Cancer-associated mesothelial cells are regulated by the anti-Müllerian hormone axis.

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2-/- CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2-/- tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Are we overtreating patients with malignant colorectal polyps? A 5-year review of the ACPGBI position statement.

INTRODUCTION: In 2013, The Association of Coloproctology of Great Britain and Ireland (ACPGBI) issued a position statement regarding management of malignant polyps. We reviewed the management of endoscopically resected malignant colorectal polyps in a district general hospital to evaluate whether patients were being overtreated as per these guidelines. METHODS: All patients who underwent a complete, non-piecemeal endoscopic removal of a malignant polyp between October 2013 and September 2018 were studied. Polyps were risk stratified for residual disease and followed up as per the ACPGBI. Patients were divided into two groups based on management after polypectomy. Primary outcome measured was the presence of residual tumour or involved lymph nodes in the resection specimen. Secondary outcomes included complications and recurrence. RESULTS: Thirty-three patients were included: 21 in the non-operative group (NOG) and 12 in the operative group (OG). The ACPGBI risk score in the NOG varied between 1 and over 4 compared with the OG who all scored over 4. Two patients in the OG (16%) demonstrated residual disease. Five patients suffered a postoperative complication. No recurrences were noted in the OG and one in the NOG. CONCLUSION: Our findings against a backdrop of the available literature suggest that the risk of residual disease after malignant polypectomy may not be as high as stated by the ACPGBI. As a result, there is a risk of overtreating patients and exposing them to the significant complications of surgery if careful consideration is not exercised.

Neck failure following pathologically node-negative neck dissection (pN0) in oral squamous cell carcinoma: a systematic review and meta-analysis.

Due to the risk of occult cervical metastasis, elective neck dissection (END) is recommended in the management of patients with early oral cavity squamous cell carcinoma (OSCC) and a clinically node-negative (cN0) neck. This paper presents a systematic review and meta-analysis of studies that recorded isolated regional recurrence (RR) in the pathologically node-negative neck dissection (pN0) neck following END in order to quantify the failure rate. Pubmed and Ovid databases were systematically searched for relevant articles published between January 2009 and January 2019. Studies reporting RR following END in patients with OSCC who had no pathological evidence of lymph node metastasis were eligible for inclusion in this meta-analysis. In addition, a selection of large head and neck units were invited to submit unpublished data. Search criteria produced a list of 5448 papers, of which 18 studies met the inclusion criteria. Three institutions contributed unpublished data. This included a total of 4824 patients with median follow-up of 34 months (2.8 years). Eight datasets included patients staged T1-T4 with RR 17.3% (469/2711), 13 datasets included patients staged T1-T2 with RR 7.5% (158/2113). Overall across all 21 studies, isolated neck recurrence was identified in 627 cases giving a RR of 13.0% (627/4824) on meta-analysis. Understanding the therapeutic effectiveness of END provides context for evaluation of clinical management of the cN0 in these patients. A pathologically negative neck does not guarantee against future recurrence.

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Emergency hip disarticulations for severe necrotising fasciitis of the lower limb: a series of rare cases from a rural district general hospital.

Hip disarticulation is the removal of the entire lower limb through the hip joint by detaching the femur from the acetabulum. This major ablative procedure is rarely performed for infection but may be required in severe necrotising fasciitis. We present a single centre retrospective review of all cases of emergency hip disarticulations in patients with necrotising fasciitis between 2010 and 2020. All five patients included in the review presented with acute lower limb pain and sepsis. Three patients had comorbidities predisposing them to necrotising fasciitis. Three were deemed to be high risk and two were at intermediate risk of developing necrotising fasciitis. There were two deaths in the postoperative period. Of the three survivors, two required revision surgery for a completion hindquarter amputation and one for flap closure. All three survivors had good functional outcomes after discharge from hospital. Despite its associated morbidity, emergency amputation of the entire lower limb is a life-saving treatment in cases of rapidly progressing necrotising fasciitis and should be considered as a first-line option in managing this condition.

Volume and location of the defect as predictors of speech outcome after glossectomy: correlation with a classification.

The evaluation of speech outcomes after resection and reconstruction of the oral tongue remains largely unsystematic. A cross-sectional study was performed to analyse the speech outcomes of patients who underwent curative treatment with appropriate reconstruction. Sixty-nine patients were assessed for speech intelligibility and phonetics using a validated speech intelligibility assessment tool in the local language. Volume defects were classified as class I (less than one third), II (one third to half), III (half to two-thirds), or IV (two-thirds to total glossectomy). Defect location was defined as lateral, tip, or sulcus. The χ2 test and Kruskal-Wallis test were used to test volume and location as predictors. Twenty-six patients had class I defects, 29 had class II defects, seven had class III defects, and seven had class IV defects. Twenty-two patients (31.9%) received adjuvant radiotherapy. Mean vowel, consonant, word, and paragraph intelligibility were 99.27%, 86.86%, 85.52%, and 88.72%, respectively. The incremental volume of the glossectomy defect was significantly correlated with speech intelligibility scores and phonatory alterations. In classes II and III, tip resection significantly affected interdental sounds. All patients in class III had affected alveolar and alveo-palatal sounds. The results positively corroborated the volume and location of the glossectomy defect to a classification system.

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

Efficacy of small-volume gastrografin videofluoroscopic screening for detecting pharyngeal leaks following total laryngectomy.

OBJECTIVES: Pharyngocutaneous fistulae are dreaded complications following total laryngectomy. This paper presents our experience using 3-5 ml gastrografin to detect pharyngeal leaks following total laryngectomy, and compares post-operative videofluoroscopy with clinical follow-up findings in the detection of pharyngocutaneous fistulae. METHODS: A retrospective case-control study was conducted of total laryngectomy patients. The control group (n = 85) was assessed clinically for development of pharyngocutaneous fistulae, while the study group (n = 52) underwent small-volume (3-5 ml) post-operative gastrografin videofluoroscopy. RESULTS: In the control group, 24 of 85 patients (28 per cent) developed pharyngocutaneous fistulae, with 6 requiring surgical correction. In the study group, 24 of 52 patients (46 per cent) had videofluoroscopy-detected pharyngeal leaks; 4 patients (8 per cent) developed pharyngocutaneous fistulae, but all cases resolved following non-surgical management. Patients who underwent videofluoroscopy had a significantly lower risk of developing pharyngocutaneous fistulae; sensitivity and specificity in the detection of pharyngocutaneous fistulae were 58 per cent and 100 per cent respectively. CONCLUSION: Small-volume gastrografin videofluoroscopy reliably identified small pharyngeal leaks. Routine use in total laryngectomy combined with withholding feeds in cases of early leaks may prevent the development of pharyngocutaneous fistulae.

Propensity score-matched analysis of early outcomes after laparoscopic-assisted versus open pancreaticoduodenectomy.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (PD) is a feasible option for periampullary tumours. However, it remains a complex procedure with no proven advantages over open PD (OPD). The aim of the study was to compare the outcomes between laparoscopic-assisted PD (LAPD) and OPD using a propensity score-matched analysis. METHODS: Retrospective review of 40 patients who underwent PD for periampullary tumours between January 2014 and December 2016 was conducted. The patients were matched 1:1 for age, gender, body mass index, Charlson comorbidty index, tumour size and haematological indices. Peri-operative outcomes were evaluated. RESULTS: LAPD appeared to have a longer median operative time as compared to OPD (LAPD, 425 min (285-597) versus OPD, 369 min (260-500)) (P = 0.066). Intra-operative blood loss was comparable between both groups. Respiratory complications were five times higher in the OPD group (LAPD, 5% versus OPD, 25%) (P = 0.077), while LAPD patients required less time to start ambulating post-operatively (LAPD, 2 days versus OPD, 2 days) (P = 0.021). Pancreas-specific complications and morbidity/mortality rates were similar. CONCLUSION: LAPD is a safe alternative to OPD in a select group of patients for an institution starting out with minimally invasive PD, and can be used to bridge the learning curve required for total laparoscopic PD.

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PURPOSE: In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. METHODS: In this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). RESULTS: After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained. CONCLUSIONS: With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.

Impact of postoperative radiotherapy on survival and loco-regional control in node-negative oral cavity tumours classified as T3 using the AJCC Cancer Staging Manual eighth edition.

According to the eighth edition of the AJCC Cancer Staging Manual (AJCC8), a depth of invasion (DOI) >10mm is classified as pT3, representing a locally advanced tumour requiring postoperative radiotherapy (PORT). When node-negative, however, evidence regarding whether PORT improves loco-regional control or survival is unclear. To clarify this, two cohorts of patients were studied: (1) patients classified as pT3N0 by the seventh edition of the AJCC manual (AJCC7), with DOI >10mm and a tumour diameter >4cm (17 patients who received PORT), and (2) patients classified as pT1N0 and pT2N0 by AJCC7, with DOI >10mm and a tumour diameter <4cm (55 patients who did not receive PORT). Loco-regional control and survival were analysed. PORT was found not to impact overall survival or disease-free survival. It was also found not to impact local, regional, or distant recurrence. Although the two subsets of patients considered here (DOI >10mm with tumour diameter below or above 4cm) were previously distinct, they are both considered pT3 in AJCC8. Data from this study indicate that the routine administration of PORT to patients with a DOI >10mm may not be warranted in the absence of other risk features such as nodal disease or close margins.

Secondary lymphedema after head and neck cancer therapy: A review.

Secondary head and neck lymphedema (SHNL) is a chronic condition affecting patients who have undergone treatment for head and neck cancers. It results from the disruption of normal lymphatic flow by surgery and/or radiation. The incidence of secondary head and neck lymphedema varies anywhere between 12 and 54% of all patients treated for head and neck cancer, but it is still commonly under-diagnosed in routine clinical practice. In spite of awareness of this condition, treatment has been difficult as definitive staging, diagnostic, and assessment tools are still under development. This review article is aimed at looking at the evidence, standards of management, and deficiencies in current literature related to SHNL to optimize management of these patients and improve their quality of life.

Determinants of level Ib involvement in oral squamous cell carcinoma and implications for submandibular gland-sparing neck dissection.

Traditional neck dissection for oral squamous cell carcinoma (OSCC) involves removal of the submandibular salivary gland. Several studies have cited the low incidence of direct gland invasion by tumours and have recommended gland-sparing neck dissection. In this study, a detailed audit of level Ib involvement in OSCC was performed in order to assess the feasibility of submandibular gland-sparing in neck dissection; the rate of direct involvement by the primary tumours, the involvement of periglandular level Ib nodes, and their determinants were investigated. A total of 586 neck dissection specimens obtained between 2005 and 2014 from patients operated on at the study institution for floor of mouth, tongue, and buccal primaries, were evaluated for direct invasion of the gland and periglandular lymphadenopathy. Of 226 node-positive patients, 21 (9.3%) had direct gland invasion by tumour. Risk factors were tumour diameter >4cm (P=0.002) and depth of invasion >10mm (P=0.003). Determinants of periglandular lymphadenopathy were depth of invasion >10mm (P<0.001), perineural invasion (P=0.02), lymphovascular invasion (P=0.014), and moderate/poor differentiation (P<0.0001). Gland-sparing neck dissection is safe in early tumours (pT1pN0-1), with a good chance of minimizing xerostomia without radiotherapy. Larger tumours without clear evidence of submandibular gland invasion or suspicious level Ib lymphadenopathy may be considered for gland preservation, however the oncological safety is unclear.

Frey's syndrome following a facial burn treated with botulinum toxin.

Frey's syndrome occurs as a result of damage to the auriculotemporal nerve, which causes inappropriate regeneration of damaged parasympathetic fibres to salivary glands to innervate the sympathetic receptors of sweat glands in the face. The symptoms are pathological flushing and sweating with gustatory stimuli. It most commonly occurs following parotid surgery and has not previously been reported following burn injury. We present a 50-year-old man who sustained 1% TBSA full thickness burn to the right side of his face as a child. This was excised and reconstructed with skin grafts as well as further revision procedures in his adult life. He incidentally reported copious amounts of gustatory sweating over his right temple region that had been present since his initial injury, occurring prior to any reconstruction, consistent with Frey's syndrome. This was confirmed with a starch iodine test, and successfully treated with Botulinum toxin injections post reconstruction. This case is the first report of Frey's syndrome following burn injury. We highlight the potential development of Frey's syndrome following facial burns, even in the reconstructed area. Botulinum toxin treatment remains effective.

Le syndrome de Frey est le résultat d'une lésion du nerf auriculo- temporal. C'est la régénération aberrante, au cours de leur trajet vers les glandes salivaires, des fibres parasympathiques endommagées innervant les récepteurs sympathiques des glandes sudoripares de la face, qui en est responsable. Les symptômes sont une rougeur pathologique et une hypersudation lors de stimulations gustatives. Il apparaît plus généralement lors de la chirurgie parotidienne et n'a jamais été rapporté après une brûlure. Nous rapportons l'observation d'un homme de 50 ans qui avait présenté dans l'enfance une brûlure profonde du côté droit du visage (surface 1 %). Cette brûlure avait été excisée et réparée par des greffes cutanées, et suivie de plusieurs retouches chirurgicales à l'âge adulte. Il décrivait, la survenue, lors de stimulations gustatives, d'importants phénomènes de sudation, au niveau de sa région temporale droite, et ce depuis le traumatisme initial et avant toute réparation réalisant un syndrome de Frey. Ceci fut confirmé par un test à l'iode-amidon et fut traité par des injections de toxine botulique après la reconstruction. Ce cas est le premier report d'un syndrome de Frey après une brûlure. Nous soulignons le développement possible d'un syndrome de Frey à la suite d'une brulure de la face, évoluant même après sa réparation. La toxine botulique reste une thérapeutique efficace.

Peri-operative outcomes following major surgery for head and neck cancer in the elderly: institutional audit and case-control study.

OBJECTIVE: Elderly patients have been consistently shown to receive suboptimal therapy for cancers of the head and neck. This study was performed to determine the peri-operative outcomes of these patients and compare them with those of younger patients. METHODS: In this retrospective analysis, 115 patients aged 70 years or more undergoing major surgery for head and neck cancers were matched with 115 patients aged 50-60 years, and univariate analysis was performed. RESULTS: Elderly patients had a reduced performance status (p < 0.001) and more co-morbid illnesses (p = 0.007), but a comparable intra-operative course. They had a longer median hospital stay (p = 0.016), longer intensive care unit stay (p = 0.04), longer median tracheostomy dependence (p = 0.04) and were more often discharged with feeding tubes (p < 0.001). They also had a higher incidence of post-operative non-fatal cardiac events (p = 0.045). CONCLUSION: Elderly patients with good performance status should receive curative-intent surgery. Although hospital stay and tube dependence are longer, morbidity and mortality are comparable with younger patients.

Real-world outcomes in patients with ALK-positive non-small cell lung cancer treated with crizotinib.

BACKGROUND: Crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with anaplastic lymphoma kinase-positive (alk+) non-small cell lung cancer (nsclc), but little information is available on its use and outcomes in real-world settings. We therefore assessed treatment patterns and outcomes in alk+ nsclc patients treated with crizotinib in regular clinical practice. METHODS: A retrospective medical record review was conducted in North America for adults with alk+ nsclc treated with crizotinib as first- or later-line therapy for metastatic disease between 1 August 2011 and 31 March 2013 (for the United States) or 1 May 2012 and 31 March 2013 (for Canada). Crizotinib-related trial enrollees were excluded. Descriptive analyses were conducted to assess treatment patterns and objective response rate (orr). Progression-free survival (pfs) and overall survival (os) were descriptively analyzed using Kaplan-Meier methods. RESULTS: Data were extracted for 212 patients in the United States (n = 147) and Canada (n = 65). Mean (standard deviation [sd]) age was 58.9 (9.5) years, and 69% were male. Seventy-nine patients (37%) were deceased at record abstraction. Sixty-five percent (n = 137) initiated crizotinib as first-line therapy. Mean (sd) duration of crizotinib treatment was 8.7 (4.9) months. Objective response rate was 66% (69% for first-line recipients, 60% for second-/later-line). Median (95% ci) pfs and os from crizotinib initiation were 9.5 (8.7, 10.1) and 23.4 (19.5, -) months, respectively. One- and two-year survival probabilities were 82% and 49%, respectively. CONCLUSIONS: Outcomes for crizotinib recipients in this study align with previous trials, with orr appearing more favourable in first-line recipients. Our findings indicate that crizotinib outcomes in clinical studies may translate to regular clinical practice.