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Objectives The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. Methods Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged Results Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. Conclusion The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

Simple Summary Therapies for squamous cell carcinomas of the head and neck (SCCHN) have been rapidly evolving, initially with the inclusion of immunotherapy, but more recently with the consideration of anti-angiogenic therapies. Recent preclinical and clinical data reveal a strong correlation between vascular endothelial growth factor (VEGF) and the progression of SCCHN, with nearly 90% of these malignancies expressing VEGF. Our review article not only elaborates on the utility of anti-VEGF therapies on SCCHN but also its interaction with the immune environment. Furthermore, we detailed the current data on immunotherapies targeting SCCHN and how this could be coupled with anti-angiogenics therapies. Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has been correlated with a worse clinical prognosis and an increased resistance to chemotherapeutic agents. As immunotherapy is currently at the forefront of the management of advanced SCCHN, revisiting the rationale for targeting angiogenesis in this disease has become an even more attractive proposition.

Background When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs). Aim To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies. Methods A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea. Results We included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide. Conclusions Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.

Background : Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease. Methods : The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia ( Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients. Three (14%) patients had an ANC 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98). Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC Disclosures No relevant conflicts of interest to declare.

Background : Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods : 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.