Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Outcomes of induction chemotherapy followed by chemoradiation using intensity-modulated radiation therapy for esophageal adenocarcinoma.

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.

GHB614 × T304-40 × GHB119 × COT102 Cotton: Protein Expression Analyses of Field-Grown Samples.

Food and feed safety assessment is not enhanced by performing protein expression analysis on stacked trait products. The expression levels of six proteins in cotton matrices from four single cotton events and three conventionally stacked trait cotton products are reported. Three proteins were for insect control; two proteins confer herbicide tolerance; and one protein was a transformation-selectable marker. The cotton matrices were produced at three U.S., five Brazil, and two Argentina field trials. Similar protein expression was observed for all six proteins in the stacked trait products and the single events. However, when two copies of the bar gene were present in the stacked trait products, the expression level of phosphinothricin acetyl transferase herbicide tolerance was additive. Conventional breeding of genetically engineered traits does not alter the level or pattern of expression of the newly introduced proteins, except when multiple copies of the same transgene are present.

Frozen sections in patients undergoing breast conserving surgery at a single ambulatory surgical center: 5 year experience.

OBJECTIVES: To evaluate outcomes of our breast frozen section (FS) practice in its first 5 years, including our specialized FS of margins (FSM) procedure for breast conserving therapy (BCT) patients. METHODS: One thousand two hundred and forty eight patients undergoing 1303 breast FSM and/or sentinel lymph node (SLN) FS were included. Clinicopathologic features were assessed by chart review. RESULTS: Use of SLN FS declined, from 43.5% of FS cases before to 19.2% of FS cases after 2012. FSM patients had a decline in overall reexcision to 12.3% in 2013-2014 (p = 0.063). There was also decline in reexcision for focally close margins (p < 0.0001) but no change in reexcision for extensively close margins. Reexcision was significantly associated with lobular subtype, multifocality and larger (≥T2) size. False negative FSM cases were most often influenced by extensively close or positive final (reexcised) margins sent for permanent section only (96/148; 64.9%). CONCLUSIONS: Despite changing surgical practices, FSM remains a valuable service that reduces reexcision in BCT patients.

Extended stimulated parotid and submandibular secretion in a healthy young and old population.

BACKGROUND: Previous morphological studies have shown that both the human parotid and submandibular glands display age-related reductions in the proportion of fluid secreting acinar cells. In contrast, short-term functional studies of fluid secretion do not show such a consistent disparity among different-aged persons. This study compared the ability of a population of healthy young and old individuals to secret saliva from the parotid and submandibular glands for an extended period of time under conditions of intense gustatory stimulation. METHODS: Saliva was collected over 30 minutes from 30 healthy, unmedicated individuals using 10% citric acid as a gustatory stimulus. Of the 30 subjects, 15 were young (age range 27-40 years) and 15 were old (age range 60-97 years). Parotid salivary flow rates were determined every minute, and submandibular flow rates were determined at 2, 10, 20, and 30 minutes. A comparison was made between the slopes of the two groups. The slopes were derived from the average salivary flow rate at each time point. RESULTS: There was no difference in the ability of the parotid glands of young and old individuals to secrete saliva. In contrast, the submandibular glands of the elderly individuals did not show the same pattern of secretion when compared to their younger counterparts, who demonstrated increasing flow rates over the test period. CONCLUSIONS: The parotid glands of young and old persons are able to maintain high secretory ability under the stress of intense stimulation for an extended period of time. Conversely, the submandibular gland demonstrates an age-related, statistically significant difference in the pattern of fluid secretion with an intense gustatory stimulus.

Salivary gland dysfunction: causes, symptoms, treatment.

The three most common known causes of salivary gland dysfunction are medication usage, radiation therapy and Sjogren's syndrome. Current therapeutic options to treat salivary dysfunction are limited. Clinical considerations as well as the outlook for individuals experiencing salivary dysfunction are discussed.

Xerostomia--clinical evaluation and treatment in general practice.

Xerostomia is a common symptom with various causes that, if ignored, can lead to serious oral consequences. Clinical evaluation of patients complaining of dry mouth must include some additional history and specific examination of the salivary glands, oral mucosa, and teeth. Additional evaluation may include consultation with the patient's physician, request for microbial culture, or labial salivary gland biopsy. No one form of treatment for patients with chronic xerostomia is sufficient, but comprehensive treatment is effective in improving patient oral comfort and function and preventing unnecessary loss of teeth. This treatment must include ongoing dental caries prevention and treatment, salivary flow stimulation, recognition and treatment of oral candidiasis, selective use of saliva substitutes, and possible changes in the patients' prescription and nonprescription drug use.

Lamivudine is not effective in primary Sjögren's syndrome.

BACKGROUND: Retroviral infection has been implicated in the pathogenesis of primary Sjögren's syndrome. OBJECTIVE: To examine the efficacy of the reverse transcriptase inhibitor lamivudine in patients with this syndrome. METHODS: 16 patients with primary Sjögren's syndrome were randomised to receive either lamivudine 150 mg twice daily or placebo for three months. Measures of lacrimal and salivary function, including minor salivary gland biopsies, were obtained before and after treatment. RESULTS: Treatment with lamivudine did not result in significant improvement in the primary outcome measure of unstimulated whole salivary flow or other secondary measures, including minor salivary gland biopsy focus scores. CONCLUSION: Lamivudine is not effective in patients with primary Sjögren's syndrome, suggesting either that a retroviral aetiology is not present or that it may be important only in early disease.

Sjögren's syndrome.

This article reviews the diagnostic criteria for Sjörgen's syndrome (SS), as well as some of the more common associated signs and symptoms. Dermatological manifestations associated with SS will be evaluated. Finally, general treatment strategies will be discussed.

A characterization of major salivary gland flow rates in the presence of medications and systemic diseases.

The purpose of this study was to characterize the effects of medications and systemic diseases on major salivary gland flow rates. Unstimulated and 2% citrate-stimulated parotid and submandibular salivas were collected from 293 subjects of the oral physiology component of the Baltimore Longitudinal Study of Aging. The influence of the number of medications and diseases on salivary flow rates was determined by separate one-way ANOVA tests. There was an overall decrease in both parotid and submandibular flow rates with increasing numbers of medications and systemic diseases. However, this was significant (p < 0.05) only for unstimulated submandibular flow rates (with increasing numbers of systemic diseases) and stimulated submandibular flow rates (with increasing numbers of systemic diseases and medications). Unstimulated flow rates rapidly approached zero with increasing numbers of medications and diseases. These results suggest that the submandibular gland may be more sensitive to physiologic permutations than the parotid gland. In addition, individuals being treated for multiple systemic diseases and taking numerous medications may be more susceptible to salivary hypofunction.

[Changes of enamel intake of fluoride amount while PH and fluoride concentration varies]

The four enamel pieces,which are from one bovine tooth,are treated individually by 2.7% NaF gel(pH4),2.7% NaF gel(pH7),1%NaF gel (pH7.0) and the control group gel.The fluoride amount in enamel pieces is measured by fluoride electrode.The aim of present study is to observe the changer of enamel intake of fluoride amount when the pH and fluoride concentration varies.In results the most fluoride amount in enamel pieces treated by 2.7% NaF gel(pH4) is measured.The more fluoride amount is measured in group of 2.7%NaF gel(pH7) than 1% NaF gel (pH7).The Results show lower pH and higher fluoride concentration can increase more fluoride amount in enamel.

Salivary gland function and aging: a model for studying the interaction of aging and systemic disease.

This review describes an approach to examining the interaction of aging and systemic disease on a key aspect of oral physiology, salivation. The approach requires several steps: defining general health, and a specific physiological function, at different ages; defining a disease of interest and the influence of the disease on the specific physiological function; and determining if the disease can affect performance of the physiological function with increased age.

Comparison of stimulated parotid salivary gland flow rates in normotensive and hypertensive persons.

Although hypertension is a prevalent condition among the elderly, little is known with respect to the influence of hypertension on oral health and function. Therefore a study was conducted that compared stimulated parotid salivary flow rates in elderly persons (65 years and older) from two diverse populations who are normotensive, mild, and severe hypertensive. The normotensive group consisted of 45 healthy subjects with systolic blood pressures of less than 140 mm Hg and diastolic pressures less than 90 mm Hg. The mildly hypertensive group consisted of 14 otherwise healthy subjects with either systolic pressures greater than 140 mm Hg or diastolic pressures greater than 90 mm Hg. The severely hypertensive group consisted of 10 otherwise healthy subjects with either systolic pressures greater than 180 mm Hg and/or diastolic pressures greater than 100 mm Hg. All three groups were not taking any prescription or nonprescription medications. Samples of 2% citrate-stimulated parotid saliva were collected from each subject. The results showed no significant differences in stimulated parotid flow between normotensive, mildly hypertensive, and severely hypertensive subjects. These results suggest that hypertension per se has no influence on stimulated parotid salivary gland flow rates in otherwise healthy, elderly unmedicated white and African-American persons.

Interferon-gamma induces a decrease in the intracellular calcium pump in a human salivary gland cell line.

Interferon-gamma (IFN-gamma) +/- tumor necrosis factor-alpha (TNF-alpha) induces antiproliferation and intracellular Ca2+ store depletion in a human submandibular ductal cell line (HSG), which can be reversed on cytokine removal [A. J. Wu, G. C. Chen, B. J. Baum, and I. S. Ambudkar. Am. J. Physiol. 270 (Cell Physiol. 39): C514-C521, 1996]. Here we have examined a possible mechanism for the IFN-gamma-induced intracellular Ca2+ store depletion. There was a time-dependent decrease in thapsigargin-dependent internal Ca2+ release after exposure of the cells to the cytokines. The intracellular Ca2+ pump [sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)] protein in lysates and membranes of cells treated with IFN-gamma +/- TNF-alpha, but not with TNF-alpha alone, showed a similar time-dependent decrease (examined using a SERCA2 antibody). Removal of the cytokines, which resulted in recovery of cell growth and refill of internal Ca2+ stores, also increased the level of SERCA protein. The decrease in SERCA is not a result of decreased cell proliferation, since thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone, or serum-free growth conditions induced antiproliferative effects on HSG cells without any corresponding decrease in SERCA. We suggest that the IFN-gamma-induced decrease in the level of SERCA accounts for the depleted state of internal Ca2+ stores in cytokine-treated HSG cells. These data suggest a novel mechanism for the inhibition of HSG cell growth by IFN-gamma.

Interferon-gamma-induced JAK2 and STAT1 signalling in a human salivary gland cell line.

We have used a human salivary gland cell line (HSG) as a possible in vitro model to evaluate the effects of IFN-gamma on human salivary gland epithelium (Wu et al., 1994, 1996, 1997). In the present study, we examined the JAK-STAT signal-transduction pathway in IFN-gamma-treated HSG cells. We demonstrate that JAK2 and Stat1 are phosphorylated at tyrosine residues in a time- and concentration-dependent manner following exposure to IFN-gamma. In addition, we show that activation of this signalling pathway is decreased by the addition of a blocking antibody to the IFN-gamma receptor. The same maneuver is also able to reduce by approximately 50-70% the surface expression of two IFN-gamma-induced immunoregulatory molecules: HLA-DR and ICAM-1. These results demonstrate that the JAK2 and Stat1 signalling pathway is active in salivary-derived epithelial cells and may contribute to their immunopathologic destruction.