Vascular Endothelial Growth Factor Receptor Inhibitors for Recurrent or Metastatic Adenoid Cystic Carcinoma: A Systematic Review and Meta-Analysis.

Importance: There is no systemic therapy for recurrent or metastatic adenoid cystic carcinoma (ACC) approved by the US Food and Drug Administration. Objective: To examine the efficacy, safety, and tolerability of vascular endothelial growth factor receptor (VEGFR) inhibitors in recurrent or metastatic ACC. Data Sources: PubMed, Embase, and Cochrane Library were systematically searched for studies of VEGFR inhibitors in recurrent or metastatic ACC from database inception to August 31, 2023. Study Selection: Inclusion criteria were prospective clinical trials of recurrent or metastatic ACC treated with VEGFR inhibitors, reporting at least 1 outcome of interest specifically for ACC. Of 1963 identified studies, 17 (0.9%) met inclusion criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline was followed to extract data. Data were pooled using a random-effects generalized linear mixed model with 95% CIs. Main Outcomes and Measures: The primary efficacy outcome was best overall response to VEGFR inhibitors, including objective response, stable disease, or progressive disease (PD). Safety and tolerability outcomes included incidence of grade 3 or higher adverse events, rates of exit from trial due to PD or drug-related toxic effects, and dose reduction rate (DRR). Results: A total of 17 studies comprising 560 patients with recurrent or metastatic ACC treated with 10 VEGFR inhibitors were included. The objective response rate was 6% (95% CI, 3%-12%; I2 = 71%) and stable disease was the most frequent best overall response (82%; 95% CI, 74%-87%; I2 = 67%). The 6-month disease control (defined as objective response and stable disease) rate was 54% (95% CI, 45%-62%; I2 = 52%). The rate of grade 3 or higher adverse events was 53% (95% CI, 42%-64%; I2 = 81%) and of DRR was 59% (95% CI, 40%-76%). Most patients (57%; 95% CI, 44%-70%; I2 = 83%) continued therapy until PD; 21% (95% CI, 15%-28%; I2 = 62%) of patients suspended therapy for toxic effects. In subgroup analysis by specific VEGFR inhibitor, the objective response rate was 14% (95% CI, 7%-25%; I2 = 0%), stable disease rate was 76% (95% CI, 63%-85%; I2 = 0%), proportion treated until PD was 61% (95% CI, 14%-94%; I2 = 94%), and DRR was 78% (95% CI, 66%-87%; I2 = 39%) with lenvatinib. Corresponding axitinib results were objective response rate of 8% (95% CI, 4%-15%; I2 = 0%) and stable disease rate of 85% (95% CI, 72%-92%; I2 = 69%), with 73% (95% CI, 63%-82%; I2 = 0%) of patients treated until PD, and the DRR was 22% (95% CI, 12%-38%; I2 = 77%). Rivoceranib had the highest objective response rate (24%; 95% CI, 7%-57%) but high heterogeneity among studies (I2 = 95%) and the lowest rate of patients who continued therapy until PD (35%; 95% CI, 20%-55%; I2 = 90%). Conclusions and Relevance: This systematic review and meta-analysis found that VEGFR inhibitors were associated with high rates of disease stabilization in recurrent or metastatic ACC. Of 10 included VEGFR inhibitors, lenvatinib and axitinib were associated with the best combined and consistent efficacy, safety, and tolerability profiles, substantiating their inclusion in treatment guidelines.

First Use of AXL Targeting in Metastatic, Refractory, Adenoid Cystic Carcinoma: A Case Report.

First use of AXL-targeting in adenoid cystic carcinoma (ACC); with positive results, ACC now included in AXL studies.

Prognostic value of tumor volume doubling time in lung-metastatic adenoid cystic carcinoma.

OBJECTIVES: Lung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT). METHODS: The study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), the correlation coefficient (r) and coefficient of determination (R2) were calculated for measured lung nodules. TTP was assessed per RECIST 1.1; TVDT was calculated using the Schwartz formula. Overall survival was analyzed using the Kaplan-Meier method. RESULTS: The study included 75 patients. Sixty-seven patients (89%) had lung-only metastasis on first CT scan. The TGR was overall constant (median R2 = 0.974). Median TTP and TVDT were 11.2 months and 7.5 months. Shorter TVDT (<6 months) was associated with poor overall survival (HR = 0.48; p = 0.037), but TTP was not associated with survival (HR = 1.02; p = 0.96). Cox regression showed that TVDT but not TTP significantly correlated with OS. TVDT calculated using estimated tumor volume correlated with TVDT obtained by segmentation. CONCLUSION: Most ACC lung metastases have a constant TGR. TVDT may be a better prognostic indicator than TTP in lung-metastatic ACC. TVDT can be estimated by single longitudinal measurement in clinical practice.

Quantitative and qualitative comparison of Rubidium-82 and Oxygen-15 water cardiac PET.

BACKGROUND: Differences in tracer characteristics may influence the interpretation of positron emission tomography myocardial perfusion imaging (MPI). We compare the reading of MPIs with a low-extraction retention tracer (82Rb) and a high-extraction non-retention tracer (15O-water) in a selected cohort of patients with known coronary artery disease (CAD). METHODS: Thirty-nine patients with known CAD referred to 82Rb MPI due to angina underwent rest and stress imaging with both tracers and experienced MPI readers provided blinded consensus reads of all studies. In addition, a comparison of regional and global quantitative measures of perfusion was performed. RESULTS: The results showed 74 % agreement in the reading of 82Rb and 15O-water MPI for regional reversible ischemia and global disease, and 82 % agreement for regional irreversible ischemia. The 15O-water MPI identified more cases of global disease (n = 12 (15O-water) vs n = 4 (82Rb), p = 0.03), whereas differences in reversible ischemia (n = 22 vs n = 16, p = 0.11) and, irreversible ischemia (n = 8 vs n = 11, p = 0.45) were not significant. The correlation between myocardial blood flow measured using the two tracers was similar to previous studies (R2 = 0.78) with wide limits of agreement (-0.93 to 0.84 ml/g/min). CONCLUSIONS: Agreement between consensus readings of 82Rb and 15O-water MPI was good in patients with known CAD. In this limited size study, no significant differences in the identification of reversible and irreversible ischemia found, whereas 15O-water MPI had a higher positive rate for suspected global disease.

Analysis of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance.

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.

Targeted Therapies in Colorectal Cancer: Recent Advances in Biomarkers, Landmark Trials, and Future Perspectives.

In 2022, approximately 600,000 cancer deaths were expected; more than 50,000 of those deaths would be from colorectal cancer (CRC). The CRC mortality rate in the US has decreased in recent decades, with a 51% drop between 1976 and 2014. This drop is attributed, in part, to the tremendous therapeutic improvements, especially after the 2000s, in addition to increased social awareness regarding risk factors and diagnostic improvement. Five-fluorouracil, irinotecan, capecitabine, and later oxaliplatin were the mainstays of mCRC treatment from the 1960s to 2002. Since then, more than a dozen drugs have been approved for the disease, betting on a new chapter in medicine, precision oncology, which uses patient and tumor characteristics to guide the therapeutic choice. Thus, this review will summarize the current literature on targeted therapies, highlighting the molecular biomarkers involved and their pathways.

Cell-Free DNA as a Surveillance Tool for Hepatocellular Carcinoma Patients after Liver Transplant.

The liver is the world's sixth most common primary tumor site, responsible for approximately 5% of all cancers and over 8% of cancer-related deaths. Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, accounting for approximately 75% of all primary liver tumors. A major therapeutic tool for this disease is liver transplantation. Two of the most significant issues in treating HCC are tumor recurrence and graft rejection. Currently, the detection and monitoring of HCC recurrence and graft rejection mainly consist of imaging methods, tissue biopsies, and alpha-fetoprotein (AFP) follow-up. However, they have limited accuracy and precision. One of the many possible components of cfDNA is circulating tumor DNA (ctDNA), which is cfDNA derived from tumor cells. Another important component in transplantation is donor-derived cfDNA (dd-cfDNA), derived from donor tissue. All the components of cfDNA can be analyzed in blood samples as liquid biopsies. These can play a role in determining prognosis, tumor recurrence, and graft rejection, assisting in an overall manner in clinical decision-making in the treatment of HCC.

Incidental FDG-Avid Focuses in Palatine Tonsils on PET/CT.

OBJECTIVES: The management of incidental findings of FDG-avid tonsils on PET/CT (IFT) is unclear. We aimed to explore the prevalence of malignancy in IFT, identify risk factors for malignancy, and calculate optimal cutoffs of maximum standardized uptake values (SUVmax ) to discriminate between benign and malignant lesions. METHODS: All patients who were tonsillectomized at our institution because of IFT from October 2011 to December 2020 were included. Patients undergoing PET/CT due to suspected tonsillar disease or cancer of unknown primary were excluded. RESULTS: In total, 77 patients were included, of which 11 (14%) of them had IFT malignancy. Dysphagia (p = 0.019) and alcohol abuse (p = 0.035) were associated with malignancy. Absolute SUVmax cutoff (≥9: sensitivity 100%; specificity 53%) was superior to SUVmax side-to-side ratio (≥1.5: sensitivity 64%; specificity 70%) to discriminate between benign and malignant lesions. CONCLUSION: We recommend tonsillectomy for patients with IFT displaying SUVmax ≥ 9.0, ratio ≥ 1.5, or symptoms or findings suggesting malignancy. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2370-2378, 2022.

Activity regimes for 82Rb cardiac PET: Effects on absolute MBF and MPI.

BACKGROUND: Selection of optimal tracer activity for 82Rb PET is based on a trade-off between necessary count-statistics in the late static phase and detector saturation in the early blood-pool phase. Administered tracer activity recommended in prescribing information differs substantially from recommendations in current literature. The present study examines the effect on both absolute myocardial blood flow (MBF), myocardial flow reserve (MFR) and relative myocardial perfusion imaging (MPI) of reducing dose. METHODS: Forty patients were scanned twice on a PMT-based PET/CT (GE D690): At recommended activity (1110 MBq) and at either 740 or 370 MBq. MBF, MFR, total perfusion deficit (TPD) and ejection fractions (EF) were quantified. Results were compared using linear regression and Bland-Altman plots. RESULTS: Linear correlation between MBF at 1110 MBq at either reduced activity had an R2 > 0.98. A small bias (± 5%-9%) was observed with opposite signs for 1110/740 and 1110/370. Limits of agreement for MBF were larger for 1110/370. MFR had a lower linear correlation (R2 = 0.96), but wide limits of agreement especially for 1110/370. TPD and EF correlated well at 1110/740 (R2 = 0.96 and 0.99, respectively), but large scatter was observed for 1110/370. CONCLUSION: Reduction of the tracer activity to 740 MBq, significantly reduced dead-time correction factors, while still producing reliable static and gated images. However, despite large dead-time at 1110 MBq, no systematic bias on absolute MBF was observed compared to reduced activities.

Impact of Distinct Therapies on Antibody Response to SARS-CoV-2 Vaccine in Systemic Lupus Erythematosus.

OBJECTIVE: To date, the only study that has assessed the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 mRNA) vaccine in systemic lupus erythematosus (SLE) observed a moderate response, but the sample size precluded an accurate analysis of the effect of individual drugs. Therefore, we evaluated the immunogenicity of an inactivated SARS-CoV-2 vaccine (Sinovac-CoronaVac) and the influence of different medications in SLE. Safety was also assessed. METHODS: We conducted a prospective controlled study of 232 SARS-CoV-2-naive SLE patients and 58 SARS-CoV-2-naive controls who were vaccinated with 2 doses of Sinovac-CoronaVac with a 28-day interval (day 0/day 28 [D0/D28]). Immunogenicity analysis at D0/D28 and D69 included anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralizing antibodies (NAb) positivity. The influence of individual drugs on immune response and safety was assessed. RESULTS: Patients and controls were well balanced for age (P = 0.771). At D69, SLE patients showed a moderate SC (70.2% versus 98.1%; P < 0.001) and moderate frequency of NAb positivity (61.5% versus 84.6%; P = 0.002), although both frequencies were lower than in controls. Factors associated with lower SC in univariate analysis at D69 were prednisone use (odds ratio [OR] 0.215 [95% confidence interval (95% CI) 0.108-0.427], P < 0.001) and mycophenolate mofetil (MMF) use (OR 0.201 [95% CI 0.107-0.378], P < 0.001), whereas hydroxychloroquine (HCQ) use led to a 2.5 increase in SC (P = 0.011). SLE patients who were receiving HCQ monotherapy had similar SC to controls at D69 (100% versus 98.1%; P = 1.000). In multivariate analysis, prednisone and MMF use were independently associated with lower SC (P < 0.001) and NAb positivity (P < 0.001). Safety analysis revealed no moderate/severe adverse events. CONCLUSION: Sinovac-CoronaVac has a moderate immunogenicity in SARS-CoV-2-naive SLE patients with an excellent safety profile. We further demonstrate that HCQ may improve SC, whereas prednisone and MMF had a major deleterious effect in vaccine response, reinforcing the need to investigate the role of temporary MMF withdrawal or a vaccine-booster dose (ClinicalTrials.gov identifier: NCT04754698).

Outcomes and Prognostic Factors in a Large Cohort of Hospitalized Cancer Patients With COVID-19.

PURPOSE: Patients with cancer are at increased risk for unfavorable outcomes from COVID-19. Knowledge about the outcome determinants of severe acute respiratory syndrome coronavirus 2 infection in this population is essential for risk stratification and definition of appropriate management. Our objective was to evaluate prognostic factors for all-cause mortality in patients diagnosed with both cancer and COVID-19. METHODS: All consecutive patients with cancer hospitalized at our institution with COVID-19 were included. Electronic medical records were reviewed for clinical and laboratory characteristics potentially associated with outcomes. RESULTS: Five hundred seventy-six consecutive patients with cancer and COVID-19 were included in the present study. An overall in-hospital mortality rate of 49.3% was demonstrated. Clinical factors associated with increased risk of death because of COVID-19 were age over 65 years, Eastern Cooperative Oncology Group performance status > 0 zero, best supportive care, primary lung cancer, and the presence of lung metastases. Laboratory findings associated with a higher risk of unfavorable outcomes were neutrophilia, lymphopenia, and elevated levels of D-dimer, creatinine, C-reactive protein, or AST. CONCLUSION: A high mortality rate in patients with cancer who were diagnosed with COVID-19 was demonstrated in the present study, emphasizing the need for close surveillance in this group of patients, especially in those with unfavorable prognostic characteristics.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.

Effect of remote ischemic conditioning on myocardial perfusion in patients with suspected ischemic coronary artery disease.

BACKGROUND: Remote ischemic conditioning (RIC) confers protection against myocardial ischemia-reperfusion injury and may modulate coronary blood flow. We investigated whether RIC affects resting myocardial perfusion (MP) in patients with suspected ischemic coronary artery disease by quantitative MP imaging. METHODS AND RESULTS: We included 49 patients with suspected ischemic coronary artery disease. Resting MP was quantified by 82Rubidium positron emission tomography/computed tomography (82Rb-PET/CT) imaging before and after RIC, performed as four cycles of 5 minutes upper arm ischemia and reperfusion. Subsequent adenosine 82Rb-PET/CT stress-imaging identified non-ischemic and reversibly ischemic myocardial segments. MicroRNA-144 plasma levels were measured before and after RIC. Normalized for rate pressure product, RIC did not affect MP globally (P = .64) or in non-ischemic myocardial segments (P = .58) but decreased MP in reversibly ischemic myocardial segments (-0.11 mL/min/g decrease in MP following RIC; 95% CI -0.17 to -0.06, P < .001). However, we found no effect of RIC when MP was normalized for cardiac work. MicroRNA-144 plasma levels increased following RIC (P = .006) but did not correlate with a change in global MP in response to RIC (P = .40). CONCLUSIONS: RIC did not substantially affect resting MP globally or in non-ischemic and reversibly ischemic myocardial territories in patients with suspected ischemic coronary artery disease.

Noninvasive Detection of Cardiac Allograft Vasculopathy by Stress Exercise Echocardiographic Assessment of Myocardial Deformation.

BACKGROUND: The aim of this study was to evaluate the value of noninvasive assessment of cardiac allograft vasculopathy (CAV) in heart-transplanted patients by exercise stress myocardial deformation and coronary flow reserve (CFR) assessment. METHODS: Fifty-eight heart-transplanted patients underwent semisupine exercise echocardiography with assessment of left ventricular (LV) longitudinal myocardial deformation. CAV was assessed by coronary angiography and noninvasive CFR by (15)O-H2O positron emission tomographic imaging and Doppler echocardiography. Patients were divided into three groups on the basis of angiographic CAV: no CAV (n = 21), mild CAV (n = 19), and severe CAV (n = 18). RESULTS: Patients with severe CAV had significantly lower LV global longitudinal strain (GLS) at rest (no CAV, -16 ± 2%; mild CAV, -15 ± 2%; severe CAV, -12 ± 4%; P < .001), failed to increase LV GLS during exercise (no CAV, -5.7 ± 2.0%; mild CAV, -3.3 ± 2.9%; severe CAV, -0.2 ± 2.8%; P < .0001), and had significantly lower echocardiographic coronary flow velocity reserve (CFVR) (no CAV, 3.2 ± 0.4; mild CAV, 2.7 ± 0.7; severe CAV, 1.8 ± 0.5; P < .0001) and PET CFR (no CAV, 3.4 ± 0.9; mild CAV, 3.1 ± 0.9; severe CAV, 1.9 ± 0.8; P < .0001). Furthermore, patients with mild CAV had significantly lower exercise LV GLS and echocardiographic CFVR than patients with no CAV. Exercise LV GLS, echocardiographic CFVR, and PET CFR were significantly correlated with the presence of severe CAV in a logistic regression model (LV GLS odds ratio, 0.71; 95% CI, 0.60-0.84; P < .0001; echocardiographic CFVR odds ratio: 0.06; 95% CI, 0.01-0.23; PET CFR odds ratio, 0.17; 95% CI, 0.07-0.46). This relation remained significant after adjustment for symptoms and time since transplantation. CONCLUSIONS: Noninvasive assessment of LV longitudinal myocardial deformation during exercise is feasible and strongly associated with the presence and degree of CAV. Exercise stress myocardial deformation analysis, echocardiographic CFVR, or PET CFR may serve as a noninvasive model for the detection of CAV.

Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma--a prospective study.

BACKGROUND: Head and neck cancer patients with high hemoglobin respond better to irradiation compared to patients with low hemoglobin possibly due to hypoxia induced radioresistance. The hemoglobin level is, however, a crude indicator of the amount of oxygen available to the tissue and may be influenced by a number of factors, smoking being of potential importance. The aim of the present study was to examine the effect of smoking on available oxygen to tumors and the effect on outcome in head and neck cancer patients treated with radiotherapy in a prospective study. MATERIALS AND METHODS: A total of 232 consecutive patients with squamous cell carcinoma of the larynx, pharynx and oral cavity completed questionnaires on smoking habits prior to treatment. Venous blood samples were collected before and/or during treatment to determine the hemoglobin and carboxyhemoglobin level. Patients were treated with primary curative radiotherapy 62-68 Gy, 2 Gy/fx, 5 fx/week. RESULTS: All but 12 patients had a history of smoking, 35 were long term quitters, 23 recent quitters, 54 moderate smokers and 108 heavy smokers (>1 pack/day). There was no relationship between total hemoglobin and carboxyhemoglobin, but effective hemoglobin and carboxyhemoglobin were linearly correlated. The amount of carboxyhemoglobin increased with increasing smoking status. Actuarial 5-year univariate analysis showed that heavy smokers had a significantly reduced probability of loco-regional control (44% vs. 65%, p = 0.001), disease-specific (56% vs. 77%, p = 0.003) and overall survival (39% vs. 66%, p = 0.0004) compared to non-smoking patients. Multivariate analyses showed that patients characterized as non-smokers, with low T and N classifications and high hemoglobin level had the best outcome measurements. A rise in carboxyhemoglobin significantly decreased the probability of loco-regional control and each additional pack year increased the risk of death. Smokers and former smokers develop secondary cancers. CONCLUSION: The study showed a significant negative impact of smoking during radiotherapy for head and neck cancer and the risk of death was increased with each additional pack year of smoking. The effect on loco-regional control could be explained by a rise in carboxyhemoglobin level in smokers, e.g. a reduced oxygen supply to tumors. The data strongly advocate that smoking should be avoided in order to improve the therapeutic efficacy of radiotherapy and development of other smoking-related diseases and/or secondary cancers.

Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy.

INTRODUCTION: Hypoxia induced radioresistance has been acknowledged for decades. One of the indirect evidences of the influence of hypoxia on radiation response comes from the observations of a correlation between tumor control and hemoglobin level. This review examines the clinical data on the prognostic and predictive role of hemoglobin level and hemoglobin manipulation in radiotherapy of squamous cell carcinomas of the head and neck, a tumor type where hypoxic radioresistance have been previously documented. THE INFLUENCE OF HEMOGLOBIN CONCENTRATION ON TUMOR OXYGENATION AND OUTCOME: The aim is to evaluate the existing literature for information of the influence of hemoglobin concentration and hemoglobin modifications on tumor oxygenation and outcome in head and neck squamous cell cancer patients. The data from several randomized trials show that while most studies have confirmed the prognostic value of hemoglobin, increasing the hemoglobin level through transfusion or erythropoietin stimulation did not result in improved outcome for patients with low initial hemoglobin levels. Clinical studies showed that smoking reduced the oxygen carrying capacity of the blood through formation of carboxyhemoglobin, and lead to poorer response to radiotherapy in smokers compared to non-smokers. Smoking also increased the risk of the development of secondary cancers. CONCLUSION AND FUTURE PERSPECTIVES: In conclusion, low hemoglobin is a significant negative prognostic factor for radiotherapy of head and neck cancer. Correction of pre-treatment low hemoglobin by blood transfusion and/or erythropoietin stimulating agents does, however, not improve the outcome. Smoking leads to a decrease in effective hemoglobin and poorer treatment outcome. Smoking should be avoided in order to improve the therapeutic efficacy of radiotherapy and development of other smoking-related diseases and/or secondary cancers.

Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. MATERIAL AND METHODS: Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range. RESULTS: A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. CONCLUSION: Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival.

The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy--results from the randomized DAHANCA 5 study.

BACKGROUND AND PURPOSE: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed as a subrandomization in the DAHANCA 5 trial. MATERIAL AND METHODS: Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with "low" pre-irradiation Hb values (females<13 g/dL; males<14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a Hb level in the "high" value range. RESULTS: A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive transfusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels had a significantly better probability of locoregional control, disease-specific survival and overall survival compared to 'low Hb no transfusion' patients. In the low Hb group, transfusion did not improve the outcome in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and N classifications were significant for all outcome measures, whereas there was no significant influence of transfusion or Hb level on endpoints. CONCLUSION: The univariate prognostic significance of high Hb level was demonstrated in patients with HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve the outcome in patients with low Hb values.

Cancer of the external auditory canal and middle ear in Denmark from 1992 to 2001.

BACKGROUND: In the context of the Danish Head and Neck Cancer Group, nationwide material from 1992-2001 was analyzed to study the extent and nature of the disease, evaluate treatment, compare staging systems, and examine prognosis and survival. METHODS: Review of 68 consecutive cases: 47 squamous cell carcinoma, 10 basal cell carcinoma, and 11 other histologies. Moody (modified Pittsburgh) stages were T1 (26), T2 (9), T3 (8), T4 (23), Tx (2). Sixty-four patients were treated with curative intent: 24 primary radiotherapy, 18 primary surgery, and 22 combined. Surgery was limited to tumor excision and mastoidectomy and in 1 case temporal bone excision. RESULTS: Twenty-seven of 28 recurrences involved primary site. Kaplan-Meier analysis showed 5-year locoregional control of 48%, disease-specific survival 57%, and overall survival 44%. CONCLUSION: This nationwide study confirmed that local failure is the main problem, and future improvements should focus on more aggressive local treatment.

Modifiable determinants of fetal macrosomia: role of lifestyle-related factors.

BACKGROUND: Newborn macrosomia is associated with both short- and long-term health risks for the infant, and increases the prevalence of birth complications. Parity, maternal age and gender of the child are known variables that influence fetal growth. The purpose of the present investigation was to evaluate prospectively the contributions of modifiable maternal predictors of fetal macrosomia (> or =4,200 g), which included lifestyle-related factors, such as nutritional intake, physical activity, and plasma glucose values, in addition to overweight and pregnancy weight gain. METHODS: Some 553 women were followed through pregnancy. Predictive variables were subjected to univariate and multiple logistic regression analysis. Among these were: body mass index (BMI), weight gain, maternal subcutaneous fat (mm), fasting and 2-h plasma glucose, self-reported physical activity before and during pregnancy, and nutritional intake of macronutrients. Gestational age, parity and gender were also included in the model. All continuous variables were dichotomized using the upper quartile as the cut-off point in most cases. RESULTS: If physical activity was left out of the analyses, BMI, weight gain, plasma glucose and gestational age were independent determinants of macrosomia. After including low level pre-gestational physical activity in the model, we found that this was now a significant determinant of delivering a macrosomic infant with an OR=2.9 (95% CI: 1.9, 7.3). CONCLUSION: The present study indicates that a low level of pre-gestational physical activity adds to the modifiable determinants of newborn macrosomia.