Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study

Hyperselection; Metastatic colorectal cancerHiperselección; Cáncer colorrectal metastásicoHiperselecció; Càncer colorectal metastàticPurpose: To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. Experimental Design: The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case–control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group. Results: PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. Conclusions: PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting.This study was supported by AIRC IG 23624 (to F. Pietrantonio), and by the NIH Cancer Center Core Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center

Laparoscopic surgery does not reduce the need for red blood cell transfusion after resection for colorectal tumour: a propensity score match study on 728 patients

Background: Patients with colorectal tumour often present with anaemia, and up to 60% will receive red blood cells (RBC) transfusion. Some evidence suggests a correlation between RBC transfusion and worse outcomes. Since laparoscopy minimizes intraoperative blood loss, we retrospectively investigated its role in reducing haemoglobin (Hb) drop and requirements for postoperative RBC transfusions. Methods: Patients were identified from consecutive cases undergone elective surgery for non-metastatic colorectal tumour between 2005 and 2019. Laparoscopic cases were matched 1:1 with open controls through propensity score matching (PSM). The main outcome measures were postoperative Hb drop and requirement for RBC. The secondary aim was evaluation of risk factors for postoperative RBC transfusions. Results: After application of PSM, 364 patients treated by laparoscopy were matched with 364 patients undergone open surgery. The two groups presented similar clinical and pathological characteristics, as well as comparable postoperative outcomes. 56 patients in the open group and 47 in the laparoscopic group required postoperative RBC (P = 0.395). No difference was observed in terms of mean number of RBC units (P = 0.608) or Hb drop (P = 0.129). Logistic regression analysis identified preoperative anaemia and occurrence of postoperative complications as relevant risk factors for postoperative RBC transfusion, while surgical approach did not prove statistically significant. Conclusion: Laparoscopy did not influence postoperative requirements for RBC transfusions after elective colorectal surgery. Preoperative anaemia and occurrence of postoperative complications represent the major determinants for postoperative transfusions after open as well as laparoscopic surgery

EPSILoN score: Validation cohort of a prognostic score in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy

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Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect &gt;= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

Long-Lasting Efficacy of Radio Electric Asymmetric Conveyer Neuromodulation Treatment on Functional Dysmetria, an Adaptive Motor Behavior

BackgroundFluctuating asymmetry (FA) is widely defined as the deviation from perfect bilateral symmetry and is considered an epigenetic measure of environmental stress. Rinaldi and Fontani hypothesized that the FA morpho-functional changes originate from an adaptive motor behavior determined by functional alterations in the cerebellum and neural circuits, not caused by a lesion, but induced by environmental stress. They called this phenomenon functional dysmetria (FD). On this premise, they developed the radio electric asymmetric conveyer (REAC) technology, a neuromodulation technology aimed at optimizing the best neuro-psycho-motor strategies in relation to environmental interaction.AimsPrevious studies showed that specific REAC neuro postural optimization (NPO) treatment can induce stable FD recovery. This study aimed to verify the duration of the NPO effect in inducing the stable FD recovery over timeMaterials and methodsData were retrospectively collected from a population of 29,794 subjects who underwent a specific semiological FD assessment and received the NPO treatment, regardless of the pathology referred.ResultsThe analysis of the data collected by the various participants in the study led us to ascertain the disappearance of FD in 100% of the cases treated, with a stability of the result detected up to 18 years after the single administration of the REAC NPO treatment.ConclusionsThe REAC NPO neurobiological modulation treatment consisting of a single administration surprisingly maintains a very long efficacy in the correction of FD. This effect can be explained as the long-lasting capacity of the NPO treatment to induce greater functional efficiency of the brain dynamics as proven in previous studies

Thrombocytopenias: a clinical point of view

The finding of thrombocytopenia may sometimes be a warning sign of high-risk situations requiring swift therapeutic decisions. The diagnosis must start with the patient\u2019s history and data, with a careful evaluation of all blood counts and confirmation of the thrombocytopenia, followed by a morphological evaluation of the peripheral blood smear which, together with objective clinical findings, such as bleeding, lymphadenopathy and splenomegaly, will indicate the need for immediate therapy or appropriate further diagnostic investigations. Thrombocytopenia occurring in surgical patients can basically be attributed to DIC or HIT: the differential diagnosis is made on the basis of the correct laboratory investigations. In our opinion, the possibility of an ongoing pregnancy should always be evaluated in thrombocytopenic women of childbearing age, since a confirmed pregnancy implies that clinical forms of strictly obstetric pertinence are also possible. In conclusion, the overall picture of thrombocytopenias is extremely variegated, leading to numerous diagnostic and therapeutic problems whose solutions require close collaboration between clinicians and laboratory specialists

The Evaluation of Response to Immunotherapy in Metastatic Renal Cell Carcinoma: Open Challenges in the Clinical Practice

Immunotherapy has changed the therapeutic scenario of metastatic renal cell carcinoma (mRCC), however the evaluation of disease response to immune-checkpoint inhibitors is still an open challenge. Response evaluation criteria in solid tumors (RECIST) 1.1 criteria are the cornerstone of response assessment to anti-neoplastic treatments, but the use of anti-programmed death receptor 1 (PD1) and other immunotherapeutic agents has shown atypical patterns of response such as pseudoprogression. Therefore, immune-modified criteria have been developed in order to more accurately categorize the disease response, even though their use in the everyday clinical practice is still limited. In this review we summarize the available evidence on this topic, with particular focus on the application of immune-modified criteria in the setting of mRCC

Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective

19noNeuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.openopenMichele Prisciandaro, Maria Antista, Alessandra Raimondi, Francesca Corti, Federica Morano, Giovanni Centonze, Giovanna Sabella, Alessandro Mangogna, Giovanni Randon, Filippo Pagani, Natalie Prinzi, Monica Niger, Salvatore Corallo, Erica Castiglioni di Caronno, Marco Massafra, Maria Di Bartolomeo, Filippo de Braud, Massimo Milione, Sara PuscedduPrisciandaro, Michele; Antista, Maria; Raimondi, Alessandra; Corti, Francesca; Morano, Federica; Centonze, Giovanni; Sabella, Giovanna; Mangogna, Alessandro; Randon, Giovanni; Pagani, Filippo; Prinzi, Natalie; Niger, Monica; Corallo, Salvatore; Castiglioni di Caronno, Erica; Massafra, Marco; Di Bartolomeo, Maria; de Braud, Filippo; Milione, Massimo; Pusceddu, Sar