Personalized First-Line Treatment of Metastatic Pancreatic Neuroendocrine Carcinoma Facilitated by Liquid Biopsy and Computational Decision Support.

BACKGROUND: We present the case of a 50-year-old female whose metastatic pancreatic neuroendocrine tumor (pNET) diagnosis was delayed by the COVID-19 pandemic. The patient was in critical condition at the time of diagnosis due to the extensive tumor burden and failing liver functions. The clinical dilemma was to choose between two registered first-line molecularly-targeted agents (MTAs), sunitinib or everolimus, or to use chemotherapy to quickly reduce tumor burden. METHODS: Cell-free DNA (cfDNA) from liquid biopsy was analyzed by next generation sequencing (NGS) using a comprehensive 591-gene panel. Next, a computational method, digital drug-assignment (DDA) was deployed for rapid clinical decision support. RESULTS: NGS analysis identified 38 genetic alterations. DDA identified 6 potential drivers, 24 targets, and 79 MTAs. Everolimus was chosen for first-line therapy based on supporting molecular evidence and the highest DDA ranking among therapies registered in this tumor type. The patient's general condition and liver functions rapidly improved, and CT control revealed partial response in the lymph nodes and stable disease elsewhere. CONCLUSION: Deployment of precision oncology using liquid biopsy, comprehensive molecular profiling, and DDA make personalized first-line therapy of advanced pNET feasible in clinical settings.

Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer.

PURPOSE: Oral mucositis (OM) is a frequent and painful sequela of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in patients with HNC. METHODS AND MATERIALS: Patients with HNC undergoing adjuvant radiation therapy (60-66 Gy; 5 × 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 µg (n = 56), 100 µg (n = 65), or placebo (n = 62) via a topical mucobuccal tablet starting 1 to 3 days before and continuing during treatment. The primary endpoint was the incidence of severe OM (severe OM [SOM], World Health Organization grade 3/4). RESULTS: SOM developed in 45% versus 60% (P = .06) of patients treated with clonidine compared with placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; hazard ratio, 0.75 [95% confidence interval, 0.484-1.175], P = .21); median time to onset was 45 versus 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% versus 98.4%, nausea in 49.6% versus 71.0%, dysphagia in 32.8% versus 48.4%, and reversible hypotension in 6.7% versus 1.6% of patients on clonidine versus placebo, respectively. CONCLUSIONS: Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably affect the course and severity of CRT-induced SOM and support further evaluation.

Patritumab or placebo, with cetuximab plus platinum therapy in recurrent or metastatic squamous cell carcinoma of the head and neck: A randomised phase II study.

BACKGROUND: The fully human monoclonal antibody patritumab blocks HER3 activation, a resistance mechanism to cetuximab, induced by heregulin (HRG). A phase Ib study in recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) demonstrated tolerability and tumour response of patritumab + cetuximab + platinum. METHODS: This was a randomised, double-blind, phase II study of patritumab + cetuximab with platinum-based therapy for first-line treatment of R/M SCCHN (Clinicaltrials.gov identifier: NCT02633800). Patients aged ≥18 years received patritumab or placebo, both combined with cetuximab + cisplatin or carboplatin. Co-primary end-points were progression-free survival (PFS) in the intent-to-treat (ITT) and the high-expression HRG (HRG high) populations. RESULTS: Eighty-seven patients (n = 43 in the patritumab group; n = 44 in placebo group) enrolled. A median (range) of 6.5 (1-24) patritumab cycles were completed. Median PFS was similar between the patritumab group and placebo group in the ITT population (5.6 versus 5.5 months; hazard ratio [HR] 0.99 [95% confidence interval [CI], 0.6-1.7]; P = 0.96) and HRG-high subgroup (n = 51; 5.6 versus 5.6 months; HR 0.93 [95% CI, 0.5-1.8]; P = 0.82). Median overall survival in the ITT population was also similar (10.0 versus 12.7 months; HR 1.3 [95% CI, 0.69-2.29]; P = 0.46). All patients experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥III TEAEs were more frequent in the patritumab than the placebo group (84.1% versus 60.5%). The most common grade ≥III patritumab-related TEAE in the patritumab group (20.5% overall) was rash (6.8%). CONCLUSION: Patritumab + cetuximab + platinum was tolerable but not superior to cetuximab + platinum.

Capecitabine in Combination with Docetaxel in First Line in HER2-Negative Metastatic Breast Cancer: an Observational Study.

Due to the limited experience with capecitabine plus docetaxel (XT) combination in the first-line treatment of metastatic breast cancer in Hungary, the main objective of the study was to analyze the effectiveness and tolerability of XT therapy. A prospective, open-label, non-randomized, single-arm, multicenter, observational study was designed. All female patients were eligible whose metastatic breast cancer could be treated with the XT protocol according to the summary of product characteristics of the drugs. The median progression free survival was 9.9 ± 3.0 months. Time to treatment failure was 4.6 ± 5.1 months on average. The overall response rate was 28.9 %, the clinical benefit rate was 73.3 %. The treatment was discontinued in 35.6 % of patients due to disease progression and in 20.0 % due to adverse events (AE). 33 patients with a total of 73 AEs have been reported, and 13 of them had serious adverse events (SAE). The efficacy and the safety profile of XT chemotherapy proven in the study are consistent with the results demonstrated in randomized trials. First-line XT chemotherapy effectively improves the PFS in metastatic breast cancer.

[Systemic therapy of breast cancer: practice guideline]. / Az emlõrák szisztémás kezelése: szakmai útmutatás.

The article presents the practice guideline of systemic treatment of breast cancer and recommendations of the 3rd Hungarian Breast Cancer Consensus Conference. It reflects the recent international guidelines (ESMO, NCCN, ABC2, St Gallen's) irrespectively of the current financial opportunities. Here we follow the early - locally advanced - locally relapsed - metastatic breast cancer line for didactic considerations and we discuss the different subgroups of breast cancer based on hormone receptor and HER2 receptor status. Diagnosis and treatment options of rare clinical entities are summarised at the end of the paper.

Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer.

OBJECTIVE: This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC). MATERIALS AND METHODS: Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR). RESULTS: 155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation. CONCLUSION: Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS.

miRNA expression profiles of oral squamous cell carcinomas.

BACKGROUND: Oral squamous cell carcinoma (OSCC) development involves complex machinery of genomic and epigenetic regulations including microRNA (miRNA) expression changes. We aimed to analyze the expression patterns of a set of miRNAs in human TNM stage I and II OSCC samples in an autologous normal mucosa-controlled experimental design. MATERIALS AND METHODS: Forty samples of OSCC and 40 matched normal tissues were evaluated for miR-21, miR-155, miR-191, miR-146a, miR-221 and miR-222 expression in a LightCycler 480(PCR) system. RESULTS: Our results showed significant overexpression of miR-21, miR-155, miR-191 and miR-221 in paired-sample t-test and the sensitivity/specificity of tests were over 90% in the case of miR-21 and miR-155 on the receiver operating characteristic curve (ROC) analysis. CONCLUSION: Our results underline the role of miR-21 in OSCC and support the possible causal role of miR-155 and miR-221 in oral carcinogenesis. The overexpression of miR-191 is a novel finding in squamous cell carcinoma.

[Impact of microRNAs on molecular epidemiology]. / Mikro-RNS-ek jelentosége a molekuláris epidemiológiában.

Cancer research concerning short non-coding RNA sequences and functionally linked to RNA interference (RNAi) have reached explosive breakthrough in the past decade. Molecular technology applies microRNA in extremely wide spectrum from molecular tumor prediction, diagnostics, progression monitoring and prevention. Functional analysis of tissue miRNA and cell-free serum miRNA in posttranscription and translation regulation innovated and restructured the knowledge on the field. This review focuses on molecular epidemiology and primary prevention aspects of the small non-coding RNA sequences.

Effects of isoflurane on Nfκb p65, Gadd45a and Jnk1 expression in the vital organs of CBA/CA mice.

BACKGROUND: Isoflurane is administered to patients during general anaesthesia to diminish the effects of surgical invasion. MATERIALS AND METHODS: CBA/CA mice were exposed to 2% isoflurane during general anaesthesia. Gene expressions were measured 6 and 12 hours later by quantitative real-time PCR on total RNA isolated from the lung, liver and kidneys of the animals. Expressions of growth arrest and DNA-damage-inducible 45 alpha (Gadd45 α), Jun N-terminal kinase 1 (Jnk1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells p65 subunit (Nfκb p65) were analyzed. RESULTS: Gadd45α and Jnk1 showed significant inverse expression changes in the different tissues compared to the Nfκb p65. The length of anaesthesia also modified the gene induction. CONCLUSION: Isoflurane has significant modulatory effect on the transcription of genes regulating inflammation and apoptotic signalling.

Heterogeneity of pT3 colorectal carcinomas according to the depth of invasion.

Colorectal carcinomas (CRCs) infiltrating through the muscularis propria layer without infiltration of adjacent structures, organs or the serosa-i.e. the pT3 tumors, compose the largest subset of large intestinal carcinomas treated by surgical resection. They are heterogeneous in terms of prognosis. CRCs treated by surgery in a period of 69 months were prospectively classified as pT3a tumors (invading to a maximum of 5 mm beyond the muscularis propria) and pT3b tumors (invading deeper). Their nodal status, incidence of vascular invasion and the presence or absence of distant metastases were analyzed in relation to the depth of invasion. Of the 593 CRCs primarily treated by surgery 429 were pT3 tumors. CRCs categorized as pT3a had significantly lower rates of nodal involvement (44% vs 75%), massive nodal involvement (pN2) (9% vs 39%), venous invasion (17% vs 30%) and distant metastasis (11% vs 28%) than pT3b tumors. Significant differences in these prognostic variables in pT3a and pT3b cancers were observed both for carcinomas of the colon and those of the rectum. Such differences were not obvious in further 66 ypT3 cases of rectal carcinoma receiving neoadjuvant treatment before surgery. Tumors in the pT3a category are associated with a better prognostic profile than pT3b tumors. This subdivision might be useful in both prognostication and treatment planning.

Polymorphisms of glutathione-S-transferase and arylamine N-acetyltransferase enzymes and susceptibility to colorectal cancer.

BACKGROUND: Glutathione-S-transferases (GSTs) and N-acetyltransferases (NATs) are involved in the metabolism of a wide range of carcinogenic chemicals. Allelic polymorphism of these enzymes is associated with variations in enzyme activity, hence it may affect the concentration of activated carcinogenic chemicals in the body. Previous studies suggest a possible cancer risk-modifying effect of these allelic polymorphisms, but the results are still controversial. We evaluated the effect of GSTM1, GSTT1, GSTP1, NAT1 and NAT2 enzymes on individual susceptibility to colorectal cancer, with particular attention to possible interactions between the studied genotypes. MATERIALS AND METHODS: Five hundred colorectal cancer patients and 500 matched cancer-free controls were included in the study. The allelic polymorphisms of GSTM1, GSTT1 and GSTP1, NAT1 and NAT2 enzymes were determined by PCR-based methods, from peripheral blood leukocytes, and allelic distributions were compared between colorectal cancer patients and controls. RESULTS: The GSTM1 0 allele (OR: 1.48, 95% CI: 1.15-1.92) and rapid acetylator genotypes of NAT2 (OR: 1.52, 95% CI: 1.17-1.98) were associated with an elevated risk No statistically significant correlation between NAT1, GSTT1, GSTP1 genotypes and colorectal cancer was found. Remarkably increased risk was associated with the GSTM1 0 allele--NAT2 rapid acetylator genotype combination (OR: 2.39, 95% CI: 1.75-3.26) and with the GSTM1 0 allele--NAT2 and NAT1 rapid acetylator triple combination (OR: 3.28, 95% CI: 2.06-5.23). Carrying 4 or 5 putative "high-risk" alleles substantially increased the risk of colorectal cancer (OR: 3.69, 95% CI: 2.33-5.86). CONCLUSION: The genotype of certain metabolizing enzymes affects the risk for colorectal cancer. This effect is particularly important when certain allelic combinations are studied. In the near future, individual level risk assessment may be reached by further increasing the number of studied polymorphisms, combining them with traditional epidemiological risk factors.