RETRO-TAS, a Retrospective Observational Study of Trifluridine/Tipiracil in Chemorefractory Metastatic Colorectal Cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) is an oral antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue that inhibits cell proliferation following its incorporation into DNA, and tipiracil that helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which inactivates trifluridine. It is approved as a third-line treatment option for patients with metastatic colorectal cancer (mCRC) and is administered at 35 mg/m2 two times daily from day 1 to 5 and from day 8 to 12 every 28 days. The aim of this investigator-initiated retrospective study (RETRO-TAS; NCT04965870) was to document real-world data on the clinical efficacy of FTD/TPI in patients with chemorefractory mCRC. METHODS: The clinical characteristics of patients with mCRC treated with FTD/TPI in 8 Cancer Centres were collected to assess physician's choice in the third or beyond line of treatment as well as the duration of treatment, dose modification, and toxicity. In addition, other important prognostic features related to mCRC such as molecular profile, performance status (PS), and primary site were analyzed. Statistical analysis for progression-free survival (PFS), overall survival (OS), 6-/8-month PFS rate and disease control rate (DCR) along with Cox regression model, Kaplan-Meier curves, and log-rank tests were carried out by using Stata/MP 16.0 for Windows. RESULTS: From October 2018 to October 2021, a total of 200 patients with mCRC and a median age of 67.0 (IQR 58.0, 75.0) years were treated with FTD/TPI. Τhe median follow-up time was 14 months (IQR 7, 23), 158 PDs and 106 deaths were reported at the time of this analysis. Of all the patients, 58% were males and 58% had mCRC at diagnosis. The molecular analysis identified mutations in KRAS (52%), NRAS (5%), HER2 (3.5%), BRAF (3.5%), and MSI (9%). Previous treatments included radical surgery in 51.5% and adjuvant chemotherapy in 39.5% of patients. FTD/TPI was administered in the third- (70.5%), fourth- (17.0%), or fifth-line (12.5%) treatment setting. Serious adverse events related to FTD/TPI included neutropenia (2%), anaemia (1%), thrombocytopenia (0.5%), diarrhoea (0.5%), nausea (0.5%), and fatigue (4%). A reduction of FTD/TPI dose, delay of next cycle initiation, and shorter duration were reported in 25%, 31%, and 14.5% of patients, respectively. Of all the patients 71.5% received FTD/TPI as monotherapy, 24.5% in combination with bevacizumab, and 4.0% with an anti-EGFR agent. The median FTD/TPI treatment duration was 119.5 days and 81% of patients discontinued treatment due to progressive disease. The DCR recorded by investigators' assessment was 45.5%. The median PFS was 4.8 and the median OS was 11.4 months. The 6- and the 8-month PFS rate was 41.4% and 31.5%, respectively. In the multivariate analysis, PS > 1 and presence of liver and lung metastasis were adversely associated with PFS and OS whereas mutational status and tumor sidedness were not. CONCLUSIONS: RETRO-TAS is a real-world observational study that confirms and adds on the findings of the pivotal RECOURSE Phase III study in relation to the efficacy of FTD/TPI in the third-line setting and in all subgroups of patients regardless of mutational status and sidedness.

High grade neuroendocrine carcinoma of the breast, first line and maintenance immunotherapy.

Small cell carcinomas (SCCs) are poorly differentiated neuroendocrine tumors that arise predominantly in the lung and gastrointestinal tract (GIT). Neuroendocrine carcinomas can occur in a variety of extrapulmonary sites throughout the body, including breast, larynx, GIT, prostate, urinary bladder, ovary and cervix. This is a case report of a 55-year-old Asian female patient with metastatic high-grade neuroendocrine carcinoma of unknown origin that responded notably to off-label nivolumab maintenance treatment after first-line carboplatin - etoposide chemotherapy and radiation. After 2 years of nivolumab after platinum-based chemotherapy results from PET-CT showed no residual disease and we proceeded to mastectomy.

Central neurotoxicity induced by trastuzumab emtansine (T-DM1): a case report.

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.

Posterior Reversible Encephalopathy Syndrome Associated with Oxaliplatin Use for Pancreatic Adenocarcinoma.

The posterior reversible encephalopathy syndrome (PRES) was first described by Hinchey's group in 1996 as a reversible vasogenic brain edema on magnetic resonance imaging (MRI). Hypertension represents the most frequent manifestation associated with PRES. In the present report, we present a patient diagnosed with locally advanced pancreatic adenocarcinoma who received 3 cycles of a 5-fluoruracil plus oxaliplatin-based chemotherapy regimen and developed PRES after the third cycle. Several days after receiving the second cycle of FOLFOX chemotherapy, the patient started having episodes of hypertensive crisis (systolic pressure = 180, diastolic pressure = 100), that was controlled with amlodipine, irbesartan, and hydrochlorothiazide. After the administration of the third cycle, this time with the FOLFIRINOX regimen, he appeared lethargic and disoriented in place and time. MRI revealed bilateral areas of signal hyperintensity in the thalamus, hypothalamus, fibers of reticular formation, anterior section of cerebral vermis and a mild edema of left parahippocampal gyrus, with no signs of brain metastases. Ultimately, the patient was diagnosed with PRES syndrome, and he was treated with glucose, 5% saline, thiamine supplementation, levetiracetam (Keppra®), and i.v. dexamethasone. Three weeks later, he gradually became conscious, with cognitive function recovery, and capable of executing movements.

Correlation between LGR5 stem cells and location of tumor as well as age, sex and metastasis in colon adenocarcinoma.

PURPOSE: G-protein receptors belong to a large family of receptors which includes more than 800 kinds. An interest for these receptors arose upon noticing their expression on skin, intestine and breast stem cells. METHODS: We examined the tissues of 53 patients who had been diagnosed with adenocarcinoma of the colon. There were no exclusion criteria. We measured the expression levels of LGR5 by immunohistochemistry and we correlated those and the location of the colon primary tumor with the age, sex and the metastatic potential. RESULTS: The median values of the two groups- the orthosigmoid and the other colon location- were 1 and 3.5 respectively with no statistical significance and with p=0.132. Spearman Rho indicated no statistical significance between the expression of LGR5 and age with p=0.219. Moreover, the Mann-Whitney U test showed no statistical significance between LGR5 and sex with p=0.778. Fisher's test, however, showed a statistically significant result between metastasis and expression of LGR5 with p=0.025. CONCLUSION: It becomes apparent that patients with increased expression of these two markers are characterized by a more aggressive form of the disease with an increased rate of metastasis. Also, interactions on both paths lead to a simultaneous overexpression, thus proving the diversity of carcinogenic pathways. Racial and other factors are not affected, and ultimately the need to target these indicators in treatment protocols is imperative.

Spot urine albumin to creatinine ratio outperforms novel acute kidney injury biomarkers in patients with acute myocardial infarction.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication in patients hospitalized for acute myocardial infarction (AMI), and is associated with in-hospital and long-term morbidity and mortality. We prospectively assessed the diagnostic performance of spot urine albumin to creatinine ratio (uACR) in an adequately sized multicenter cohort of patients admitted to hospital with AMI. We further compared uACR to novel renal injury associated biomarkers regarding their diagnostic ability. METHODS: We enrolled 805 consecutive patients presenting with acute ST-elevation and non-ST elevation AMI. Patients were assessed for presence of AKI at 48h post-admission and at hospital discharge using the Acute Kidney Injury Network (AKIN), the Acute Dialysis Quality Initiative [Risk, Injury and Failure (RIFLE)] criteria and the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Blood and urine sampling for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin-C, and uACR assessment was performed during admission. RESULTS: The predictive accuracy of uACR was good (Area Under the Curve (AUC), 0.725; 95% CI 0.676-0.774) and was better compared to urine NGAL (P=0.007), urine (P<0.001) and plasma Cystatin-C (P=0.001). ROC analysis identified concentrations of ≥66.7µg/mg as having the best diagnostic accuracy. The use of uACR exhibited good discriminating ability independent to possible cofounders and additive regarding the use of novel biomarkers. CONCLUSIONS: The use of uACR can easily be applied in the clinical setting, allows for robust risk assessment and offers the potential to improve the management of AMI patients at risk for acute kidney injury.