Diagnostic performance of non-invasive liver fibrosis scores in patients with early-intermediate hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) arises in individuals with underlying liver disease. Diagnosing the degree of hepatic fibrosis helps to determine the severity of the underlying liver disease and may influence therapeutic decisions in HCC patients. Non-invasive fibrosis scores can be used to estimate the degree of fibrosis in liver disease patients, but most of these scores were developed in patients with viral hepatitis and without HCC. This study explored the ability of the Fibrosis-4 Index (FIB-4), the AST/Platelet Ratio Index (APRI), and the AST/ALT ratio to diagnose or exclude advanced fibrosis (METAVIR F3/4 versus F0-2) in patients with early-intermediate, potentially resectable HCC. METHODS: We retrospectively reviewed 119 patients who underwent hepatic resection for HCC at a tertiary centre (2007-2019), 75 of whom had advanced fibrosis (prevalence 63%). Histological assessment of the surgical liver specimen was used as a reference standard for the degree of fibrosis. RESULTS: Overall diagnostic performance was highest for the FIB-4 Index, with an area under the receiver operating characteristic curve (AUROC) of 0.82, compared with 0.78 for APRI, and 0.56 for the AST/ALT ratio. Using established cut-off values, FIB-4 achieved a 90% positive predictive value at the higher cut-off (3.25) and a 90% negative predictive value at the lower cut-off (1.45). CONCLUSION: The FIB-4 Index could reliably diagnose or exclude advanced fibrosis in patients with early-intermediate HCC, and may thus have a role in guiding therapeutic decisions in these patients.

Systemic Drugs for Hepatocellular Carcinoma: What Do Recent Clinical Trials Reveal About Sequencing and the Emerging Complexities of Clinical Decisions?

Liver cancer was the fourth leading cause of cancer death in 2015 with increasing incidence between 1990 and 2015. Orthotopic liver transplantation, surgical resection and ablation comprise the only curative therapy options. However, due to the late manifestation of clinical symptoms, many patients present with intermediate or advanced disease, resulting in no curative treatment option being available. Whereas intermediate-stage hepatocellular carcinoma (HCC) is usually still addressable by transarterial chemoembolization (TACE), advanced-stage HCC is amenable only to pharmacological treatments. Conventional cytotoxic agents failed demonstrating relevant effect on survival also because their use was severely limited by the mostly underlying insufficient liver function. For a decade, tyrosine kinase inhibitor (TKI) sorafenib was the only systemic therapy that proved to have a clinically relevant effect in the treatment of advanced HCC. In recent years, the number of substances for systemic treatment of advanced HCC has increased enormously. In addition to tyrosine kinase inhibitors, immune checkpoint inhibitors (ICI) and antiangiogenic drugs are increasingly being applied. The combination of anti-programmed death ligand 1 (PD-L1) antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has become the new standard of care for advanced HCC due to its remarkable response rates. This requires more and more complex clinical decisions regarding tumor therapy. This review aims at summarizing recent developments in systemic therapy, considering data on first- and second-line treatment, use in the neoadjuvant and adjuvant setting and combination with locoregional procedures.

Chemotherapy and Targeted Therapy Strategies in Patients with Unresectable or Borderline Resectable Metastatic Colorectal Cancer: Evidence for a Lack of Focus on Resection Rates.

BACKGROUND AND AIMS: Chemotherapy (CTx) with targeted therapy (TT) have increased the overall response rate (ORR) and improved survival in unresectable or borderline resectable metastatic colorectal cancer (mCRC). However, the resection rate is an endpoint with often suboptimal expert involvement. The aim was to investigate whether the improvements in ORR have translated to improved resection rates (RR). STUDY DESIGN: A systematic literature search was performed using the PICO process. STATISTICAL ANALYSIS: Odds ratios, and 95% confidence intervals (OR, 95% CI) were analyzed for ORR and RR using dichotomous values with the Mantel-Haenszel method. Progression-free survival (PFS) and overall survival (OS) were analyzed using the inverse-variance method and displayed as hazard ratios and 95% confidence intervals (HR, 95% CI). RESULTS: The literature search returned 469 records. Sixteen articles with 5724 patients were selected for analysis. The qualitative analysis revealed low and moderate risk of bias endpoints. Higher ORR was observed with CTx + TT versus CTx only (OR: 0.62 [95% CI 0.45; 0.82], p = 0.002) and with triplet CTx + TT versus doublet CTx + TT (OR: 0.61 [95% CI 0.46; 0.81], p < 0.001). PFS and OS were improved by use of TT (HR: 0.68-0.84; p < 0.001 to 0.04). The overall RR was low (< 15%) and did not improve in the same way as the other endpoints. CONCLUSION: The ORR and survival rates in unresectable and borderline resectable mCRC were improved by modern CTx and TT that did not translate into higher RR, mostly due to the lack of expert involvement.

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

PURPOSE: Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC). METHODS: A total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy. RESULTS: 8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0-57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1-3. CONCLUSION: The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

Short-term outcome of diverting loop ileostomy reversals performed by residents: a retrospective cohort prognostic factor study.

AIM: The reversal of diverting loop ileostomy (DLI) is one of surgical trainees' first procedures. Complications of DLI reversal can cause life-threatening complications and increase patient morbidity. This study compared DLI reversals performed by surgical trainees with those by attending surgeons. METHOD: This retrospective cohort study was performed at a single primary care center on 300 patients undergoing DLI reversal. The primary outcome was morbidity, according to the Clavien-Dindo classification (CDC), with special attention paid to the surgeon's level of training. The secondary endpoint was postoperative intestinal motility dysfunction. RESULTS: Surgical trainees had significantly longer operation times (p < 0.001) than attending surgeons. Univariate analyses revealed no influence on the level of training for postoperative morbidity. First bowel movement later than 3 days after surgery was a significant risk factor for CDC [Formula: see text] 3 (OR, 4.348; 96% CI, 1670-11.321; p = 0.003). Independent risk factors for surgical site infections (SSIs) were an elevated BMI (OR, 1.162; 95% CI, 1.043-1.1294; p = 0.007) and a delayed bowel movement (OR, 3.973; 95% CI, 1.300-12.138; p = 0.015). For postoperative intestinal motility dysfunction, an independent risk factor was a primary malignant disease (OR, 1.980; 95% CI, 1.120-3.500; p = 0.019), and side-to-side stapled anastomosis was a protective factor (OR, 0.337; 95% CI 0.155-0.733; p = 0.006). CONCLUSION: Even though surgical trainees needed significantly more time to perform the surgery, the level of surgical training was not a risk factor for increased postoperative morbidity. Instead, delayed first bowel movement was predictive of SSI.

Impact of IDH1 mutation on clinical course of patients with intrahepatic cholangiocarcinoma: a retrospective analysis from a German tertiary center.

PURPOSE: IDH1 mutation is a known biomarker for targeted therapy of intrahepatic cholangiocarcinoma (iCCA), while its prognostic relevance for current palliative chemotherapy is still unclear. Aim of this study was to analyze clinicopathological characteristics of patients with IDH1 mutations and to outline a potential impact on the outcome after state-of-the-art palliative chemotherapy regimens. METHODS: All patients with iCCA receiving large panel molecular profiling and follow-up treatment at Frankfurt University Hospital until 04/2022 were retrospectively analyzed. Clinicopathological characteristics were assessed for IDH1 mutated (mut) and IDH1 wild type (wt) patients, and progression-free survival (PFS) and overall survival (OS) were determined. RESULTS: In total, 75 patients with iCCA received molecular profiling. Of the patients with available DNA data, pathogenic mutations in IDH1 were found in 14.5% (n = 10). IDH1 mut status was associated with lower serum CA-19/9 (p = 0.023), lower serum lactate dehydrogenase (p = 0.006), and a higher proportion of primary resectability (p = 0.028) as well as response to chemotherapy after recurrence (p = 0.009). Median PFS was 5.9 months (95% CI 4.4-7.3 months) for IDH1 wt in comparison to 9.8 months (95% CI 7.7-12 months) for patients with IDH1 mut (p = 0.031). IDH1 wt was a significant risk factor for shortened PFS in univariate (p = 0.043), but not in multivariate analysis (p = 0.061). There was no difference in OS between both groups. CONCLUSION: Patients with IDH1 mutated iCCA seem to have a favorable tumor biology including a longer PFS for palliative chemotherapy regimens compared to IDH1 wild type.

Prognostic value of paraaortic lymph node metastases in patients with ductal adenocarcinoma of the pancreatic head.

INTRODUCTION: The role of paraaortic lymphadenectomy for cancer of the pancreatic head is controversial. The aim of this study is to analyze the prognostic role of paraaortic lymph node (PALN) metastases after resection for ductal adenocarcinoma of the pancreatic head. MATERIALS AND METHODS: A retrospective analysis of all patients, who underwent upfront resection for ductal adenocarcinoma of the pancreatic head at the Frankfurt University Hospital from 2011 to 2020 was performed. The primary endpoint was survival, according to the presence of PALN metastases. RESULTS: Out of 468 patients with pancreatic resection, 148 had an upfront resection for ductal adenocarcinoma. Of those, in 125 (85%) a paraaortic lymphadenectomy was performed. In 19 (15.2%) PALN metastases were detected. The estimated overall median survival after resection was 21.7 months (95% CI 18.8 to 26.4), the disease free survival 16 months (95% CI 12 to 18). Among the patients with lymph node metastases, PALN metastases had no significant influence on overall (18.9 versus 19 months, HR = 1.3, 95% CI 0.7 to 2.6, p = 0.392) or disease free survival (14 versus 10.7 months, HR = 1.7, 95% CI 0.9 to 3.2, p = 0.076). After adjusting for T-stage, N-stage, grade, resection margin, PALN metastases, and adjuvant therapy, only adjuvant therapy had a prognostic significance for overall survival (HR = 0.47, 95% CI 0.26 to 0.85, p = 0.013). CONCLUSION: Patients with ductal adenocarcinoma of the pancreatic head and PALN metastases do not have inferior outcomes than those with regional lymph node metastases. Thus, positive PALN should not be considered a contraindication for resection.

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). CASE PRESENTATION: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. CONCLUSIONS: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors.

INTRODUCTION: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. PATIENTS AND METHODS: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). RESULTS: 45.5% female, median age 60 years (range, 27-84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90-98), 3-year OS = 84.3 (CI: 78-90) and 5-year OS = 77.5 (CI: 70-85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. CONCLUSIONS: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.

Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis.

BACKGROUND AND AIMS: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. METHODS: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). RESULTS: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). CONCLUSIONS: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation.

Low Platelet Count Predicts Reduced Survival in Potentially Resectable Hepatocellular Carcinoma.

The prognostic role of platelet count in hepatocellular carcinoma (HCC) remains unclear, and in fact both thrombocytopenia and thrombocytosis are reported as predictors of unfavourable outcomes. This study aimed to clarify the prognostic value of preoperative platelet count in potentially resectable HCC. We retrospectively reviewed 128 patients who underwent hepatic resection for HCC at a tertiary academic centre (2007−2019). Patient data were modelled by regression analysis, and platelet count was treated as a continuous variable. 89 patients had BCLC 0/A tumours and 39 had BCLC B tumours. Platelet count was higher in patients with larger tumours and lower in patients with higher MELD scores, advanced fibrosis, and portal hypertension (p < 0.001 for all listed variables). After adjusting for BCLC stage and tumour diameter, low platelet count associated with reduced overall survival (hazard ratio 1.25 per 50/nL decrease in platelet count, 95% confidence interval (CI) 1.02−1.53, p = 0.034) and increased perioperative mortality (odds ratio 1.96 per 50/nL decrease in platelet count, 95% CI 1.19−3.53, p = 0.014). Overall, low platelet count correlates with increased liver disease severity, inferior survival, and excess perioperative mortality in resectable HCC. These insights might be applied in clinical practice to better select patients for resection.

Decomposition of Organic Perovskite Precursors on MoO3: Role of Halogen and Surface Defects.

Despite the rapid progress in perovskite solar cells, their commercialization is still hindered by issues regarding long-term stability, which can be strongly affected by metal oxide-based charge extraction layers next to the perovskite material. With MoO3 being one of the most successful hole transport layers in organic photovoltaics, the disastrous results of its combination with perovskite films came as a surprise but was soon attributed to severe chemical instability at the MoO3/perovskite interface. To discover the atomistic origin of this instability, we combine density functional theory (DFT) calculations and X-ray photoelectron spectroscopy (XPS) measurements to investigate the interaction of MoO3 with the perovskite precursors MAI, MABr, FAI, and FABr. From DFT calculations we suggest a scenario that is based upon oxygen vacancies playing a key role in interface degradation reactions. Not only do these vacancies promote decomposition reactions of perovskite precursors, but they also constitute the reaction centers for redox reactions leading to oxidation of the halides and reduction of Mo. Specifically iodides are proposed to be reactive, while bromides do not significantly affect the oxide. XPS measurements reveal a severe reduction of Mo and a loss of the halide species when the oxide is interfaced with I-containing precursors, which is consistent with the proposed scenario. In line with the latter, experimentally observed effects are much less pronounced in case of Br-containing precursors. We further find that the reactivity of the MoO3 substrate can be moderated by reducing the number of oxygen vacancies through a UV/ozone treatment, though it cannot be fully eliminated.

Sequence Therapy with FOLFIRINOX and Gemcitabine/Nab-Paclitaxel for Patients with Advanced Pancreatic Cancer: A Monocentre Retrospective Cohort Study.

BACKGROUND AND AIMS: While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, gemcitabine monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of gemcitabine and nab-paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial. METHODS: Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective monocentre study (November 2010 - July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival (OS), and secondary end points included progression-free survival (PFS), response rate, and safety. RESULTS: In most of the patients, FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response [PR]: 50% and stable disease [SD]: 18%), whereas tumour progression was observed in 23% of the patients. The median PFS time for FOLFIRINOX treatment was 7.3 months and median OS 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumour. During first-line therapy, in 8 (18%) patients, laparotomy was performed to proof resectability of the tumour. Hereby, in 3 patients R0- and in 3 patients R1 resection was achieved, whereas 2 patients stayed irresectable. Twenty-five of the 44 patients (57%) received second-line therapy, namely, 24 patients gemcitabine/nab-paclitaxel and 1 patient gemcitabine and erlotinib. Hereby, gemcitabine/nab-paclitaxel led again to temporary tumour control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patients, disease progression was observed. Corresponding median PFS for gemcitabine and nab-paclitaxel treatment was 3.5 months. Patients who received second-line treatment with nab-paclitaxel and gemcitabine had a more favourable prognosis (median OS: 17 vs. 9.2 months; HR 0.32 [0.14-0.70], p < 0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients' survival and tumour response to chemotherapy in both therapeutic lines and µGT concentrations below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed. CONCLUSION: These real-world data suggest that gemcitabine/nab-paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to gemcitabine monotherapy are needed.

Genetic × environment variation in sheep lines bred for divergent resistance to strongyle infection.

Drug-resistant parasites threaten livestock production. Breeding more resistant hosts could be a sustainable control strategy. Environmental variation linked to animal management practices or to parasite species turnover across farms may however alter the expression of genetic potential. We created sheep lines with high or low resistance to Haemonchus contortus and achieved significant divergence on both phenotypic and genetic scales. We exposed both lines to chronic stress or to the infection by another parasite Trichostrongylus colubriformis, to test for genotype-by-environment and genotype-by-parasite species interactions respectively. Between-line divergence remained significant following chronic stress exposure although between-family variation was found. Significant genotype-by-parasite interaction was found although H. contortus-resistant lambs remained more resistant against T. colubriformis. Growth curves were not altered by the selection process although resistant lambs were lighter after the second round of divergence, before any infection took place. Breeding for resistance is a sustainable strategy but allowance needs to be made for environmental perturbations and worm species.

Time from first tumor manifestation to diagnosis in patients with GEP-NET: Results from a large German tertiary referral center.

ABSTRACT: Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis.Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms.Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods.Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12-28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42).A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.

Partial Breast Irradiation and Surgical Clip Usage for Tumor Bed Delineation After Breast-Conserving Surgery in Canada: A Radiation Oncology Perspective.

PURPOSE: Our purpose was to evaluate the usage and perceived benefit of surgical clips for breast radiation therapy planning in Canada, focusing on partial breast irradiation (PBI) after breast-conserving surgery. METHODS AND MATERIALS: A retrospective institutional review identified patients eligible for PBI based on clinicopathologic criteria, and tumor bed visualization was determined from computed tomography-planning scans. An online survey was subsequently distributed to Canadian radiation oncologists addressing the usage and added value of surgical clips for breast radiation therapy planning purposes. The survey also evaluated PBI usage and regimens. Responses were collected over a 4-week period. PBI regimen usage at our institution was also reviewed from May 1 to December 18, 2020. RESULTS: Based on clinicopathologic criteria, 306 patients were identified between 2013 and 2018 who were eligible for PBI. However, only 24% (72/306) of cases were noted to have surgical clips, of which over 50% did not assist in tumor bed localization due to inconsistent clip positioning. Similarly, nearly two-thirds (28/43) of survey respondents indicated that surgical clips are placed in the tumor bed in less than 50% of cases. Almost all respondents (42/43) indicated that surgical clips facilitate breast radiation therapy planning and favor the development of guidelines to increase the consistent placement of surgical clips in the tumor bed after breast-conserving surgery. Approximately two-thirds of respondents (28/43) offer PBI to eligible patients as routine treatment, with moderate hypofractionated regimens most commonly recommended. However, the 1-week daily regimen of 26 Gy in 5 fractions is now offered to the majority (77%) of patients at our institution. CONCLUSIONS: There was strong agreement among Canadian radiation oncologists that surgical clip placement facilitates breast radiation therapy planning, and most favor the development of surgical guidelines for the consistent placement of surgical clips in this setting. With the growing use of PBI, accurate localization of the tumor bed is extremely important.

Magnetic Resonance Imaging for Breast Tumor Bed Delineation: Computed Tomography Comparison and Sequence Variation.

PURPOSE: Our purpose was to investigate the interobserver variability in breast tumor bed delineation using magnetic resonance (MR) compared with computed tomography (CT) at baseline and to quantify the change in tumor bed volume between pretreatment and end-of-treatment MR for patients undergoing whole breast radiation therapy. METHODS AND MATERIALS: Forty-eight patients with breast cancer planned for whole breast radiation therapy underwent CT and MR (T1, T1 fat-suppression [T1fs], and T2) simulation in the supine treatment position before radiation therapy and MR (T1, T1fs, and T2) at the end of treatment in the same position. Two observers delineated 50 tumor beds on the CT and all MR sequences and assigned cavity visualization scores to the images. The primary endpoint was interobserver variability, measured using the conformity index (CI). RESULTS: The mean cavity visualization scores at baseline were 3.14 (CT), 3.26 (T1), 3.41 (T1fs), and 3.58 (T2). The mean CIs were 0.65, 0.65, 0.72, and 0.68, respectively. T1fs significantly improved interobserver variability compared with CT, T1, or T2 (P < .001, P < .001, and P = .011, respectively). The CI for T1fs was significantly higher than T1 and T2 at the end of treatment (mean 0.72, 0.64, and 0.66, respectively; P < .001). The mean tumor bed volume on the T1fs sequence decreased from 18 cm3 at baseline to 13 cm3 at the end of treatment (P < .01). CONCLUSIONS: T1fs reduced interobserver variability on both pre- and end-of-treatment scans and measured a reduction in tumor bed volume during whole breast radiation therapy. This rapid sequence could be easily used for adaptive boost or partial breast irradiation, especially on MR linear accelerators.

Complete Pathological Response After Neoadjuvant Short-Course Immunotherapy with Ipilimumab and Nivolumab in Locally Advanced MSI-H/dMMR Rectal Cancer.

BACKGROUND: Patients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. MATERIAL AND METHODS: A 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. RESULTS: After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. CONCLUSION: In MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer. KEY POINTS: Immune checkpoint inhibitors are more active in treatment-naïve patients than in patients with refractory high-grade microsatellite instability (MSI-H)/deficiency in mismatch repair (dMMR) colorectal cancer. Standard neoadjuvant chemoradiation is less effective in MSI-H/dMMR rectal cancer patients than in patients with proficient mismatch repair. A young patient with Lynch syndrome and MSI-H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility. After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented. Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI-H/dMMR rectal cancer and thereafter to evaluate organ-preservation strategies.

Integrative biology defines novel biomarkers of resistance to strongylid infection in horses.

The widespread failure of anthelmintic drugs against nematodes of veterinary interest requires novel control strategies. Selective treatment of the most susceptible individuals could reduce drug selection pressure but requires appropriate biomarkers of the intrinsic susceptibility potential. To date, this has been missing in livestock species. Here, we selected Welsh ponies with divergent intrinsic susceptibility (measured by their egg excretion levels) to cyathostomin infection and found that their divergence was sustained across a 10-year time window. Using this unique set of individuals, we monitored variations in their blood cell populations, plasma metabolites and faecal microbiota over a grazing season to isolate core differences between their respective responses under worm-free or natural infection conditions. Our analyses identified the concomitant rise in plasma phenylalanine level and faecal Prevotella abundance and the reduction in circulating monocyte counts as biomarkers of the need for drug treatment (egg excretion above 200 eggs/g). This biological signal was replicated in other independent populations. We also unravelled an immunometabolic network encompassing plasma beta-hydroxybutyrate level, short-chain fatty acid producing bacteria and circulating neutrophils that forms the discriminant baseline between susceptible and resistant individuals. Altogether our observations open new perspectives on the susceptibility of equids to strongylid infection and leave scope for both new biomarkers of infection and nutritional intervention.