Pathologic Assessment of Rectal Carcinoma after Neoadjuvant Radio(chemo)therapy: Prognostic Implications

Neoadjuvant radio(chemo)therapy is increasingly used in rectal cancer and induces a number of morphologic changes that affect prognostication after curative surgery, thereby creating new challenges for surgical pathologists, particularly in evaluating morphologic changes and tumour response to preoperative treatment. Surgical pathologists play an important role in determining the many facets of rectal carcinoma patient care after neoadjuvant treatment. These range from proper handling of macroscopic specimens to accurate microscopic evaluation of pathological features associated with patients' prognosis. This review presents the well-established pathological prognostic indicators and discusses challenging features in order to provide both surgical pathologists and treating physicians with a checklist that is useful in a neoadjuvant setting

Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints

Pathologic Assessment of Rectal Carcinoma after Neoadjuvant Radio(chemo)therapy: Prognostic Implications

Neoadjuvant radio(chemo)therapy is increasingly used in rectal cancer and induces a number of morphologic changes that affect prognostication after curative surgery, thereby creating new challenges for surgical pathologists, particularly in evaluating morphologic changes and tumour response to preoperative treatment. Surgical pathologists play an important role in determining the many facets of rectal carcinoma patient care after neoadjuvant treatment. These range from proper handling of macroscopic specimens to accurate microscopic evaluation of pathological features associated with patients’ prognosis. This review presents the well-established pathological prognostic indicators and discusses challenging features in order to provide both surgical pathologists and treating physicians with a checklist that is useful in a neoadjuvant setting

Cisplatin-modified de Gramont in second line therapy for pancreatic adenocarcinoma

Introduction : Today there is growing evidence supporting the benefit of 2nd line chemotherapy after gemcitabine failure in pancreatic cancer. However, which type of chemotherapy is preferred has not been defined yet. Different therapeutic regimens have been tested in small trials and have shown a limited significant clinical benefit. In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil (5FU) + leucovorin according to the modified de Gramont schedule is the treatment of choice. Combination therapy with cisplatinum and 5FU has yielded positive results in 3 trials. Aim : We analyzed retrospectively the data in two Belgian centres in a non-selected population. Methods : Between January 2004 and October 2011, 48 patients with histologically proven recurrent, or unresectable pancreatic adenocarcinoma who had received cisplatin and 5FU - leucovorin (modified de Gramont) as 2nd line therapy were identified. We retrospectively analyzed the following parameters : progression free survival and overall survival for each line (after the start of 1st and 2nd line). We also assessed the efficacy of the 2nd line regimen by the growth modulation index or progression free survival ratio. Results : The median progression free survival after the start of 1st line was 5,4 months (95% CI 4,1 - 6,6). The median progression free survival after the start of 2nd line was 3,6 months (95% CI 1,8-5,5). More interestingly, the median overall survival after the start of 1st line was 12 months (95% CI 9,4-14,6). The 2- and 1-year survival rate after the start of 1st line therapy were 8% (4/48) and 50% (24/48), respectively. Twenty three percent of patients had a growth modulation index > 1,33, referring to a benefit in progression free survival of 2nd line therapy that was greater than that of treatment in 1st line. Conclusions : We show an overall survival close to 12 months with cisplatinum-5FU in 2nd line therapy in a retrospective analysis, an overall survival that is higher than what has been described before. This good result was not due to selection of a patient population that responds well to chemotherapy, since 23% of patients showed a longer progression free survival in 2nd line than in 1st line. These results are in agreement with what is found in the literature : both combination therapy with oxaliplatin and cisplatin show promising results in pancreatic cancer. Oxaliplatin may be preferred because of its lower toxicity, but a recent meta-analysis shows more efficacy for cisplatin. Sequential therapy with good overall survival and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer

Prognostic value of tumor shrinkage versus fragmentation following radiochemotherapy and surgery for rectal cancer

Most patients with rectal cancer receive neoadjuvant radiochemotherapy (RCT), causing a variable decrease in tumor mass. We evaluated the prognostic impact of pathologic parameters reflecting tumor response to RCT, either directly or indirectly. Seventy-six rectal cancer patients receiving neoadjuvant RCT between 2006 and 2009 were included. We studied the association between disease-free survival (DFS) and the "classical" clinicopathologic features as well as tumor deposits, circumferential resection margin (CRM), Dworak regression grade, and tumor and nodal downstaging. Patients with tumor downstaging had a longer DFS (p = 0.05), indicating a more favorable prognosis when regression was accompanied by a decrease in tumor infiltrative depth, referred to as tumor shrinkage. Moreover, tumor downstaging was significantly associated with larger CRM and nodal downstaging (p = 0.02), suggesting that shrinkage of the primary tumor was associated with a decreased nodal tumor load. Higher Dworak grade did not correlate with tumor downstaging, nor with higher CRM or prolonged DFS. This implies that tumor mass decrease was sometimes due to fragmentation rather than shrinkage of the primary tumor. Lastly, the presence of tumor deposits was clearly associated with reduced DFS (p = 0.01). Assessment of tumor shrinkage after RCT via tumor downstaging and CRM is a good way of predicting DFS in rectal cancer, and shrinkage of the primary tumor is associated with a decreased nodal tumor load. Assessing regression based on the amount of tumor in relation to stromal fibrosis does not accurately discern tumor fragmentation from tumor shrinkage, which is most likely the reason why Dworak grade had less prognostic relevance