scholarly journals Impact of dose reduction and treatment delay of neoadjuvant chemotherapy in gastric and esophageal adenocarcinoma

2019 ◽  
Author(s):  
David Borg ◽  
Charlotta Hedner ◽  
Karin Jirström ◽  
Anders Johnsson
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Total Duration ◽  
Binary Logistic Regression ◽  
Residual Cancer ◽  
Treatment Delays ◽  
Histopathologic Response ◽  
Time To Recurrence ◽  
Kaplan Meier

Abstract Background Neoadjuvant chemotherapy in resectable gastric and esophageal adenocarcinoma is often hampered by toxicities and fragile patients resulting in dose reductions and/or treatment delays. The aim of this study was to assess how these treatment modifications affect outcome. Methods A series of 63 consecutive patients treated 2008-2014 with neoadjuvant EOX (epirubicin, oxaliplatin and capecitabine) and surgical resection, with or without adjuvant treatment, were reviewed. Chemotherapy dose index (DI), i.e. the ratio of actual to planned cumulative dose, and time index (TI), i.e. the ratio of planned to actual total duration, were calculated. Associations of neoadjuvant EOX DI and TI with histopathologic response were analysed with binary logistic regression. Time to recurrence (TTR) and overall survival (OS) were estimated using Kaplan-Meier analyses. Results Statistically significant associations were found between neoadjuvant EOX TI >= 0.95 and a major histopathologic response (0-10% residual cancer cells) and between neoadjuvant EOX DI >= 0.95 and a response with 0-50% residual cancer cells. Significantly improved TTR and OS were seen in patients with a major histopathologic response. Conclusions Our results suggest that treatment delays of neoadjuvant chemotherapy in gastric or esophageal adenocarcinoma should be avoided in order to achieve a major response.

scholarly journals Toll-like Receptor 9 in breast carcinoma is a good prognostic marker in patients treated with neoadjuvant chemotherapy

2020 ◽  
Author(s):  
Aradhana Singh ◽  
Arghya Bandyopadhyay ◽  
Narendranath Mukherjee ◽  
Anupam Basu
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Prognostic Marker ◽  
Immune Surveillance ◽  
Breast Cancer Patients ◽  
Tlr9 Expression ◽  
Kaplan Meier ◽  
Prognostic Importance

AbstractPurposeTLR9 is the sensor of fragmented nucleic acid signature as a part of innate immune surveillance. TLR9 can recognize the DNA fragments released from the chemotherapy-treated cancer cells in tumour tissue and induce an inflammatory response.The aim of this was toinvestigate the prognostic importance and survivability benefit of TLR9 expression in breast cancer patients treated with neoadjuvant chemotherapy.MethodsExpression of TLR9 in breast carcinoma samples was studied in two patient cohorts, with neoadjuvant chemotherapy (NACT), and without NACT, by immunohistochemistry. Expression of TLR9 was analysed in relation to prognosis, overall survivability as well as risk factor analysis for neoadjuvant chemotherapy treatment using web-tools like SurvExpress and K-M Plotter.ResultsTLR9 was expressed in malignant epithelial cancer cells as well as in adjacent stromal cells. TLR9 in malignant epithelial cells was significantly high in patients treated with neoadjuvant chemotherapy compared to the patients without neoadjuvant chemotherapy. The prognostic and survival analysis by SurvExpress and Kaplan-Meier plotter demonstrated that high TLR9 expression is related to better overall survival in patients treated with NACT.ConclusionsThus, we are showing for the first time that TLR9 is good prognostic marker in breast cancer treated with neoadjuvant chemotherapy and can be used for the selection of the neo-adjuvant regime.

scholarly journals Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

2021 ◽  
Author(s):  
Stacey J. Scott ◽  
Xiaodun Li ◽  
Sriganesh Jammula ◽  
Ginny Devonshire ◽  
Catherine Lindon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Cell Biology ◽  
Time Lapse ◽  
Rna Seq ◽  
Cancer Evolution ◽  
Mitotic Slippage ◽  
Quantitative Immunofluorescence ◽  
Cancer Types ◽  
Eac Cells

AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals Management of local recurrence after radical nephrectomy: surgical removal with or without systemic treatment is still the gold standard. Results from a multicenter international cohort

2021 ◽  
Vol 53 (11) ◽  
pp. 2273-2280
Author(s):  
Michele Marchioni ◽  
Petros Sountoulides ◽  
Maria Furlan ◽  
Maria Carmen Mir ◽  
Lucia Aretano ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Local Recurrence ◽  
Systemic Therapy ◽  
Radical Nephrectomy ◽  
Systemic Treatment ◽  
Survival Rates ◽  
Surgical Removal ◽  
Cancer Specific Survival ◽  
Time To Recurrence ◽  
Kaplan Meier

Abstract Objective To evaluate the survival outcomes of patients with local recurrence after radical nephrectomy (RN) and to test the effect of surgery, as monotherapy or in combination with systemic treatment, on cancer-specific mortality (CSM). Methods Patients with local recurrence after RN were abstracted from an international dataset. The primary outcome was CSM. Cox’s proportional hazard models tested the main predictors of CSM. Kaplan–Meier method estimates the 3-year survival rates. Results Overall, 96 patients were included. Of these, 44 (45.8%) were metastatic at the time of recurrence. The median time to recurrence after RN was 14.5 months. The 3-year cancer-specific survival rates after local recurrence were 92.3% (± 7.4%) for those who were treated with surgery and systemic therapy, 63.2% (± 13.2%) for those who only underwent surgery, 22.7% (± 0.9%) for those who only received systemic therapy and 20.5% (± 10.4%) for those who received no treatment (p < 0.001). Receiving only medical treatment (HR: 5.40, 95% CI 2.06–14.15, p = 0.001) or no treatment (HR: 5.63, 95% CI 2.21–14.92, p = 0.001) were both independently associated with higher CSM rates, even after multivariable adjustment. Following surgical treatment of local recurrence 8 (16.0%) patients reported complications, and 2/8 were graded as Clavien–Dindo ≥ 3. Conclusions Surgical treatment of local recurrence after RN, when feasible, should be offered to patients. Moreover, its association with a systemic treatment seems to warrantee adjunctive advantages in terms of survival, even in the presence of metastases.

scholarly journals Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3394
Author(s):  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Stella Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

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