describe the clinicopathological features of an IBD-related NEC and review the previously reported cases.

Biopsy and re-biopsy in lung cancer: the oncologist requests and the role of endobronchial ultrasounds transbronchial needle aspiration.

As the leading cause of death worldwide, lung cancer has proven itself incurable in the advanced stages. For early stages, endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) is now considered the standard to assess mediastinal lymph node, to define the multimodality therapeutic approach. In recent years, EBUS-TBNA has extended its use also in the metastatic and locally recurrent disease. New molecules, with specific mutations that give resistance to current target therapies, have made re-biopsy at disease progression an important assessment, with therapeutic and clinical implication. Here we present the oncologist's point of view on EBUS-TBNA in the staging process, at recurrence and progression.