The detection of plasma cell-free tumor DNA (ctDNA) is prognostic in colorectal cancer (CRC) and has potential for early prediction of disease recurrence. In clinical routine, ctDNA-based diagnostics ...are limited by the low concentration of ctDNA and error rates of standard next-generation sequencing (NGS) approaches. We evaluated the potential to increase the stability and yield of plasma cell-free DNA (cfDNA) for routine diagnostic purposes using different blood collection tubes and various manual or automated cfDNA extraction protocols. Sensitivity for low-level ctDNA was measured in
-mutant cfDNA using an error-reduced NGS procedure. To test the applicability of rapid evaluation of ctDNA persistence in clinical routine, we prospectively analyzed postoperative samples of 67 CRC (stage II) patients. ctDNA detection was linear between 0.0045 and 45%, with high sensitivity (94%) and specificity (100%) for mutations at 0.1% VAF. The stability and yield of cfDNA were superior when using Streck BCT tubes and a protocol by Zymo Research. Sensitivity for ctDNA increased 1.5-fold by the integration of variant reads from triplicate PCRs and with PCR template concentration. In clinical samples, ctDNA persistence was found in ∼9% of samples, drawn 2 weeks after surgery. Moreover, in a retrospective analysis of 14 CRC patients with relapse during adjuvant therapy, we successfully detected ctDNA (median 0.38% VAF; range 0.18-5.04% VAF) in 92.85% of patients significantly prior (median 112 days) to imaging-based surveillance. Using optimized pre-analytical conditions, the detection of postoperative ctDNA is feasible with excellent sensitivity and allows the prediction of CRC recurrence in routine oncology testing.
Over 50% of patients with colorectal cancer will develop liver metastases. Only a minority of patients present with technically resectable disease. Around 40% of those undergoing surgical resection ...are alive five years after their diagnosis compared with less than 1% for those with disseminated disease treated with systemic chemotherapy. Surgical resection remains the only possibility for long-term survival for these patients and great efforts have been made to increase the rates of resection whilst improving long-term outcomes.
This review considers current technical and oncological criteria for resection, as well as targeted approaches to stratify underlying tumor biology in order to better predict long-term benefit. The role of neoadjuvant and perioperative systemic chemotherapy is critically reviewed, with suggestions for patient stratification in order to identify those who are likely to derive the greatest benefit. The key role of multidisciplinary assessment and decision making for these complex patients is also discussed.
Surgery remains the optimal treatment for colorectal liver metastases (CRLM). Despite the curative intent of surgical resection, the majority of patients develop recurrence. Surgical strategies should therefore be adopted to maximize the potential for repeat resections in the event of recurrence. Although a number of preoperative prognostic markers have been identified, none are absolute contraindications to resection. In order to reduce postoperative recurrence, neo-adjuvant chemotherapy is now the standard of care in a number of countries. The evidence base for this approach is contentious, and the potential benefit of such a strategy is likely to be greatest in patients with high oncological risk disease. Multidisciplinary care is essential to ensure the optimal management of these complex patients. In addition, all patients with CRLM should be discussed with specialist hepatobiliary surgeons.
During the first wave of the COVID-19 pandemic in 2020, the German government implemented legal restrictions to avoid the overloading of intensive care units by patients with COVID-19. The influence ...of these effects on diagnosis and treatment of cancer in Germany is largely unknown.
To evaluate the effect of the first wave of the COVID-19 pandemic on tumor board presentations in a high-volume tertiary referral center (the German Comprehensive Cancer Center NCT/UCC Dresden), we compared the number of presentations of gastrointestinal tumors stratified by tumor entity, tumor stage, and treatment intention during the pandemic to the respective data from previous years.
The number of presentations decreased by 3.2% (95% CI -8.8, 2.7) during the COVID year 2020 compared with the pre-COVID year 2019. During the first shutdown, March-May 2020, the total number of presentations was 9.4% (-18.7, 1) less than during March-May 2019. This decrease was significant for curable cases of esophageal cancer
= 37, 25.5% (-41.8, -4.4) and colon cancer
= 36, 17.5% (-32.6, 1.1) as well as for all cases of biliary tract cancer
= 26, 50% (-69.9, -15) during the first shutdown from March 2020 to May 2020.
The impact of the COVID-19 pandemic on the presentation of oncological patients in a CCC in Germany was considerable and should be taken into account when making decisions regarding future pandemics.
Although neoadjuvant radiochemotherapy (nRCTx) is an established oncological treatment in patients with advanced rectal cancer, little is known about its effects on the tumor microenvironment. ...Quantity and composition of tumor infiltrating lymphocytes (TILs) are known to influence patients' prognosis but nRCTx-induced modifications are still unclear. We determined the composition of the immune cell infiltrate in rectal cancer after nRCTx and its influence on tumor regression, local recurrence rate and survival.
We investigated density and composition of tumor infiltrating CD3
+
and CD8
+
T-cells and the quantity and ratio of CD8
+
/GrzB
+
T-cells to CD8
+
T-cells in 130 rectal cancers after nRCTx compared to a cohort of 30 primarily resected rectal cancers. Furthermore, we analyzed 22 pretherapeutic rectal cancer biopsies, later treated with nRCTx and surgery to evaluate nRCTx-induced modifications of the tumor microenvironment.
The total numbers of CD3
+
and CD8
+
T-cells in tumor stroma (p < 0.001) and tumor epithelium (p < 0.001 CD3; 0.002 CD8) were significantly lower in rectal cancers after nRCTx compared to primarily resected cases, while the ratio of CD8
+
/GrzB
+
T-cells to CD8
+
T-cells was significantly increased in the nRCTx cohort (p < 0.001). In multivariate analyses, CD8
+
/GrzB
+
T-cells in the tumor stroma were significantly associated with high regression grade and a lower likelihood of local recurrence (p = 0.029).
nRCTx modifies the tumor microenvironment of rectal cancer leading to a total decrease of TILs, but a relative increase in CD8
+
/GrzB
+
T-cells in the tumor stroma. CD8
+
/GrzB
+
T-cells may contribute to local tumor control and the better outcome.
Immunotherapy of Colon Cancer Stein, Alexander; Folprecht, Gunnar
Oncology research and treatment,
01/2018, Volume:
41, Issue:
5
Journal Article
Peer reviewed
In contrast to other tumour types inhibitors of PD-1/-L1 or CTLA 4 have not yet shown relevant efficacy in unselected colorectal cancer. Based on the high mutational burden, deficient mismatch repair ...(dMMR) or microsatellite instable (MSI-H) tumours are yet the only subgroup, which is amenable to checkpoint inhibition. These tumours show relevant and durable responses in the refractory setting by PD-1/-L1 +/- CTLA 4 inhibition. Thus, ongoing phase 3 trials in this subgroup evaluate immunotherapy in the adjuvant setting as well as in the first line metastatic setting with or without chemotherapy. For the by far larger subgroup of non-dMMR/MSI-H patients (95% in the metastatic setting) combination regimen are urgently required, either with chemotherapy and/or molecular targeting drugs, local ablative treatments or other immunotherapeutic agents (e.g. CEA-TCB).
Neoadjuvant radiochemotherapy (nRCT) can significantly influence the tumor immune architecture that plays a pivotal role in regulating tumor growth. Whereas, various studies have investigated the ...effect of nRCT on tumor-infiltrating T cells, little is known about its impact on the frequency and activation status of human dendritic cells (DCs). Plasmacytoid DCs (pDCs) essentially contribute to the regulation of innate and adaptive immunity and may profoundly influence tumor progression. Recent studies have revealed that higher pDC numbers are associated with poor prognosis in cancer patients. 6-sulfo LacNAc-expressing monocytes (slanMo) represent a particular proinflammatory subset of human non-classical blood monocytes that can differentiate into DCs. Recently, we have reported that activated slanMo produce various proinflammatory cytokines and efficiently stimulate natural killer cells and T lymphocytes. slanMo were also shown to accumulate in clear cell renal cell carcinoma (ccRCC) and in metastatic lymph nodes from cancer patients. Here, we investigated the influence of nRCT on the frequency of rectal cancer-infiltrating pDCs and slanMo. When evaluating rectal cancer tissues obtained from patients after nRCT, a significantly higher density of pDCs in comparison to pre-nRCT tissue samples was found. In contrast, the density of slanMo was not significantly altered by nRCT. Further studies revealed that nRCT significantly enhances the proportion of rectal cancer-infiltrating CD8
T cells expressing the cytotoxic effector molecule granzyme B. When exploring the impact of nRCT on the phenotype of rectal cancer-infiltrating pDCs and slanMo, we observed that nRCT markedly enhances the percentage of inducible nitric oxide synthase (iNOS)- or tumor necrosis factor (TNF) alpha-producing slanMo. Furthermore, nRCT significantly increased the percentage of mature CD83
pDCs in rectal cancer tissues. Moreover, the proportion of pDCs locally expressing interferon-alpha, which plays a major role in antitumor immunity, was significantly higher in post-nRCT tissues compared to pre-nRCT tumor specimens. These novel findings indicate that nRCT significantly influences the frequency and/or phenotype of pDCs, slanMo, and CD8
T cells, which may influence the clinical response of rectal cancer patients to nRCT.
Zusammenfassung
Die Therapie von Patienten mit einem CUP-Syndrom (
CUP
:„cancer of unknown primary“) entsprechend dem Ursprungsgewebe ist Teil der Standardbehandlung, wenn sich in der Immunhistologie ...oder in der Kombination mit klinischen und laborchemischen Parametern große Ähnlichkeiten mit bekannten Tumoren erweisen. Auch mittels Genexpressions- oder Methylierungsanalysen können molekulare Ähnlichkeiten mit bekannten Tumoren nachgewiesen werden. Wenige retrospektive Untersuchungen scheinen einen Vorteil für Patienten zu zeigen, die eine Behandlung passend zu dem molekular definierten Tumor erhielten. Ein Nachweis der Überlegenheit einer auf eine solche Testung basierenden Therapiestrategie steht jedoch aus. Die Suche nach molekularen Zielen führt bei einem kleinen Teil der Patienten zur Möglichkeit der zielgerichteten Behandlung mit für andere Indikationen zugelassenen Medikamenten und kasuistischen Berichten über entsprechende Therapien.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
30.
Liver Metastases in Colorectal Cancer Folprecht, Gunnar
American Society of Clinical Oncology educational book,
2016, Volume:
36, Issue:
36
Journal Article
Peer reviewed
Resection of colorectal liver metastases is a treatment standard because patients experience long-term disease-free survival or are even cured after undergoing this procedure. Improved surgical ...techniques for liver resection in combination with downsizing liver metastases by chemotherapy, interventions to induce liver hypertrophy before resection, and the use of ablative techniques have allowed us to expand the indications for liver surgery and local treatment in situations with limited metastatic colorectal cancer. Resectability and identification of patients who might benefit from liver surgery and local ablative techniques are key factors for the treatment of patients with colorectal cancer. Despite the wide acceptance of liver surgery and ablative techniques, there are many open questions on the management of limited metastatic disease, such as which patients benefit from an aggressive surgical approach, what the indications for ablative and other local techniques are, and what the role of chemotherapy is for patients with resectable or resected disease. Unfortunately, results of randomized trials are only available for a limited number of these questions.
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