Postoperative chemoradiotherapy in patients with locally advanced gastric cancer with poor pathologic response to neoadjuvant chemotherapy.

PURPOSE: To evaluate the effect of postoperative chemoradiotherapy (CRT) in patients with locally advanced gastric cancer (LAGC) who respond poorly to neoadjuvant chemotherapy (ChT). MATERIALS AND METHODS: The database of a tertiary medical center (2009-2020) was retrospectively reviewed for patients with LAGC in whom the initial treatment strategy consisted of perioperative ChT and surgery. Those who were subsequently referred for postoperative CRT because of a poor pathologic primary-tumor response (ypT3-4, ypN2-3, R1 resection) were selected for the study. CRT consisted of 45 Gy in 25 fractions of 1.8 Gy combined with capecitabine 825 mg/m2 twice daily on radiotherapy days or continuous infusion of 5-fluorouracil 180 mg/m2/day. RESULTS: The cohort included 26 patients of median age 61 years with LAGC (clinical stage IIA-III) after surgery with D1-D2 lymphadenectomy. R0 resection was achieved in 15 (58%). The pathological stage was III in 69% (IIA-IVA). Treatment was well tolerated. During a median follow-up time of 39 months, recurrences were documented in 14 patients (54%): 11 distant and 3 locoregional. Median progression-free survival was 23 months, and median overall survival was 65 months. Estimated 5-year survival rates were 42 and 54%, respectively. CONCLUSIONS: This small retrospective study suggests that in patients with LAGC who show a poor pathologic response to neoadjuvant ChT, a good outcome relative to reference arms in randomized trials can still be achieved with the addition of postoperative CRT. Further studies of the benefit of a tailored adaptive treatment approach to LAGC based on the response to neoadjuvant ChT are warranted.

Mitomycin C and capecitabine: An additional option as an advanced line therapy in patients with metastatic colorectal cancer.

BACKGROUND: In recent years survival of patients with metastatic colorectal cancer (mCRC), though still limited, has improved significantly; clearly, when the disease becomes refractory to standard regimens, additional treatment options are needed. Studies have shown that mitomycin C (MMC), an antitumor antibiotic, and capecitabine, a precursor of 5-fluorouracil, may act synergistically in combination. The efficacy of MMC/capecitabine has been demonstrated in the first-line setting, but only a few small studies have tested it in the advanced-line setting, with contradictory results. AIM: To summarize our experience using MMC/capecitabine as an advanced line treatment for mCRC. METHODS: A retrospective study was conducted at a tertiary medical center including all patients with histologically proven mCRC who were treated with MMC/capecitabine after at least two previous lines of standard chemotherapy in 2006-2020. Data on patient demographics and past medical history, laboratory, pathological, and radiological factors, and treatment and survival were collected from the files. Survival analyses were performed using the Kaplan-Meier method. The association of patient and tumor characteristics with treatment effectiveness and toxicity was evaluated with univariate and multivariate proportional hazard Cox regression analyses. P ≤ 0.05 was considered statistically significant. RESULTS: The cohort consisted of 119 patients of median age 64 years (range 37-85). Patients received a median of 2 MMC/capecitabine cycles (range 0.5-9.0). Thirty-four patients (28.6%) experienced grade ≥ 3 toxicity, including 2 (1.7%) with grade 4; there was no drug-related mortality. The objective response rate was 0.8%, and the disease control rate, 24.4%. Median progression-free survival (PFS) was 2.1 mo (range 0.2-20.3), and median overall survival, 4.8 mo (range 0.2-27.5). The 6-month overall survival rate was 44%; 8.7% of patients remained progression-free. Factors associated with longer PFS were lower gamma-glutamyl transferase level (P = 0.030) and primary tumor location in the left colon (P = 0.017). Factors associated with longer overall survival were lower gamma-glutamyl transferase level (P = 0.022), left-colon tumor location (P = 0.044), low-to-moderate histological grade (P = 0.012), Eastern Cooperative Oncology Group performance status 0-1 (P = 0.036), and normal bilirubin level (P = 0.047). CONCLUSION: MMC/capecitabine is an active, available, and relatively safe regimen for use beyond standard lines of therapy in mCRC. Several clinical and laboratory parameters can identify patients more likely to benefit.

Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity.

Introduction: The success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance. Methods: We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls. Results: In contrast to previous studies, our approach successfully stratifies non-infected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients. Discussion: These features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Introduction: Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. Methods: A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Results: Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. Conclusions: In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

A Highly Sensitive Flow Cytometric Approach to Detect Rare Antigen-Specific T Cells: Development and Comparison to Standard Monitoring Tools.

Personalized vaccines against patient-unique tumor-associated antigens represent a promising new approach for cancer immunotherapy. Vaccine efficacy is assessed by quantification of changes in the frequency and/or the activity of antigen-specific T cells. Enzyme-linked immunosorbent spot (ELISpot) and flow cytometry (FCM) are methodologies frequently used for assessing vaccine efficacy. We tested these methodologies and found that both ELISpot and standard FCM [monitoring CD3/CD4/CD8/IFNγ/Viability+CD14+CD19 (dump)] demonstrate background IFNγ secretion, which, in many cases, was higher than the antigen-specific signal measured by the respective methodology (frequently ranging around 0.05-0.2%). To detect such weak T-cell responses, we developed an FCM panel that included two early activation markers, 4-1BB (CD137) and CD40L (CD154), in addition to the above-cited markers. These two activation markers have a close to zero background expression and are rapidly upregulated following antigen-specific activation. They enabled the quantification of rare T cells responding to antigens within the assay well. Background IFNγ-positive CD4 T cell frequencies decreased to 0.019% ± 0.028% and CD8 T cells to 0.009% ± 0.013%, which are 19 and 13 times lower, respectively, than without the use of these markers. The presented methodology enables highly sensitive monitoring of T-cell responses to tumor-associated antigens in the very low, but clinically relevant, frequencies.

Differences in Toxicity Between Ashkenazi and Sephardic Jews With Colon Cancer Treated With Adjuvant Chemotherapy: A Prospective Study.

BACKGROUND/AIM: Ethnicity of cancer patients is increasingly being recognized as an important factor that may influence intergroup variation in toxicity and efficacy of chemotherapy. Data from our institution suggested that differences in chemotherapy-associated toxicity are not limited to distanced ethnic subgroups, such as Caucasians, Afro-Americans, or Asians, but may exist even between two closely related Caucasian ethnic subgroups, such as Ashkenazi and Sephardic Jews. This study aimed to explore differences in severity and frequency of various side effects, including neurotoxicity between patients from the two Jewish subgroups receiving oxaliplatin-containing adjuvant chemotherapy for colon cancer (CC). PATIENTS AND METHODS: We recruited 75 patients, with performance status 0-1 and no background of neuropathy between 2012 and 2016. All patients completed a neurotoxicity questionnaire (NQ) and a QoL questionnaire (QoLQ) at baseline and the NQ also at each treatment cycle; during follow up, patients filled out the NQ and the QoLQ every four months for a total of one year. RESULTS: Of the 75 participants, 66 were evaluable for the study including 34 (52%) Sephardic and 32 (48%) Ashkenazi Jews. Grade ≥2 vomiting and diarrhea occurred more often in Sephardic than in Ashkenazi patients (p=0.008 and 0.012, respectively). Of the 66 evaluable patients, 11 (17%) developed grade 3 neurotoxicity; of these, 9 were Sephardic and 2 were Ashkenazi (p=0.028). There were no significant differences in the dynamics of QoL between both subgroups. CONCLUSION: Sephardic patients receiving oxaliplatin-containing regimens are at an increased risk for neurotoxicity and other side effects as compared to their Ashkenazi counterparts.

Strong Synergic Growth Inhibition and Death Induction of Cancer Cells by Astragalus membranaceus and Vaccaria hispanica Extract.

We present here a new, classification-based screening method for anti-cancer botanical combinations. Using this method, we discovered that the combination of Astragalus membranaceus and Vaccaria hispanica (AV) has strong synergic anti-proliferative and killing effects on cancer cells. We showed that AV induces the hyper activation of proliferation and survival pathways (Akt and ERK1/2) and strongly downregulates the cell cycle control proteins p21 and p27. Moreover, FACS analyses revealed that AV induces accumulation of cells in G2/M phase, supported by accumulation of cyclin A. Taken together, our results suggest that AV interferes with the cell cycle in cancer cells, leading to accumulation in G2/M and apoptosis. Further studies are needed to validate the generalizability of the anti-cancer effect of the AV combination, to fully understand its mechanism of action and to evaluate its potential as a new anti-cancer treatment.

Tumor Lymphocyte Infiltration Is Correlated with a Favorable Tumor Regression Grade after Neoadjuvant Treatment for Esophageal Adenocarcinoma.

(1) Background: We aimed to explore the association between neoadjuvant treatment, tumor-infiltrating immune lymphocyte (TIL), and tumor-associated macrophage (TAM) and survival in patients with esophageal adenocarcinoma. (2) Methods: Patients who underwent esophagectomy were divided into three groups according to their treatment modality and tumor regression grade (TRG): (i) surgery-only group (SG), (ii) good responders (GR) group (TRG 0−1), and (iii) bad responders (BR) group (TRG 2−3). We then carried out statistical correlations of the immunofluorescence analysis of the immune infiltrate in the esophageal surgical specimens with several clinical and pathological parameters. In addition, we analyzed The Cancer Genomic Atlas (TCGA) dataset for differences in TILs, TAMs, and protein expression in immune pathways. (3) Results: Forty-three patients (SG­15, GR­13, and BR­13) were evaluated. The highest enrichment of CD3+ (p < 0.001), CD8+ (p = 0.001) and CD4+ (p = 0.009) was observed in the stroma of GR patients. On multivariate analysis, only CD8+ T cell and signet-ring features were independent prognostic factors for overall survival. In TCGA analysis, we identified overexpression of TAM and colony-stimulating factor 1 receptor (CSF-1R). (4) Conclusions: High enrichment of lymphocyte subpopulations in the microenvironment of esophageal adenocarcinoma is associated with a favorable response to neoadjuvant treatment and an improved patient outcome.

Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.

Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.

The Dynamic Changing Incidence of Gastric Cancer in Israel: Time for a National Surgical Management Committee?

BACKGROUND: There has been a general reduction over the last 20 years in the incidence within Israel of gastric cancer (GC). This has particularly been noted in the Jewish population with a slight increase in the incidence of cancer of the gastroesophageal junction among Jews of Sephardi origin. Given the diversity of individual ethnic subpopulations, the effects of GC incidence in second-generation immigrant Jews, particularly from high prevalence regions (e.g., the former Soviet Union, Iraq, and Iran), awaits determination. There are currently no national data on GC-specific mortality. The most recent available cross-correlated Israeli National Cancer Registry (INCR) and International Association for Cancer Research (IARC) incidence data for GC of the body and antrum in Israel are presented. Some of the challenges associated with GC monitoring in the changing Israeli population are discussed. We propose the establishment of a national GC management committee designed to collect demographic and oncological data in operable cases with the aim of recording and improving GC-specific outcomes. We believe that there is value in the development of a national surgical planning program, which oversees training and accreditation in a dynamic environment that favors the wider use of neoadjuvant therapies, minimally invasive surgery and routine extended (D2) lymphadenectomy. These changes should be supported by assessable enhanced recovery programs.

Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.

OBJECTIVE: To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. BACKGROUND: Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. PATIENTS AND METHODS: Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. RESULTS: The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23 kg/m2 (range: 16-40 kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1-2.8, P = 0.02), DSS (HR = 1.8, 95%CI: 1.03-3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1-2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1-3.1, P = 0.01). CONCLUSION: Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Proteomic analysis to identify markers for response to neoadjuvant treatment in esophageal and gastroesophageal cancer.

BACKGROUND: Esophageal cancer represents a global challenge. Despite significant evolution of treatment protocols in the past decade, recurrence rates are still high and survival rates are poor. Current treatment paradigm for localized gastroesophageal junction (GEJ) carcinoma remains to be further elucidated as for the role of neoadjuvant chemoradiation versus perioperative chemotherapy. AIM: To identify biomarkers for response to chemoradiation in esophageal and gastroesophageal cancer, we performed an in-depth proteomic analysis of esophageal and gastroesophageal tumors, to describe differences in pathway activation between patients with favorable and poor prognosis following neoadjuvant chemoradiation. METHODS: Patients with locally advanced esophageal and gastroesophageal cancer following neoadjuvant chemoradiation were included in the cohort. The study cohort was dichotomized into two groups of patients, named "favorable prognosis" and "poor prognosis" according to the postoperative disease-free interval. We performed a mass spectrometry analysis of proteins extracted from the malignant regions of surgical specimens and analyzed data from electronic medical records. Clinical data was correlated with differences in protein expression between patient with a favorable and poor prognosis using validated gene expression pathways. RESULTS: The study included 35 patients with adenocarcinoma. All patients in this cohort had esophageal adenocarcinoma. Patients median age was 62 years. Twenty-five (71.3%) patients underwent neoadjuvant chemoradiation, and 28.7% underwent neoadjuvant chemotherapy only. A proteomic analysis of our cohort identified 2885 proteins. Enrichment levels of 98 of these proteins differed significantly between favorable and poor prognosis cohorts in patients who underwent neoadjuvant chemoradiation (p < .05) but not in patients who underwent neoadjuvant chemotherapy. The favorable prognosis patients group analysis exhibited differential enrichment of 87 proteins related to cellular respiration and oxidative phosphorylation pathways as well as proteins of the RAS oncogene family. CONCLUSION: In this study we identified differential enrichment of pathways related to oxidative phosphorylation and RAS oncogene pathway in esophageal cancer patients with a favorable response to chemoradiation. Following further validation, our findings may portray potential surrogate signature of biomarkers based upon these pathways.

Early prediction of residual disease after neoadjuvant chemoradiotherapy and cetuximab for locally advanced esophageal cancer using 18F-FDG PET-CT imaging: a prospective cohort study.

Background: Previous studies in locally advanced esophageal cancer (LAEC) suggested that a change in the tumor's metabolic response, i.e., decrease of its interim 18F-FDG uptake compared with baseline, may predict histopathological response. We evaluated the possible predictive correlation between various PET-CT and histopathological parameters following a neoadjuvant biological-containing chemoradiotherapy (CRT) regimen. Methods: Patients with resectable LAEC received neoadjuvant cisplatin/5-fluorouracil-based CRT and cetuximab following one cycle of induction chemotherapy and cetuximab. Changes in maximum and mean standardized uptake values (ΔSUV-max and ΔSUV-mean, respectively) and metabolic tumor volume (ΔMTV), measured by PET-CT at baseline and 2 weeks after the onset of treatment, were compared with histopathological findings at surgery. Histopathological response was defined by tumor regression grade (TRG), pathological complete response (pCR) and microscopic or macroscopic residual disease (RD). Results: Of 18 patients, 13 (72%) with adenocarcinoma (AC) and 5 (28%) with squamous cell carcinoma (SCC), were included. None of the changes in the parameters of PET was associated with pCR; only ΔSUV-mean was associated with TRG in the AC cohort. In contrast, both ΔSUV-mean% and ΔSUV-max% were significantly associated with RD, both in the whole cohort and in the AC cohort. Changes in FDG-uptake predicted RD2 at surgery: only patients with less than 13% decrease in SUV-mean% or less than 29% decrease in SUV-max% had RD2, while all patients with RD0 or RD1 had greater reductions [100% specificity and 100% positive predictive value (PPV)]. Conclusions: Changes in ΔSUV-max and ΔSUV-mean after two weeks of onset of cetuximab-based neoadjuvant chemotherapy for LAEC may predict macroscopic RD but not TRG or pCR at surgery.

Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer.

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear. Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls. Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel). Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL. Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses. Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (ß, -3.5; 95% CI, -5.6 to -1.5). Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.

Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases.

BACKGROUND: Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). METHODS: The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR <3 (normal) or >3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. RESULTS: The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). CONCLUSIONS: A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Cancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1-Mediated Secretion of Extracellular Vesicles.

Gastric cancer is the third most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancer-associated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from patients with gastric cancer. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A and thrombospondin 2, which were secreted in CAF-derived extracellular vesicles to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment. SIGNIFICANCE: This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/7/1639/F1.large.jpg.

The trichoscopic features of hair shaft anomalies induced by epidermal growth factor receptor inhibitors: A case series.

BACKGROUND: Although the clinical hair changes that occur under treatment with epidermal growth factor receptor inhibitors (EGFRIs) are documented, their trichoscopic features have not been reported. OBJECTIVE: To evaluate the trichoscopic findings in scalp and facial hair, induced by EGFRI treatment. METHODS: Patients treated with EGFRIs at a tertiary oncodermatology clinic in 2015 through 2017 were evaluated for macroscopic and trichoscopic changes. RESULTS: The cohort included 23 patients (13 women; median age, 68 years) treated with EGFRIs for an average of 13 months (range, 2-40 months). Macroscopically, 18 patients (78%) had dry, lusterless, coarse, kinky, brittle scalp hair, and 17 (74%) had trichomegaly of the eyebrows/eyelashes. Trichoscopic findings were of hair shaft anomalies including pili torti, affecting scalp hair in 20 patients (87%), eyebrows in 6 (26%), and eyelashes in 8 (50%), and asymmetric hyperpigmented fusiform widening of hair scalp in 3 (13%), eyebrows in 10 (43%), and eyelashes in 4 (25%). Dermoscopic findings of the peri- and interfollicular skin were scale, whitish erythematous structureless areas, and branching vessels. LIMITATIONS: Lack of trichoscopic-histologic correlation, lack of baseline examination. CONCLUSION: The trichoscopic correlates of the macroscopic hair changes under EFGRI treatment include pili torti, and asymmetric hyperpigmented fusiform widening, with dermoscopic cutaneous manifestations of scale, whitish erythematous structureless areas, and branching vessels.

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

PURPOSE: The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. METHODS: Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). RESULTS: A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. CONCLUSION: The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.