A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer.

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.

Interleukin-6 as a Predictive Factor of Pathological Response to FLOT Regimen Systemic Treatment in Locally Advanced Gastroesophageal Junction or Gastric Cancer Patients.

BACKGROUND: Perioperative treatment is a gold standard in locally advanced gastric cancer or GEJ cancer in the Western population. Unfortunately, the response rate after neoadjuvant chemotherapy (NAC) remains limited. Moreover, there are currently no biomarkers enabling an individual prediction of therapeutic efficacy. The aim of this study was the identification of serum biomarkers of early response to NAC. METHODS: We conducted this prospective study in the MSCNRIO in Warsaw, Poland. A total of 71 patients and 15 healthy volunteers gave informed consent. Complete blood count, carcinoembryonic antigen (CEA), carcinoma antigen 125 (CA125), carcinoma antigen 19.9 (CA19.9), and fibrinogen (F) were measured at baseline and before every cycle. Circulating tumour cells (CTCs) and interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) were measured in a pilot group of 40 patients at baseline and before cycle two (C2) and cycle three (C3). RESULTS: Of all the measured parameters, only the IL-6 serum level was statistically significant. The IL-6 level before C2 of chemotherapy was significantly decreased in the complete pathological response (pCR) vs. the non-pCR group (3.71 pg/mL vs. 7.63 pg/mL, p = 0.004). In all patients with an IL-6 level below 5.0 pg/mL in C2, tumour regression TRG1a/1b according to the Becker classification and ypN0 were detected in postoperative histopathological specimens. The IL-6 level before C1 of chemotherapy was significantly elevated in ypN+ vs. ypN0 (7.69 pg/mL vs. 2.89 pg/mL, p = 0.022). CONCLUSIONS: The trial showed that an elevated level of IL-6 prior to treatment and C2 might be a predictor of pathological response to NAC.

Which tumour factors preclude organ preservation in patients with rectal cancer?

BACKGROUND: cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes, extramural vascular invasion (EMVI) and mesorectal fascia threatening (MRF+) have been utilized as exclusion criteria in several studies on the watch-and-wait (w&w) strategy. Here, our aim was to validate these criteria through a post hoc analysis of two pooled prospective studies on w&w following routine radio(chemo)therapy. METHODS: A review of baseline magnetic resonance imaging was performed in a subgroup of 223 patients treated at a single institution. Of these, 17.9 % started w&w, 12.6 % achieved clinical complete response (cCR) and 9.0 % sustained cCR during median follow-up of 54 months. RESULTS: The multivariable logistic analysis showed that the proportion of circumferential bowel involvement and EMVI significantly influenced the chance of sustained cCR; odds ratios were 0.063 (95 % confidence interval [CI] 0.008-0.489, p = 0.008), and 0.109 (95 % CI 0.014-0.850, p = 0.034), respectively. Sustained cCR was observed in none of the 57 patients with 90 %-100 % circumferential bowel involvement and in only one of the 89 patients with EMVI. In contrast, cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes or MRF+ were not independently associated with sustained cCR. Among the subgroups of patients with these features but without (near-)circular tumour or EMVI+, sustained cCR was observed in 12 %-25 % of patients. CONCLUSION: Sustained cCR after routine preoperative radio(chemo)therapy is unlikely in patients with (near-)circular tumour or EMVI, whereas patients with cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes and MRF+ should not be denied w&w.

To push or to pull? A clinical audit on the efficacy and safety of the pull and push percutaneous endoscopic gastrostomy techniques in oncological patients.

BACKGROUND: The peroral "pull" technique and the direct "push" procedure are the two main methods for percutaneous endoscopic gastrostomy (PEG) placement. Although pull-PEG is generally recommended as the first-line modality, many oncological patients require a push-PEG approach to prevent tumor seeding or overcome tumor-related obstruction. OBJECTIVE: We aimed to compare the efficacy and safety of both PEG procedures in cancer patients. METHODS: We retrospectively analyzed all consecutive PEG procedures within a tertiary oncological center. Patients were followed up with the hospital databases and National Cancer Registry to assess the technical success rate for PEG placement, the rate of minor and major adverse events (AEs), and 30-day mortality rates. We compared those outcomes between the two PEG techniques. Finally, risk factors for PEG-related adverse events were analyzed using a multivariable Cox proportional-hazard regression model adjusted for patients' sex, age, performance status (ECOG), Body Mass Index (BMI), diabetes, chemoradiotherapy (CRT) status (pre-/current-/post-treatment), and type of PEG. RESULTS: We included 1055 PEG procedures (58.7% push-PEG/41.4% pull-PEG) performed in 994 patients between 2014 and 2021 (mean age 62.0 [±10.7] yrs.; 70.2% males; indication: head-and-neck cancer 75.9%/other cancer 24.1%). The overall technical success for PEG placement was 96.5%. Although the "push" technique had a higher rate of all AEs (21.4% vs. 7.1%, Hazard Ratio [HR]  = 2.9; 95% CI = 1.9-4.3, p < 0.001), most of these constituted minor AEs (71.9%), such as tube dislodgement. The methods had no significant difference regarding major AEs and 30-day mortality rates. Previous CRT was associated with an increased risk of major AEs (hazard ratio = 2.7, 95% CI = 1.0-7.2, p = 0.042). CONCLUSION: The risk of major AEs was comparable between the push- and pull-PEG techniques in cancer patients. Due to frequent tube dislodgement in push-PEG, the pull technique may be more suitable for long-term feeding. Previous CRT increases the risk of major AEs, favoring early ("prophylactic") PEG placement when such treatment is expected.

Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial.

BACKGROUND: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. METHODS: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-ß, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10). RESULTS: RNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. CONCLUSIONS: This exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. TRIAL REGISTRATION NUMBER: NCT02370498.

Safety and efficacy of the FLOT regimen in the Polish population - an analysis of the prospective trial.

As gastric cancer is associated with poor prognosis, the preferred management of locally advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancer in European patients is perioperative chemotherapy using the FLOT regimen. Previously published data demonstrate that such treatment is associated with improved disease-free survival (DFS) as well as overall survival (OS) compared to ECF/ECX regimen. In order to collect biomaterial for the identification of serum biomarkers of an early response to neoadjuvant chemotherapy, we performed a prospective study and here, we report the safety and clinical efficacy of this prospective cohort. It was an academic, nonrandomized, prospective study, conducted at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland. Between January 2018 and November 2019, we analyzed a total of 61 patients aged 30-77 (median 63 years, 52.5% males and 47.5% females) with histologically confirmed GC or GEJ cancer. The patients were qualified by a multidisciplinary team for perioperative treatment (FLOT regimen). All cases of reported adverse events were recorded and analyzed. All patients received G-CSF prophylactically. After gastrectomy, an assessment of pathological regression was performed according to the Becker classification. A total of 93.4% (57) patients completed four cycles of preoperative chemotherapy and 78.7% (48) received postoperative chemotherapy. All of them experienced grade 1/2 toxicities. The common AE G1/G2 in preoperative versus postoperative chemotherapy were: fatigue (75% vs. 60%), anemia (64% vs. 62%), nausea (60% vs. 60%), peripheral neuropathy (60% vs. 60%), and oral mucositis (59% vs. 50%), respectively. Only 24.6% (15) had G3/4 adverse events during preoperative chemotherapy and only 20.8% (10) during postoperative chemotherapy. The estimated DFS at 3 years was 53% (95% CI 40.5-66.1%) and the estimated OS at 3 years was 60.2% (95% CI 45.1-72.3%). FLOT regimen significantly improved GC and GEJ cancer patients' prognosis with acceptable side-effect profiles.

The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells.

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition. This suggests a central role of HSP70 in the suppression of the proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced autophagy, unfolded protein response, and endocytic flux, and directly chaperones the proteasome machinery. However, it does not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of cancer cells with the inhibited proteasome and HSP70.

Long-term observation of gastric patients with positive immunocytochemistry of peritoneal washing.

Prognosis in gastric cancer patients is highly dependent on the tumor stage at presentation. Surgery still remains the main therapeutic option in gastric cancer patients. However, the efficacy of this treatment may be substantially limited by the risk of peritoneal dissemination. The introduction of hyperthermic intraperitoneal chemotherapy (HIPEC) may affect the long-term outcomes in this group of patients, but high morbidity associated with this procedure provides the rationale to identify the correct population of patients for HIPEC. The aim of the study was to evaluate a long-term prognostic value of peritoneal washing immunocytochemistry as a prognostic factor in patients with gastric cancer. This is a prospective, long-term analysis of patients who underwent peritoneal lavage with immunocytochemistry assessment in the Maria Sklodowska-Curie National Research Institute of Oncology, in Warsaw, Poland. Between January 2002 and November 2004, a total of 157 patients with histologically confirmed gastric cancer were enrolled in the study. Laparotomy and intra-operative peritoneal lavage for immunocytochemistry examination were performed prior to gastrectomy. All patients were followed up with endpoints of cancer recurrence and mortality. Positive peritoneal washing immunocytochemistry was associated with clinical staging of gastric cancer, overall survival, and progression-free survival. It is an independent poor outcome prognostic factor.

Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial.

BACKGROUND: In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019). METHODS: Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models. RESULTS: 366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%). CONCLUSION: In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02370498.

Long noncoding RNA CCAT1 rs67085638 SNP contribution to the progression of gastric cancer in a Polish population.

The role of the long noncoding RNA CCAT1 NC_000008.10:g.128220661C > T (rs67085638) in the development of colon cancer has been reported. Therefore, we assessed the prevalence of rs67085638 in patients with gastric cancer (GC). We also evaluated the effect of rs67085638 on B-cell-specific Moloney leukaemia virus insertion site 1 (BMI1) transcripts in primary GC and counterpart histopathologically confirmed disease-free margin tissue. Using high-resolution melting analysis, we evaluated rs67085638 frequency in patients with the GC genotype (n = 214) and controls (n = 502) in a Polish Caucasian population. qRT-PCR was used to determine BMI1 transcripts. We observed the trend of rs67085638 association in all patients with GC (ptrend = 0.028), a strong risk of the GC genotype in male (ptrend = 0.035) but not female (ptrend = 0.747) patients, and the association with non-cardia GC (ptrend = 0.041), tumour stages T3 (ptrend = 0.014) and T4 (ptrend = 0.032), differentiation grading G3 (ptrend = 0.009), lymph node metastasis stage N3 (ptrend = 0.0005) and metastasis stage M0 (ptrend = 0.027). We found that significantly increased BMI1 transcripts were associated with the primary GC genotype classified as grade G3 (p = 0.011) and as lymph node metastasis N3 (p = 0.010) and counterpart marginal tissues (p = 0.026, p = 0.040, respectively) from carriers of the T/T versus C/C genotypes. rs67085638 may contribute to increased BMI1 transcripts and the progression and rapid growth of GC.

GWAS Links New Variant in Long Non-Coding RNA LINC02006 with Colorectal Cancer Susceptibility.

Despite great efforts, most of the genetic factors contributing to the risk of colorectal cancer (CRC) remain undetermined. Including small but homogenous populations in genome-wide association studies (GWAS) can help us discover new common risk variants specific to the studied population. In this study, including 465 CRC patients and 1548 controls, a pooled DNA samples-based GWAS was conducted in search of genetic variants associated with CRC in a Polish population. Combined with a new method of selecting single-nucleotide polymorphisms (SNPs) for verification in individual DNA samples, this approach allowed the detection of five new susceptibility loci not previously reported for CRC. The discovered loci were found to explain 10% of the overall risk of developing CRC. The strongest association was observed for rs10935945 in long non-coding RNA LINC02006 (3q25.2). Three other SNPs were also located within genes (rs17575184 in NEGR1, rs11060839 in PIWIL1, rs12935896 in BCAS3), while one was intergenic (rs9927668 at 16p13.2). An expression quantitative trait locus (eQTL) bioinformatic analysis suggested that these polymorphisms may affect transcription factor binding sites. In conclusion, four of the identified variants were located within genes likely involved in tumor invasiveness and metastasis. Therefore, they could possibly be markers of poor prognosis in CRC patients.

Watch-and-wait strategy in rectal cancer: Is there a tumour size limit? Results from two pooled prospective studies.

BACKGROUND: Frequency and predictive factors for a clinical complete response (cCR) in unselected patients are unclear. MATERIAL AND METHODS: Two prospective observational studies were designed and pooled to explore predictive factors for cCR. Both studies evaluated the watch-and-wait strategy in consecutive patients; the first single-institutional study in elderly with a small tumour, the second multi-institutional study in all the patients receiving standard of care preoperative radiotherapy. RESULTS: Four hundred and ninety patients were analysed. Short-course radiotherapy alone, or with consolidation chemotherapy or chemoradiation was given to 40.6%, 40.2% and 19.2% of the patients, respectively. The median interval from the radiation start to the first tumour response assessment was 10.2 weeks for short-course radiation and 13.2 weeks for chemoradiation. Seventy-three patients had cCR and 71 underwent w&w with the median follow-up of 24 months. The regrowth rate was 26.8%. cCR rate was 39.0% for low-risk cancer (cT1-2N0), 16.8% for intermediate-risk (cT3 with unthreatened mesorectal fascia [MRF-] or cT2N+) and 5.4% for high-risk (cT4 or MRF+). In the multivariable analysis, tumour volume (or tumour length and circumferential extent) and cN status were significant predictors for cCR. In circular cancers or with a length ≥7 cm (n = 184), cCR rate was only 2.7%, sustained cCR 1.6% and the sensitivity of cCR diagnosis 23.1%. None of 27 patients with a tumour larger than 120 cm3 achieved cCR. CONCLUSIONS: Considering watch-and-wait strategy is questionable in patients with circular tumours or with tumour length ≥7 cm.

The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice.

INTRODUCTION: The real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce. METHODS: We have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013-2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months. RESULTS: The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p < 0.01]. Estimated 4-year relapse-free survival (RFS) rate is 78%. CONCLUSIONS: The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.

Guidelines of the Association of Polish Surgeons and the Polish Society of Surgical Oncology on the accreditation of healthcare centers providing cytoreductive surgery and HIPEC for primary and secondary peritoneal cancers.

Surgical interventions in patients with peritoneal metastases combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic treatment are becoming more common and, when applied to selected patient groups, they reach 5-year survival rates of 32-52%. Good clinical outcomes require experienced and well-equipped healthcare centers, experienced surgical team and adequate patient qualification process. As a result of the discussion on the need for evaluation of quality of care and treatment outcomes and at the request of the Peritoneal Cancer Section of the Polish Society of Surgical Oncology, accreditation standards have been developed and the Accreditation Committee has been established for healthcare centers providing cytoreductive surgery and HIPEC for the management of primary and secondary peritoneal cancers.

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

The gentamicin-collagen implant and the risk of distant metastases of rectal cancer following short-course radiotherapy and curative resection: the long-term outcomes of a randomized study.

PURPOSE: A previous randomized study conducted by our group showed that application of gentamicin-collagen implant (GCI) into the pelvic cavity after total mesorectal excision (TME) reduced the incidence of distant metastases. Therefore, we decided to conduct a confirmatory study. METHODS: Patients with rectal cancer were included in the study if they met the following criteria: adenocarcinoma of the rectum, preoperative short-term radiotherapy (5 × 5 Gy), and WHO performance score 0-1. RESULTS: One hundred seventy-six patients were randomly assigned either to an experimental group in which GCI was applied (n = 81) or to a control group without GCI (n = 81). Median follow-up was 80 months. Cumulative incidence of distant metastases at 5 years was higher in the control group compared to the experimental group: 23.5 vs 8.6% (HR 2.4 [95% CI 1.1-5.5], P = 0.005). Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) did not differ between the experimental group and the control group: HR 0.95 [95% CI 0.55-1.70], P = 0.864; HR 0.85 [95% CI 0.50-1.45], P = 0.548, and HR 0.5 [95%CI 0.22-1.22], P = 0.093, respectively. The predefined by the protocol subgroup analysis for yp stage III disease showed better DFS in the experimental group compared to the control group; HR 0.47 [95%CI 0.23-0.97], P = 0.042). CONCLUSIONS: The results confirmed our previous finding that GCI applied in the pelvis significantly reduced the rate of distant metastases in patients after radical rectal cancer resection.

Conventional cytology vs. immunocytochemistry of intraoperative peritoneal washes in gastric cancer patients subjected to gastrectomy: clinical correlates and association with overall survival.

BACKGROUND: The aim of this study was to verify if positive results yielded with conventional cytology and immunocytochemical analysis of peritoneal washes correlate with established prognostic factors and overall survival (OS) in gastric cancer patients. METHODS: The study included the data of 271 gastrectomized patients. Peritoneal washes of 131 (48.3%) patients were examined by means of conventional cytology, and material from 140 (51.7%) subjects treated surgically after this date was subjected to immunocytochemical analysis. RESULTS: Free cancer cells (FCCs) were detected significantly less often in patients from conventional cytology group than in those from immunocytochemistry group (4.6% vs. 12.1%). Positive result of immunocytochemical analysis was significantly more often associated with presence of pT3/4 tumor (94.1% vs. 60.2%), lymph node ratio ≥0.2 (82.4% vs. 43.1%) and involvement of blood vessels (64.7% vs. 28.5%). Median OS in patients with immunocytochemical evidence of FCCs in peritoneal washes was significantly shorter than in those without (11 vs. 45 months). Moreover, the two groups differed significantly in terms of 5- (0% vs. 43.1%) and 10-year OS rates (0.0% vs. 29.3%). CONCLUSIONS: In contrast to conventional cytology, immunocytochemically documented presence of FCCs in peritoneal washes correlates with established prognostic factors and OS in gastric cancer patients.

Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts.

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.

The safety of low-molecular-weight heparins in the prevention of venous thromboembolism in surgically-treated cancer patients: results of a multicentre observational study.

AIM OF THE STUDY: Despite widespread use of pharmacological prophylaxis, venous thromboembolism (VTE) still constitutes a common complication in cancer patients. The aim of the study was to analyse the safety of low-molecular-weight heparins (LMWH) in the prevention of VTE in surgically-treated cancer patients. MATERIAL AND METHODS: A total of 5207 cancer patients (44.5% men and 55.5% women) aged 16-97 years participated in a prospective observational study conducted in 13 Polish cancer centres in 2005-2008. This cohort included 4782 subjects who were treated surgically and received LMWH as a pharmacological prophylaxis for VTE prior to or after the surgery. The incidence of haemorrhagic complications and thrombocytopaenia was analysed in this cohort, along with intra-hospital mortality. RESULTS: Mean duration of LMWH administration was 9.4 ±7.8 days. Haemorrhagic complications: heavy (n = 15) or light bleeding (n = 299), were observed in 314 patients (6.5%). A total of 314 patients (6.5%) presented with haemorrhagic complications: heavy (n = 15, 0.3%) or light bleeding (n = 299, 6.3%). Four cases of heavy bleeding: gastrointestinal bleeding (n = 2), retroperitoneal bleeding (n = 1), and central nervous system bleeding (n = 1), were classified as definitely related to LMWH. No significant association was found between the incidence of haemorrhagic complications and the type of administered LWMH (p = 0.523). No cases of thrombocytopaenia or deaths related to administration of LMWH were reported. CONCLUSIONS: LMWH seems to be a safe form of pharmacological prophylaxis for VTE in surgically-treated cancer patients.