The prognostic role of metastatic lymph node ratio in colon cancer: a retrospective cohort study on 241 patients in a single center.

BACKGROUND: The detection of nodal status is based on examination of lymph nodes (LN) after the tumor surgical resection and the current guidelines recommend examining at least 12 regional LN. An inadequate number of examined LN may lead to a lower N stage or to a false-negative nodal disease. To overcome these issues, many authors proposed to consider the metastatic lymph node ratio (mLNR). MLNR is the ratio of the number of metastatic LN to the number of examined LN. METHODS: Two hundred forty-one colon cancer (CC) specimens from patients who had undergone surgical resection between January 2010 and December 2015 at the General Surgery Unit of Parma University Hospital were analyzed. mLNR, which is defined as the ratio of the number of positive LN to the number of examined LN, was calculated in CCs with LN metastasis. In this study we focused on the following mLRN cutoffs: <0.15, 0.15-0.3 and >3 and we evaluated the prognostic implication of mLNRs. RESULTS: Regarding the impact of examined LN on involved LN in CC, our results showed that the number of involved LN increased with the increasing number of examined LN (P=0.03). We found a significant correlation between OS and RFS rate of patients with CCs and mLNR. Patients with mLNR<0.15 were associated with better OS and RFS rate whereas patients with mLNR>0.3 were associated with worse OS and RFS rate. OS rate for patients with a mLNR<0.15 was 95.24% (89-100%) at 1 year, 83.27% (72.7-95.4%) at 3 years and 68.07% (55.1-84.1%) at 5 years whereas patients with a mLNR>0.3 had an OS rate of 51.7% (34.6-77.3%) at 1 year, 36.55% (20.08-64.3%) at 3 years and 31.33% (16.5-59.4%) at 5 years. RFS rate for patients with a mLNR<0.15 was 100% (100-100%) at 1 year, 92.2% (84-100%) at 3 years and 85.2% (73.8-98.31%) at 5 years whereas patients with a mLNR>0.3 had a RFS of 63.2% (42.8-93.58%) at 1 year and 54.2% (33.1-88.93%) at 3 and 5 years. CONCLUSIONS: The prognostic value of pN stage could be more accurate if we consider both the number of LN metastasis and harvested LN. This can be achieved by using the mLNR that can be a useful tool in daily practice to predict the prognosis of patients who undergone surgery for CC.

Intraoperative Neuromonitoring, Nerves at Risk and Staged Thyroidectomy, our Experience on 377 Consecutive Cases.

PURPOSE: The aim of this study was firstly to report the experience of intermittent intraoperative neuromonitoring (I-IONM) and evaluate the impact of loss of signal (LOS) in staged thyroidectomy management. METHODS: We retrospectively reviewed patients who underwent total thyroidectomy, performed by a single surgeon in two years. All patients have been subjected to I-IONM. In case of intraoperative loss of signal (LOS), planned total thyroidectomy was always aborted. Six-month follow-up was performed. Postoperative dysphonia was evaluated with VHI-10 score in 3 time settings T1, during hospital stay, T2 after 30 days, T3 after 6 months. Dysphonia has been compared to IONM results to evaluate sensitivity and specificity. RESULTS: 377 patients were included. Incidence of dysphonia was calculated based on the number of nerves at risk (NAR). We evaluated a total of 724 NAR. LOS encountered were 43 cases (5.9% of total NAR), of these 14 were LOS 1 while 29 were LOS 2. 27 patients (3.7% of NAR) presented early post-operative dysphonia with VHI-10 score > 13 (T1), among these 16 had presented LOS at IONM (true positives) while11 had no LOS (false negatives). In T2 and T3 we reported a decrease in true positive cases increasing false positives. Sensitivity at T3 reached 85.7% while specificity and odds ratio were respectively 94.8% and 110. CONCLUSIONS: Given the high sensitivity and specificity, IONM should be considered a useful tool for thyroid surgery and its use should be suggested for patients undergoing planned total thyroidectomy. Its right application may cancel the risk of bilateral paralysis.

Intraoperative neuromonitoring in thyroidectomy for carcinoma in a high-volume academic hospital.

BACKGROUND: The diagnosis of thyroid carcinoma has changed in last decades, as the surgical technique during thyroidectomy (endoscopic surgery, robotic surgery, new energy device, intraoperative neuromonitoring). METHODS: We analyzed patients undergone to thyroidectomy or lobectomy for thyroid carcinoma from January 2010 to December 2019 at the General Surgery Unit of the Hospital - University of Parma. We divided patients into two groups, based on the use or not of IONM. RESULTS: We analyzed data about 638 patients, 486 (76.2%) females and 152 (23.8%) males, with a mean age of 51.8 years. Totally, 574 patients underwent total thyroidectomy and lymphadenectomy was performed in 39 patients. The lobectomy rate was higher in interventions with neuromonitoring (13.93%) than in those without IONM (3.06%). Considering the incidence of postoperative complications and the presence of infiltration of perithyroid tissues or thyroiditis or lymph node metastasis at the histological report, a statistically significant percentage of dysphonia and paraesthesia was recorded only in patients with infiltration of perithyroid tissues (P<0.0001). There was no significant difference in postoperative blood calcium values. The use of intraoperative neuromonitoring has not significantly changed the incidence of postoperative complication. CONCLUSIONS: Our study did not show a protective impact of the use of intraoperative neuromonitoring during thyroidectomy on the incidence of postoperative complications but confirmed that it increases the surgeon's feel safety during surgery and facilitates the identification of any undetected nerve lesion with visually intact nerve, inducing the interruption of the thyroidectomy after lobectomy alone, reducing the risk of bilateral recurrent paralysis.

Multifocality in patients treated for papillary Thyroid Carcinoma: a preliminary analysis of related risk factors.

Background Multifocality is usually detected afterwards surgery for papillary thyroid cancer (PTC) and has been reported in 18-87% of PTC. Methods This is a retrospective single-center study involving a series of 238 patients that underwent thyroidectomy or lobectomy after preoperative fine needle aspiration (FNA) diagnosis of Thyr 5 or Thyr 6, according to Bethesda classification, from January 2015 to December 2019 at the General Surgery Unit of the University - Hospital of Parma. We divided patients into two main groups: patients with multifocal papillary thyroid cancer at postoperative diagnosis and patients with unifocal papillary thyroid cancer. The aim of the study is to identify demographic or preoperative radiological risk factors for the presence of multifocal PTC and to verify the presence of cyto-histological features of greater aggressiveness in multifocal tumors than in unifocal ones. Results Out of our sample, 176 patients were females (73,9%) and 62 males (26,1%) with a mean age of 50,45 ±14,41. Preoperative cytological diagnosis resulted Thyr 5 in 47 cases (19,7%) and Thyr 6 in 191 cases (80,3%). Multifocal cancer was reported in 35,8% of the females and in 32,3% of the males. Older age was significatively related to the presence of multifocal papillary carcinoma (p<0.05). Preoperative bilateral thyroid nodules were associated with a higher finding of multifocal disease at histological examination (p<0.05). The presence of multifocal disease was related with a higher soft tissue invasion at the histological specimen (p<0.05).  Tumor size was not related to multifocal PTC in our study. Conclusions Older age of patient and preoperative bilateral thyroid nodules are significantly associated to multifocal thyroid cancer. In add to this, multifocal disease is related to higher finding of perithyroidal tissue invasion at histological exam. In case of predictive factors for multifocal PTC, surgeons should take total/near-total thyroidectomy always into consideration.

Wounds morphologic assessment: application and reproducibility of a virtual measuring system, pilot study.

BACKGROUND AND AIMS: Assessment of wounds morphology can be considered, in the everyday medical activity, the first step for the correct pathway of diagnosis. Authors present a pilot study focused on the statistical analysis of 32 cases of wounds measurements conducted by both the traditional method (paper ruler) both the digital smartphone analysis. MATERIALS AND METHODS: 32 lesions were morphologically evaluated. All the enrolled patients were evaluated by both the traditional method (paper ruler) both a digital smartphone analysis based on the app imitoMeasure. The extracted data were compared to the traditional measurements and a statistical analysis was based on intraclass correlation coefficients (ICC). RESULTS: Three morphological parameters were evaluated: width (expressed in cm), length (expressed in cm) and area (expressed in cm2). The area (expressed in cm2) was found to be the less comparable, but the data were close in this case, too. CONCLUSION: The present study shows that the digital measuring systems should be easily addressed as versatile tools that could be applied in daily clinical practice in the future.

How COVID-19 pandemic has changed elective surgery: the experience in a general surgery unit at a COVID-hospital.

OBJECTIVE: Evaluate the impact of Covid-19 in a critical area and analyze the changes in the daily activities in a General Surgery Unit of a tertiary Covid-Hospital. METHODS: We report and compared all the surgical procedures performed between two periods (March and April 2019 and March and April 2020) at General Surgery Department of Parma University Hospital, a tertiary Covid-Hospital. RESULTS: Between March and April 2019, a total of 232 surgical procedures were performed. Between March and April 2020 only 61 surgical procedures were performed. In 2019 84 patients underwent surgery for cancer and 171 underwent surgery for benign diseases. In 2020 only 37 patients underwent surgery for oncological reasons and 24 underwent surgery for benign diseases. CONCLUSIONS: During pandemic Covid-19 the access to health services was limited and poor. Limited access to health services and the fear of Covid-19 infection can explain the lower number of elective surgical procedures for cancer in 2020 compared to the same period in the 2019.

Relationship between surgeon experience and adverse events in thyroid surgery.

In scientific literature there are numerous authors that have highlighted how the outcome of patients undergoing surgical treatment, such as intraoperative or postoperative complications, surgical time, mean hospital stay, is related to the surgeon's experience based on the number of cases treated per year for a specific disease. In our study we decided to verify if, in our clinical practice, there are significant differences in postoperative outcomes between procedures performed by a senior surgeon, a young specialist or a surgical resident, evaluating if surgical experience affects positively either on intraoperative complications such as bleeding, hypocalcemia, dysphonia, or on surgical time, mean hospital stay and postoperative complications. In this retrospective study we examined all cases of patients that underwent surgery for thyroid disease at our Operative Unit, from January 1, 2015 to December 31, 2019. The analysis of our data highlights how the surgeon's experience affects the surgical outcome of patients undergoing lobectomy or total thyroidectomy. Our conclusion was that a high volume center, like the one we are working in, with a correct selection of the patients,  allows to train a surgical resident guaranteeing both the surgical training of the doctor and the patients safety.

The modified TIME-H scoring system, a versatile tool in wound management practice: a preliminary report.

BACKGROUND AND AIMS: The concept of WBP (wound bed preparation) has revolutionized the way to diagnose and correctly identify the best therapeutic path about the widespread clinical problem of difficult wounds. Starting from the modified TIME-H, authors conducted a preliminary study with the aim of assessing the impact of skin lesions and soft tissues for the surgical patient. MATERIALS AND METHODS: 38 patients were preliminarily evaluated. The patients were classified according to the lesion examined, in particular among those who had an infectious or vascular etiology (SSTIs), and patients with surgical site lesions (SSI) and assigned to one of three categories prognosis: favorable (with healing expected within 12 weeks) (0-3A, 0-1B), intermediate (with healing expected over 12 weeks) (4-6A, 2-4B) and uncertain healing (7- 8A, 5-8B). RESULTS: At the end of the one-year observation period, authors established the healing prediction rate among the studied lesions: the surgical site lesions presented the highest percentage of predictivity (88%), followed by the mixed etiology (72%) and the infectious/vascular injuries (63%) Conclusion.This modified-TIME-H can be considered as a versatile and useful scoringtool that should be used in daily clinical practice for the study and treatment of chronic wound diseases.

Thyroid nodules with indeterminate cytology: association between nodule size, histopathological characteristics and clinical outcome in differentiated thyroid carcinomas - a multicenter retrospective cohort study on 761 patients.

A great number of surgical diagnostic procedures are performed every year for thyroid nodules that are included in undetermined cytological classes that reveal to be malignant thyroid carcinomas in one-third of cases. In the most recent guidelines, lobectomy is the most recommended surgical approach for this classes of nodules, but total thyroidectomy is the recommended treatment for undetermined nodules larger than 4 cm. The main study aim is to support or question the dimensional criteria as an independent clinical decision element for undetermined thyroid nodules management. We examined data regarding 761 patients undergoing thyroid surgery for undetermined thyroid nodules at two high-volume endocrine surgery units in Italy. Patients were divided into three groups based on the preoperative size of the nodules (N < 1, 1 < N < 4, N > 4 cm). Among the patients belonging to the different groups, we analyzed: differences in malignancy rate, histological characteristics of invasiveness and neoplastic aggressiveness, rates of recurrence and response to therapy. Nodule size (evaluated as a categorical variable and as a continuous variable) did not show any statistically significant correlation with the rate of malignancy, histopathological characteristics of tumor aggressiveness and the patient's clinical outcome. Most of the tumors found were included in the low risk class (79.2%) and only one was classified as high risk. Follow up of cancer cases showed excellent results in terms of survival, response to therapy and disease recurrence. Malignant thyroid tumors of any size resulting from a nodule identified as cytologically indeterminate are usually characterized by a low risk follicular pattern, well-differentiated and with an excellent outcome. As a result, preferring an extended surgical attitude for undetermined nodules based on tumor size, in absence of other risk factors, can lead to overtreatment in a significant percentage of cases.

Cribiform-morular variant of papillary thyroid carcinoma and familial adenomatous polyposis: Report of a case.

Cribiform-morular thyroid carcinoma is a rare variant of papillary thyroid carcinoma. It is usually related to Familial Adenomatous Polyposis (FAP) but rarely it may be sporadic. This variant of PTC occurs in young females and it is rare in the elderly. We report a case of a 20 years old female presenting thyroid carcinoma and personal history of FAP.

A peculiar manifestation and clinical course of occult primary hyperparathyroidism: a case report.

We present the clinical case of a patient who developed acute hypercalcemia diagnosed after presenting acute pancreatitis.Male patient, age 67, arrived at the Emergency Department of the University Hospital of Parma for upper abdominal pain, radiated to the back, and associated with nausea. Laboratory tests showed elevation of lipase, serum calcium levels, PTH levels and serum creatinine.  Due to the persistence on hypercalcemia an ultrasound scan of the cervical region was performed and showed a hyperechoic nodule of about 25x26x30 mm at the level of the lower pole of the left thyroid lobe, compatible with hyperplastic parathyroid. In the light of clinical-radiological examinations, acute edematous pancreatitis due to hypercalcemia was diagnosed. Hypercalcemia was attributable to primary hyperparathyroidism, so surgical indication to parathyroidectomy was gave.After medical treatment there was a progressive improvement of the clinical conditions and a few days later the patient underwent surgical operation of lower left parathyroidectomy with progressive normalization of the serum calcium levels. If hypercalcemia persists ​​after the beginning of a specific therapy there is an indication to perform an emergency parathyroidectomy; in our case the surgical procedure was performed some days after the diagnosis because the calcium serum levels ​​had returned to normal values with significant improvement of the clinical conditions, despite persistence of high PTH values.

Can we routinely identify the external branch of the superior laryngeal nerves with neural monitoring?: a prospective report on 176 consecutive nerves at risk.

The external branch of the superior laryngeal nerve (EBSLN) provides motor function to the cricothyroid muscle (CTM). EBSLN damage produces changes in voice quality and projection. Intraoperative neuromonitoring (IONM) in thyroid surgery aims to optimize EBSLN control during dissection. We prospectively collected the data of 88 consecutive patients who underwent total thyroidectomy with IONM from July 2019 to December 2019. IONM was offered in the intermittent mode of application. We routinely searched for the EBSLN electromyographic (EMG) signal before (S1) and after (S2) dissection of the superior vascular peduncle. In the absence of the EMG signal, we observed the CTM twitch. We identified 141 (80%) S1 EMG signals, while we recorded the CTM twitch in 15 cases (8.5%). In 20 (11.3%) cases, we were unable to identify the EMG signal. Analysing the S2 results, we found loss of EBSLN signal in 11/141 cases (7.8%) identified with IONM in pre-dissection stimulation. Among the 20 cases without pre-dissection identification (we had not identified the external branch of the superior laryngeal nerve or the muscle twitch), in the post-dissection evaluation, we confirmed the loss of signal in 17 of 20 cases, equal to 85% (p < 0.001). Our data clearly show that intraoperative stimulation and recognition of EBSLN, performed before any dissection manoeuvre to the superior vascular thyroid pole, leads to a much higher rate of nerve conservation.

Mini-invasive thyroidectomy and intraoperative neuromonitoring: a high-volume single-center experience in 215 consecutive cases.

BACKGROUND: Endocrine surgery recent evolution has been characterized by introduction of mini-invasive video-assisted technique. When a new technique is introduced in surgical use the rate of adverse events must be the same of previous standardized technique. In MIVAT procedure complication rate and in particular nerve injury risk is associated surgeon's experience. The new approach is the intraoperative neuro-monitoring (IONM) use in MIVAT in order to reduce the laryngeal nerve injury rate in a more technically difficult surgical procedure. METHODS: We analyzed clinical and surgical data regarding 215 patients treated with MIVAT technique and simultaneous IONM utilization from September 2014 to December 2019 in a single high-volume surgical center. We recorded data regarding age, gender, preoperative diagnosis, surgical time, early postoperative hypocalcemia, hematoma and vocal cord palsy. We compared these data to our first 211 cases of MIVAT (July 2005 to June 2009) at the beginning of the learning curve, performed without using IONM. We tried to highlight the impact of MIVAT and IONM simultaneous use on surgical outcome comparing results to our previous studies, also highlighting the learning curve effect. RESULTS: We detected a postoperative transitory clinical hypocalcemia in 14 patients (6.5%). No postoperative hematoma was recorded. Using I-IONM during thyroidectomy, we recorded in five cases a loss of signal; in three cases (1.4%) we experienced a temporary postoperative vocal cord palsy, only one case of definitive palsy. We did not observe any significant differences in surgical complications rate between the first 211 cases and these last 215 cases. We have not found any statistically significative difference regarding IONM use during MIVAT procedure related to MIVAT performed without IONM. In our previous experience cases series of MIVAT the percentage of transitory nerve palsy reported was 2.4% (non-significant P value). Surgical indication has changed. CONCLUSIONS: In our experience we report that the use of IONM in MIVAT is as helpful to improve the safe of procedure. The risk of nerve palsy in literature associated to MIVAT is the same of the related one to classic technique (CT). We have not found statistical positivity to use IONM in MIVAT related to MIVAT without IONM. In our previous experience cases series of MIVAT the percentage of transitory nerve palsy reported was 2.4% (non-significant P value). The most important IONM effect, in our opinion is the "safety feeling" experienced by the surgeon using IONM in a more challenging procedure. As a University Hospital, training surgery residents, we also identified the IONM as a very useful teaching support.

Rightward shift in colorectal cancer: experience in 1101 patients.

BACKGROUND: In the past decades the right colon cancer showed a higher incidence rate than left colon cancer. This trend is known as "proximal shift" or "rightwards shift." We evaluated rightward shift phenomenon in our region. METHODS: We collected data from 1101 colorectal cancer patients who underwent curative surgery at Parma University Hospital from 01 January 2004 through 01 January 2018. We divided patients into seven subgroups according to the time of surgery to evaluate epidemiological changes through the years of colon cancer. RESULTS: We found a non-linear rightward shift trend of CRC. The incidence of RCC was the 40% between 2004-2005 and 51% in the biennium 2016-2017 (60% in 2012-2013 and 57% in 2014-2015). The patients with RCC were significantly older than patients with LCC. RCCs have poor differentiated tumors. Metastatic disease showed a similar distribution both in left and right CRCs. Peritoneum was the most common metastasis location from right-sided colon cancer. CONCLUSIONS: Data suggest the existence of two different tumor entities in CRC between right-sided colon cancer and left-sided colon cancer. The proximal shift may be a reflection of improved screening programs, diagnostic accuracy and population aging. Ethnicity, gender, diet, environment, and socioeconomic status contribute to CRC incidence and prevalence in different regions.

Intraoperative neuromonitoring in traditional and miniinvasive thyroidectomy. A single center experience in 1652 nerve at risk.

BACKGROUND: The injury of laryngeal recurrent nerve (RLN) is one of the most severe adverse event in thyroid surgery. The rate in literature is reported as 2-11% for transient palsy and 0,6-1,6% for permanent palsy (after 6 months from surgical procedure). METHODS: The patients undergoing thyroid surgery associated to Intraoperative Neuromonitoring (IONM were enrolled consecutively from 21/08/2014 to 30/08/2018. WE collected data from I-IONM and not by Continuos IONM (C-IONM) because we have interrupted C-IONM after a case of cardiac arrest (15TH patient) during the APS placement. RESULTS: The utility of the intraoperative neuro-monitoring system was evaluated with the following statistical methods:• Mann Withney U-test with independent samples, T-samples with coupled samples, Wilcoxon signed sign test, Chi square test., Positive predictive value (PPV), Negative predictive value (NPV),we considered the values for p <0.05 statistically positive. CONCLUSIONS: In high-volume centers the rate of transitory / permanent vocal cord palsy is low but also in these Units the need of feel safety is related to IONM. The use of the IONM is an helpful tool for dissection and anatomical identification of the nerves. IONM has a high specificity and sensitivity and a high negative predictive value. PPV as 52% definable low, may be related to the transient stupor of nerve function.

How COVID-19 pandemic has changed elective surgery: the experience in a general surgery unit at a COVID-hospital.

Objective Evaluate the impact of Covid-19 in a critical area and analyze the changes in the daily activities in a General Surgery Unit of a tertiary Covid-Hospital.   Methods We report and compared all the surgical procedures performed between two periods (March and April 2019 and March and April 2020) at General Surgery Department of Parma University Hospital, a tertiary Covid-Hospital.   Results Between March and April 2019, a total of 232 surgical procedures were performed. Between March and April 2020 only 61 surgical procedures were performed. In 2019 84 patients underwent surgery for cancer and 171 underwent surgery for benign diseases. In 2020 only 37 patients underwent surgery for oncological reasons and 24 underwent surgery for benign diseases.   Conclusions During pandemic Covid-19 the access to health services was limited and poor. Limited access to health services and the fear of Covid-19 infection can explain the lower number of elective surgical procedures for cancer in 2020 compared to the same period in the 2019.

Colorectal cancer screenings: a single center experience.

AIM: evaluating the impact of screening programmes on colorectal cancer (CRC) in Italy. METHODS: we studied 1292 patients with colorectal cancer. Data were collected from January 2004 through December 2015 in Parma University Hospital. We compared clinophatological features to evaluate the real impact of screening programmes on detecting early stage colorectal cancers in target population. RESULTS: screening programmes with fecal occult blood test (FOBT) and colonoscopy covered only patients from 50 to 69. In our study we reported that the 52,3% of patients with CRC were over 70 and out of screen time, while only 47,7% were under 70. Early detection seems to be related to early stage of CRC and to an improved overall survival. CONCLUSION: The importance of early detection in colorectal cancers represents the most important outcome for OS. The risk of colorectal cancer is increased in elderly. Actual screening programmes cover less than 50% of population with colorectal cancer. Screening should be considered for patients over 70, due to the high number of new diagnosis in symptomatic disease and worst prognosis, in accordance with advanced cancer stage and comorbidities in elderly.

Lean implementation in healthcare supply chain: a scoping review.

PURPOSE: The purpose of this paper is to identify the lean production (LP) practices applied in healthcare supply chain and the existing barriers related to their implementation. DESIGN/METHODOLOGY/APPROACH: To achieve that, a scoping review was carried out in order to consolidate the main practices and barriers, and also to evidence research gaps and directions according to different theoretical lenses. FINDINGS: The findings show that there is a consensus on the potential of LP practices implementation in healthcare supply chain, but most studies still report such implementation restricted to specific unit or value stream within a hospital. ORIGINALITY/VALUE: Healthcare organizations are under constant pressure to reduce costs and wastes, while improving services and patient safety. Further, its supply chain usually presents great opportunities for improvement, both in terms of cost reduction and quality of care increase. In this sense, the adaptation of LP practices and principles has been widely accepted in healthcare. However, studies show that most implementations fall far short from their goals because they are done in a fragmented way, and not from a system-wide perspective.

Pharmacokinetics and Safety of a Diclofenac Sodium 75 mg/1 mL Solution (Akis®/Dicloin®) Administered as a Single Intravenous Bolus Injection in Healthy Men and Women.

BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.