Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Prescription drug utilization following patient co-payment changes in Australia

In November 1990 major patient co-payment changes were introduced into the Pharmaceutical Benefits Scheme (PBS), which accounts for around 90% of all community prescriptions in Australia. Interrupted time series analyses were performed to assess the impact of these co-payment changes on the prescription levels of defined groups of discretionary and essential drugs for both the general community and for a subgroup comprising elderly returned servicemen and women. While the co-payment changes themselves had a significant immediate effect on lowering the use of both categories of drugs, the effects were substantially larger for the discretionary groups in both cases. Notably there was a clear post-intervention trend for increased prescriptions of essential drugs after the initial decline, which was not evident for the discretionary drugs. The introduction of programmes to compensate high risk groups in Australia may have enabled the co-payment to become a more selective policy instrument than has been shown in other settings

Laparoscopic right hepatectomy: a challenging, but feasible, safe and efficient procedure

BACKGROUND: Few centers are undertaking major laparoscopic liver resections, because of the well-recognized technical difficulties and lack of training opportunities.METHODS: The authors describe their technique for laparoscopic right hepatectomy, highlighting relevant details for accomplishing a safe and efficient procedure. Patients were chronologically divided into 2 groups to evaluate the impact of increasing experience on the surgical outcomes.RESULTS: Group I included 17 patients and group II 18 patients. The conversion rate to open or hybrid techniques significantly decreased from 36% in group I to 6% in group II (P = .03). The hospital stay decreased from a median of 6 days in group I to a median of 4 days in group II (P = .05). Complications occurred in 4 patients (11%), of whom 3 were in group I. The mortality was zero.CONCLUSIONS: Laparoscopic right hepatectomy is a safe and efficient procedure when performed at specialized centers with extensive experience in hepatic surgery. Long-term training is necessary to acquire adequate expertise.<br/

Single-centre comparative study of laparoscopic versus open right hepatectomy

BackgroundExpansion of laparoscopic major hepatectomy is still limited mainly due to the well-recognised technical difficulties compared to open surgery, and doubts regarding the oncological efficiency when major resections are required.MethodsPatients undergoing open right hepatectomy (ORH) were matched with patients undergoing laparoscopic right hepatectomy (LRH) and compared for perioperative outcomes.ResultsSeventy patients were included: 36 patients underwent LRH and 34 ORH. Operative time was significantly longer for LRH (median, 300 min vs. 180 min for ORH; p?&lt;?0.0001). Intensive care unit (median, 2 days for LRH vs. 4 days for ORH; p?&lt;?0.0001) and postoperative length of stay (5 days for LRH vs. 9 days for ORH; p?&lt;?0.0001) were significantly shorter for LRH. Four laparoscopic cases were converted to open surgery. No significant difference in postoperative complications and mortality was observed between LRH and ORH. Among patients with colorectal carcinoma liver metastases, R0 resection was obtained in 20/21 (95%) cases after LRH, and in 20/25 (80%) after ORH (p?=?0.198). Mid-term overall survival did not significantly differ between the laparoscopic and the open group.ConclusionsLRH can be a safe, effective, and oncologically efficient alternative to open resection in selected cases. Extensive experience in hepatic and laparoscopic surgery is required

Surgical management of benign and indeterminate hepatic lesions in the era of laparoscopic liver surgery

Background/Aims: The expansion of the laparoscopic approach for the management of benign liver lesions has raised concerns regarding the risk of widening surgical indications and compromising safety. Large single-centre series focusing on laparoscopic management of benign liver lesions are sporadic. Methods: We reviewed a prospectively collected database of patients undergoing pure laparoscopic liver resection (LLR) for benign liver lesions. All cases were individually discussed at a multidisciplinary team meeting. Results: Forty-six patients underwent 50 LLRs for benign disease. Indications for surgery were: symptomatic lesions, preoperative diagnosis of adenoma or cystadenoma, and lesions with an indeterminate diagnosis. The preoperative diagnosis was uncertain in 11 cases. Of these, histological diagnosis was hepatocellular carcinoma in one (9%) and benign lesion in 10 patients (91%). Thirteen patients (28%) required major hepatectomy. Three patients (7%) developed postoperative complications. Mortality was nil. The median postoperative hospital stay following major and minor hepatectomy was 4 and 3 days, respectively. Conclusion: The laparoscopic approach represents a safe option for the management of benign and indeterminate liver lesions, even when major hepatectomy is required. LLR should be only performed in specialized centres to ensure safety and strict adherence to orthodox surgical indication

Exploring the role of laparoscopic surgery in two-stage hepatectomy for bilobar colorectal liver metastases

BACKGROUND: The role of laparoscopy in two-stage hepatectomy for bilobar colorectal liver metastases (CRLMs) has not yet been extensively investigated.PATIENTS AND METHODS: We reviewed a prospectively collected database of 302 consecutive patients undergoing laparoscopic liver resection at our institution between 2003 and 2011.RESULTS: Eight patients undergoing laparoscopic first/second-stage hepatectomy for bilobar CRLMs (male/female 6:2; median age, 64 years) were analyzed. The first stage consisted of laparoscopic clearance of the left lobe in all patients with no postoperative morbidity and mortality. Seven patients underwent portal vein embolization or ligation. The median interval between first- and second-stage hepatic resections was 89 days (range, 36-123 days). Second-stage hepatectomy with right lobar clearance (open, n=5; laparoscopic, n=2; laparoscopic to open, n=1) was associated with no mortality and an operative morbidity rate of 50%. Adhesions were judged to be minimal or absent during the second-stage procedure. Complications included intra-abdominal collection (n=2), bleeding requiring re-operation (n=1), and bile leak (n=1). R0 resection was obtained in 7 of 8 cases after first-stage resection and in 8 of 8 cases after second-stage resection. Three patients (38%) died from disease recurrence. Of the remaining 5 patients, 4 are disease-free at a median follow-up of 24 months (range, 9-27 months).CONCLUSIONS: The well-recognized advantages of laparoscopy may play a favorable role in the management of patients with bilobar CRLMs candidate for a two-stage resection. The first-stage laparoscopic clearance of the left lobe could progressively become the "gold standard." Laparoscopic second-stage hepatectomy should be limited to selected cases