Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

Surgical site occurrences, not body mass index, increase the long-term risk of ventral hernia recurrence.

BACKGROUND: Recurrence rates after ventral hernia repair vary widely and evidence about risk factors for recurrence are conflicting. There is little evidence for risk factors for long-term recurrence. METHODS: Patients who underwent ventral hernia repair at our institution and were captured in the American College of Surgeons-National Surgical Quality Improvement Program database between 2002 and 2015 were included. We reviewed all demographic, procedural, and hernia-specific data. RESULTS: Six hundred and thirty patients were included for analysis with a median follow-up of 4.9 years (inter-quartile range, 2-7.3 years). By univariate analysis, index hernia repairs were more likely to recur if defect size was ≥4 cm (P = .019), no mesh was used (P = .026), or if the repair was for a recurrent hernia (P = .001). Five-year cumulative incidence of recurrence and reoperation was 24.3% and 16.0%, respectively. Patients with a perioperative surgical site occurrence, which included superficial, deep-incisional, and organ space surgical site infections as well as wound disruption, had a 5-year cumulative incidence of recurrence of 54.9% compared with 22.6% for those without surgical site occurrence. By multivariable analysis, non-primary hernia repair (hazard ratio 1.7, 95% confidence interval 1.2-2.4, P = .005) and any postoperative surgical site occurrence (hazard ratio 1.9, 95% confidence interval 1.1-3.6, P = .02) were the only risk factors predictive of recurrence. Patient body mass index had no independent effect on recurrence. CONCLUSION: 1 in 4 patients undergoing an open ventral hernia repair will have a recurrence after 5 years, and this risk is doubled among patients who experience any perioperative surgical site occurrence. After controlling for patient comorbidities, including body mass index, hernia size, and mesh position, the most significant risk factor for recurrence after ventral hernia repair was a non-primary hernia and surgical site occurrence.

Laparoscopic versus open splenectomy for splenomegaly: the verdict is unclear.

BACKGROUND: The benefits of laparoscopic splenectomy (LS) over open splenectomy (OS) for normal-sized spleens have been well documented. However, the role of laparoscopy for moderate and massive splenomegaly is debated. METHODS: A retrospective review of patients undergoing elective splenectomy at one institution from 1997 to 2017 was conducted. Moderate and massive splenomegaly was defined as splenic weight of 500-1000 g and greater than 1000 g, respectively. We performed a 1:2 matching of laparoscopic to open splenectomy to control for differences in splenic weight. Differences in perioperative morbidity (infection, thromboembolism, reoperation, readmission), intraoperative factors (blood loss, operative time), length of stay, and mortality were examined. RESULTS: A total of 491 elective splenectomies were identified. 268 cases were for splenic weights greater than 500 g. After a 1:2 matching of LS:OS, we identified 22 LS and 44 matched OS for moderate splenomegaly. The LS group had longer mean operative times (178 vs. 107 min, p < 0.01), with similar length of stay and blood loss. For massive splenomegaly, 26 LS were identified and matched to 52 OS. LS had longer mean operative times (171 vs. 112 min, p < 0.01) and higher readmission rates (27% vs. 6%, p < 0.05). Other factors and outcomes did not differ between LS and OS for moderate or massive splenomegaly. The conversion rate for LS was higher for massive versus moderate splenomegaly, but was not statistically significant (35% vs. 14%, p = 0.09). CONCLUSIONS: LS for moderate and massive splenomegaly is associated with longer operative times. Other perioperative outcomes were comparable to OS, with no demonstrated benefits for LS. Although LS may be a feasible approach to moderate and massive splenomegaly, its benefits require further clarification in this patient population.