In blood we trust: anemia as a negative healing prognostic factor in diabetic foot patients.

AIM: Anemia has been associated with severity of diabetic foot (DF) disease. Our study aimed to evaluate whether the presence of anemia could decrease the healing chances in DF. METHODS: We retrospectively analyzed all patients admitted in our department in 2021 for DF, dividing them according to presence (Group A) or absence (Group B) of anemia. Groups were compared for clinical and demographic characteristics, procedures and outcomes: healing rate (HR) at 6 months, healing time (HT) and recurrence rate (RR) at 12 months. RESULTS: We sorted out data from 196 consecutive patients: 114 (58%) in Group A and 82 (42%) in B. Group A had a higher male prevalence and a longer duration of disease. Group A showed lower hemoglobin concentration (10.3 ± 1.3 g/dL vs 13.1 ± 1.4 g/dL, p < 0.002) and red blood cells count (3.4 ± 0.5 × 106/mL vs 4.8 ± 0.6 × 106/mL, p = 0.004). Group A presented a lower HR (55.2% vs 76.8%, p = 0.0028), no differences in HT and a higher RR (23.6% vs 17.1%, p < 0.02). Cox's logistic regression on healing confirmed the negative impact of anemia: hazard ratio 2.8 (CI 95% 1.4-5.4, p = 0.0037). CONCLUSIONS: Anemia is frequent in DF and associates to a reduction in healing chances and an increase in recurrences representing an independent predictor of healing failure.

Higher Prevalence of Cancer in Patients with Diabetic Foot Syndrome.

Background: Diabetes mellitus (DM) is associated with a higher prevalence of many forms of cancer. Diabetic foot syndrome (DFS) is associated with higher risk of lower limb amputation and mortality not all explainable with a cardiovascular profile at greater risk compared with DM patients without DFS. DFS could be associated with an increasing cancer incidence. To explore a possible link between DFS and cancer, comparing two cohorts of patients (DFS+ and DFS-) with a cohort of superimposable non-DM controls. Methods: We retrospectively analysed the databases of our department for all consecutive patients admitted between January 2019 and December 2021, selecting all DM pts, and sorting DFS+ pts, admitted for foot complications, from DFS- ones, admitted for other reasons. Cases of pancreatic cancer as well as cancer-related admissions were excluded. Patients were compared to non-DM patients admitted for non-oncological medical problems. The primary endpoint was to compare the prevalence of cancer among the groups, while the secondary endpoint was to look for predictors for cancer in the groups studied. Results: A cohort of 445 consecutive DM inpatients (222 DFS+ and 223 DFS-) and 255 controls were studied. Cancer prevalence in DFS+ group was significantly higher than in DFS- (p = 0.008) and controls (p = 0.031), while no differences were observed between DFS- and the controls. Univariate regression analysis showed a significant association between cancer and DFS (p = 0.007), age at admission (p ≤ 0.001), years of diabetes (p = 0.017) and haemoglobin concentration [Hb] (p = 0.030). In the multivariate regression analysis with DFS, age at admission and [Hb], only DFS (p = 0.021) and age at admission (p ≤ 0.001) persisted as independent factors associated with cancer. Conclusions: A higher prevalence of cancer in DFS+ patients than in DFS- patients and non-diabetic controls is reported. DFS and age can both be considered independent predictors of cancer in patients with DM.

Charcot Neuro-Osteoarthropathy With Superimposed Osteomyelitis in a Nondiabetic Patient, as a Consequence of Cancer Chemotherapy: A MR-Monitored Case Report.

Charcot neuro-osteoarthropathy (CNO) is a manifestation of peripheral neuropathy as a chronic complication of diabetes mellitus but, less frequently, can be associated to other conditions such as alcoholism or neurotoxic therapies. An increasingly emerging cause of CNO is the use of oncological drugs which can cause neuropathic damage. The use of these therapies dramatically increased in recent years. CNO leads to a progressive degeneration of the foot's joints and to bone destruction and resorption which ends in deformities. These alterations in the foot's anatomy determine a high risk of ulceration, infection, and osteomyelitis. The superimposition of osteomyelitis on CNO increases the risk of major amputation, already high in patients suffering either from only CNO or osteomyelitis alone. We report the case of a 61-year old nondiabetic woman affected by CNO as a consequence of antiblastic therapy for breast cancer and the subsequent overlap of osteomyelitis, confirmed by magnetic resonance imaging. This case underlines how it is necessary to consider CNO as a possible complication of antiblastic therapy in the view of the severe consequences of missing its diagnosis.

The Weakness of the Strong Sex: Differences Between Men and Women Affected by Diabetic Foot Disease.

We aimed to analyze sex-related differences in clinical outcomes among patients with diabetic foot disease (DFD) managed in a third-level referral center. We retrospectively analyzed data of admissions performed in our department between 2011 and 2015 for DFD. We collected demographic and clinical data, procedures performed during the admission, and short- and long-term outcomes in terms of healing rate and healing time, major amputation, and mortality rates during the follow-up. We focused on differences between genders and tried to figure out if sex could be considered a predictive factor. We collected data from 1237 admission performed in 842 patients (615 men [73%] and 227 women [27%]; age: 68.6 ± 27.9 years; diabetes duration: 16.4 ± 13.4 years; body mass index: 28.2 ± 6.4 kg/m2; hemoglobin A1c 7.9 ± 1.9%). Men showed a higher prevalence of comorbidities and previous ulcers or revascularization procedures. Men had a significantly higher healing rate compared with women (85.4% vs 63.2%, P < .001), but a longer healing time (124 ± 27 days vs 87 ± 14 days, P = .02). Major amputation did not differ between groups, while mortality rate was significantly higher in men (24.5% vs 16.1%, P = .02). In Cox's regression analysis, male sex was a positive predictive factor for healing and a negative one for time to heal and mortality. The difference in mortality was confirmed by a Kaplan-Meier analysis (log rank test: P = .03). DFD represents a severe disease and a strong marker of mortality affecting more severely on clinical outcomes and survival on men.

Non-reversed bifurcated vein graft improves time to healing in ischemic patients undergoing lower limb distal bypass.

BACKGROUND: Bifurcated vein grafts have been described in reconstructive microsurgery. No comparative studies have been published in lower limb arterial revascularization. The aim of this study was to compare non-reversed bifurcated vs. single vein graft in patients with critical limb-threatening ischemia (CLTI) undergoing lower limb distal bypass. METHODS: Between January 2015 and December 2021 193 CLTI patients have been treated at our center with vein bypass, and distal anastomosis on infrapopliteal vessels; 137 patients (71%) received a single graft (Group SIN), and 56 patients (29%) had a bifurcated bypass (Group BIF). Primary outcomes measures were time to healing, primary patency, primary assisted patency, secondary patency, and limb salvage. Two-year outcomes according to Kaplan-Meier curves were evaluated and compared. RESULTS: Both groups were homogeneous in terms of demographic data, preoperative risk factors, and clinical presentation except for an elderly age in Group BIF (77.5 vs. 71.5 years; P<0.001). Intraoperative technical success was achieved in all patients. Overall median duration of follow-up was 19 months (interquartile range 9-36). Wound healing did not differ between the two groups (77.4% Group SIN vs. 73.2% Group BIF; P=0.33). Mean time to healing was faster in Group BIF (2.4 vs. 6.8 months; P<0.001). At 2-year follow-up there were no differences between the two groups in terms of primary patency (71.4% Group SIN vs. 54% Group BIF; P=0.10), primary assisted patency (81.7% Group SIN vs. 76.4% Group BIF; P=0.53), secondary patency (85.1% Group SIN vs. 80.9% Group BIF; P=0.79), and limb salvage (92.3% Group SIN vs. 87.2% Group BIF; P=0.64). CONCLUSIONS: Bifurcated graft improved time to healing in CLTI patients undergoing infrapopliteal non-reversed vein bypass. Two-year overall patencies and limb salvage did not differ accordingly to vein graft configuration (single vs. bifurcated).

Necrotizing Fasciitis and Diabetic Foot: Results of a Prompt Identification, Surgery and Antibiotic Therapy (P.I.S.A.) Protocol.

Necrotizing fasciitis (NF) is a rapidly progressive, life-threatening infection, involving the skin, soft tissue and fascia. We evaluated outcomes of its surgical management in diabetic foot (DF) patients in a tertiary referral centre. We retrospectively searched for NF in the database of our DF Section from 2016 to 2018. All cases were treated according to a multiprofessional integrated protocol, with Prompt Identification, Surgical debridement and systemic Antibiotic therapy (P.I.S.A. Protocol). We analysed short-term evolution (surgical procedures and major amputations), and long-term outcomes (survival and healing rates). Sixty-eight patients were referred to our DF clinic for suspicion of NF. The diagnosis was confirmed in 54 (79.4%; male/female 40/14; type 1/2 diabetes 6/48; age 62.8 ± 8.1 years; duration of diabetes 13.6 ± 10.1 years). According to the microbiological results, cases were classified as Type 1 (33-61.2%), 2 (7-12.9%) and 3 (14-25.9%). No significant differences were observed. All patients underwent a decompressive fasciotomy. Six patients (11.1%) required also a forefoot amputation and 12 (22.2%) a toe or ray amputation. No major amputation was performed in the short-term period. During the follow-up (26 ± 12 months) 46 patients (85%) healed in 94 ± 11 days. Of the remaining 8: 5 (9.2%) died for other reasons before healing, 2 (3.7%) recurred and one (1.9%) required a major amputation. Our experience reveals a relatively high prevalence of NF in DF; despite this, we observed how, when promptly and aggressively treated, NF has a good prognosis and it is not associated with an excess of limb loss and deaths.

Pilot Experience on the Use of S53P4 Bioactive Glass in the Surgical Management of Diabetic Foot Osteomyelitis.

To test safety and efficacy of bioactive glass, a novel material used to replace bone, able to completely bond itself to the host tissues on patients treated for osteomyelitis (OM) complicating a diabetic foot (DF). We evaluated a group of patients consecutively admitted in our department between September and December 2018, who underwent surgical DF procedures for OM and in whom the use of bioactive glass could limit the demolition phase of surgical procedure. Patients were treated with bioactive glass S53P4 on top of standard treatment directly in operating room. The patients were weekly controlled for 6 months or until complete healing. During follow-up, we analyzed primarily healing rate and secondarily time of healing, need for further debridement procedures, recurrences, and adverse or hypersensitivity reactions to study treatment. Ten DF patients were enrolled (male/female 6/4; mean age 56 ± 11 years; mean duration of diabetes 10.5 ± 4.7 years, mean hemoglobin A1c 7.2 ± 0.9%). Patients underwent surgical procedure during which, after an accurate debridement, bioactive glass was applied. A healing rate of 80% in a mean time of 34 ± 2 days, with only 1 patient who needed a second surgical look, was observed. Neither recurrences nor adverse events during follow-up were observed in treated patients. This pilot experience demonstrated that bioactive glass can be considered a useful tool for the surgical treatment of DF-related OM.

Bioactive Glass in a Rare Case of Osteomyelitis of the Heel in a Guillain-Barré Syndrome: A Case Report.

Guillain-Barré syndrome (GBS) represents an acute inflammatory immune-mediated demyelinating polyradiculoneuropathy with an incidence of 0.6 per 100 000 people. In this article, we report the case of a 19-year-old girl affected by GBS since the age of 2 who presented at our clinic complaining for a chronic plantar hindfoot-infected ulceration. Serology showed increase of inflammatory markers and leukocytosis, and magnetic resonance imaging revealed osteomyelitis of calcaneum and soft tissue alterations with air bubbles. The patient was treated in our clinic by an integrated multidisciplinary approach consisting of immediate admission, soft tissue and bone debridement, and administration of antibiotics under the close control of infectious disease specialist. After the control of acute condition, the patient underwent negative pressure therapy associated with instillation of antiseptic solution until the restoration of bone and soft tissue loss of substance and, eventually, to the application of bioactive glass substitute until the achievement of complete wound healing.

Diabetic foot surgery "Made in Italy". Results of 15 years of activity of a third-level centre managed by diabetologists.

AIM: To evaluate clinical outcomes in patients who underwent diabetic foot surgery (DFS) managed directly by diabetologists in a third-level Centre over 15-year. METHODS: We retrospectively evaluated 1.857 patients affected by diabetic foot (Age 67.1 ± 12.3 yrs, diabetes duration 19.2 ± 9.8 yrs, HbA1c 8.1 ± 2.0%) treated in our Department between 2001 and 2015 and divided them into 3 groups: Group 1, treated between 2001 and 2005 (448 pts), group 2, between 2006 and 2010 (540 pts) and Group 3, between 2011 and 2015 (869 pts). Main clinical outcomes [peripheral revascularization rate (PR), healing rate (HR), healing time (HT), recurrences after healing (R), major amputation (MA) and death (D) rates] were compared between groups. RESULTS: The overall outcomes of our cohort were: HR 81.6% (HT 143 ± 54 days), PR 84.8%, MA 4.9% and D 27.9%. There were no differences in clinical characteristics, except for age, higher (p < 0.05) in Group 3 (70.6 ± 14.7 yrs) than in Groups 1 (64.4 ± 11.6 yrs) and 2 (65.1 ± 11.2 yrs). No differences emerged when comparing HR and MA; HT was shorter (p < 0.05) in group 3 (104 ± 44 days) than in Group 2 (169 ± 72 days) and 1 (235 ± 67 days). D was higher (p < 0.05) in Group 3 (43.8%) than in Group 1 (23.1%) and 2 (28.1%). PR was 19.4% in Group 1, 28.1% in Group 2 and 53.8% in Group 3 (p < 0.05). CONCLUSIONS: Despite the increasing age and complexity of patients our data show improvement of outcomes throughout 15 years, probably due to better surgical techniques, more aggressive medical therapy and more effective treatment of critical limb ischemia.

Ultrasound in the Modern Management of the Diabetic Foot Syndrome: A Multipurpose Versatile Toolkit.

Ultrasound (US) is a noninvasive and versatile technology that in recent years found acceptance in almost all the medical specialties, with diagnostic and interventional applications. In the diabetic foot syndrome (DFS), US found specific indications mainly in the screening, quantification, and follow-up of the vascular component of the pathology, but also in the study of the deformities and structural modifications induced by neuropathy and in the diagnosis and surgical management of infections, especially those that induce anatomical changes, like abscesses and fasciitis. This review will summarize all these application of US, giving special attention to the vascular aspects, and on the predominant role that US gained in recent times to guide the indication to revascularization, on the new standardized approach to the study of the arterial tree of the limb and the foot, the so-called duplex ultrasound arterial mapping, which significantly increased the utilization of US to plan the revascularizations in this complex pathology. Outside the vascular fields, the diagnosis of neuropathy and infection and the intraoperative use of US in the surgical management of abscesses and fasciitis will be discussed, leaving the last part to the new and interesting applications of US in the management of DFU, a field that is still in evolution, offering new possibilities to the health care professionals involved in the management of these chronic wounds. The variety of applications both in diagnostic and operative fields makes US a rather versatile technology-a toolkit-that should have a special place among those at reach of the specialists of DFS care.

Using Skin Bioengineering to Highlight How Weight and Diabetes Mellitus Modify the Skin in the Lower Limbs of Super-Obese Patients.

AIM: To evaluate the distinct contribution of obesity and diabetes (DM) to the skin modification in metabolic diseases. METHODS: We analysed all patients admitted for bariatric surgery in our hospital with BMI between 38 and 47 kg/m2, with (Group 1) or without (Group 2) DM and compared them with a group of nonobese diabetic patients (Group 3) and healthy volunteers (Group 4). The following features were evaluated: hardness, temperature, hydration and thickness alongside with anthropometric measures of foot and leg. RESULTS: For the general characteristics, patients differed in age and body mass index. As predictable all circumferences (dorsal foot, sovramalleolar and under the knee) were significantly higher in obese with no differences depending on DM (all parameters: p<0.01 in Group 1 and Group 2 vs Group 3 and Group 4). Skin temperature was significantly higher in all obese, irrespectively from the presence of DM (1st metatarsal head: p=0.02 Group 1 and Group 2 vs Group 3 and Group 4; 5th metatarsal head: p<0.01 in Group 1 and Group 2 vs Group 3 and Group 4). Skin hydration score showed increased anhydrosis in both diabetics and severe obesity (p<0.01 in Group 1 and Group 3 vs Group 2 and Group 4). Increase in thickness of skin and subcutaneous tissues was observed (at heel: p<0.01 in Group 1 and Group 2 vs Group 3 and Group 4 and under the scaphoid p=0.03 Group 1 and Group 2 vs Group 3 and Group 4) and plantar fascia (in both regions p=0.02 Group 1 and Group 2 vs Group 3 and Group 4) in all obese patients, with or without DM. CONCLUSION: Severe obesity significantly affects both shape and structure of the foot, possibly exposing these patients to a higher risk of biomechanical stress. On such a background DM, modifying skin hydration and protective mechanisms exerts a synergistic role further increasing the risk of trauma and ulcers.

Active Surveillance in Papillary Thyroid Microcarcinomas is Feasible and Safe: Experience at a Single Italian Center.

CONTEXT: The dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases. OBJECTIVE: To evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression. DESIGN AND SETTING: In 2014 we started a prospective-observational study of active surveillance in mPTC patients. PATIENTS: Included patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis. INTERVENTION: Enrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these cases, patients were directed to surgery. RESULTS: Three patients (3/93, 3%) showed clinical progression and required surgery. Another 19 patients (19/93, 20%) decided to transition to surgical intervention even though there was no evidence of disease progression. All operated patients had excellent response to initial treatment despite the delayed surgery. CONCLUSIONS: Within an Italian medical context, active surveillance appears to be a feasible and safe alternative to immediate surgery in healthy mPTC patients. Only 3% of mPTC demonstrated disease progression during a median follow-up of 19 months (range 6-54) and importantly demonstrated excellent outcomes after surgical intervention in a short-term follow-up.

Adherence to guideline recommended medical therapies in type 2 diabetic patients with chronic critical limb ischemia.

AIM: The aim of this study was to evaluate the adherence to guideline recommended medical therapies in type 2 diabetic patients with chronic critical limb ischemia (CCLI). METHODS: We retrospectively analyzed the data of 1315 admissions performed in our Department, focusing on diabetic foot patients (842-64%) of which 603 consecutive type 2 diabetic patients with CCLI (M/F(%): 73/27; age: 70.3 ±â€¯10.4 yrs; diabetes duration: 17.3 ±â€¯13.7 yrs; BMI: 27.7 ±â€¯5.3 Kg/m2; HbA1c 7.8 ±â€¯1.8%) referred to a third-level Center from 2011 to 2015. We focused on medical therapy of diabetes, dyslipidemia, hypertension, peripheral vascular disease and smoke habits. RESULTS: In total, at admission, 66.6% of patients had HbA1c levels higher than recommended; 65.9% of patients were on statins; 81.4% on anti-hypertensive treatment and 72.4% on antiplatelet drugs. Concerning smoke habits, 27% of patients were no-smokers; 41% former smokers and 32% active smokers. Among all patients, only 24% were prescribed all five guideline recommended therapies while 32% reached four out of five of these. As for patients treated with anti-hypertensive drugs, we observed higher levels of systolic pressure (138.0 ±â€¯29.5 vs 107.7 ±â€¯36.6 p < 0.02) while no differences were observed in diastolic pressure levels. CONCLUSIONS: In conclusion, when it comes to diabetic patients with a severe limb and life threatening clinical condition, we noticed a lower-than-expected application of international guideline-recommended medical therapies. In fact, only one out of four patients was following all the recommended therapies. Nevertheless, these patients did not reach the standard targets requested to prevent cardiovascular disease.

Epidemiology of Simultaneous Medullary and Papillary Thyroid Carcinomas (MTC/PTC): An Italian Multicenter Study.

Background: The concomitant presence of papillary thyroid cancer (PTC) and medullary TC (MTC) is rare. In this multicentric study, we documented the epidemiological characteristics, disease conditions and clinical outcome of patients with simultaneous MTC/PTC. Methods: We collected data of patients with concomitant MTC/PTC at 14 Italian referral centers. Results: In total, 183 patients were enrolled. Diagnosis was mostly based on cytological examination (n = 58, 32%). At diagnosis, in the majority of cases, both PTC (n = 142, 78%) and MTC (n = 100, 54%) were at stage I. However, more cases of stage II-IV were reported with MTC (stage IV: n = 27, 15%) compared with PTC (n = 9, 5%). Information on survival was available for 165 patients: 109 patients (66%) were disease-free for both PTC and MTC at the last follow-up. Six patients died from MTC. Median time to progression was 123 months (95% confidence interval (CI): 89.3-156.7 months). Overall, 45% of patients were disease-free after >10 years from diagnosis (125 months); this figure was 72.5% for PTC and 51.1% for MTC. Conclusions: When MTC and PTC are concurrent, the priority should be given to the management of MTC since this entity appears associated with the most severe impact on prognosis.

Clinical, pathological and genetic features of anaplastic and poorly differentiated thyroid cancer: A single institute experience.

Anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) are very aggressive cancers whose histological diagnosis is not always straightforward. Clinical, pathological and genetic features may be useful to improve the identification of these rare histotypes. In the present study the clinical, pathological and genetic features of two groups of ATC (n=21) and PDTC (n=21) patients were analyzed. Clinical data were retrieved from a computerized database. The oncogenic profiles were studied using the Sanger sequencing method of a selected series of oncogenes and/or tumor suppressor genes known to be altered in these tumors. The presence of macrophages in both series of tissues was evaluated by immunohistochemistry. Patients with ATC were older and affected by a more advanced disease at diagnosis than those with PDTC. The median survival was significantly shorter in ATC compared with PDTC patients (P=0.0014). ATC showed a higher prevalence of TP53 and TERT mutations (10/21, 47.6% and 9/21, 42.8%, respectively) while TERT and BRAF mutations were the most prevalent in the PDTC group (7/21, 33.3% and 4/23, 19% respectively). Genetic heterogeneity (i.e., >2 mutations) was more frequent in ATC (10/21, 28.6%) compared with in PDTC (3/21, 4.7%) (P=0.03). Macrophages were more frequently present in ATC, particularly in those cases with TP53 mutations. In conclusion, these data indicate that ATC and PDTC may be characterized by different clinical, pathological and genetic profiles. In particular ATC, but not PDTC, were positive for TP53 and PTEN alterations. Complex mutations were also found in ATC but not in PDTC. Moreover, genetic heterogeneity was more frequent in ATC than PDTC. Finally, TP53 mutation and the accumulation of several mutations correlated with a shorter survival time.

Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life.

The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided.

Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer.

Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P<0.001). Although there was no statistically significant difference in the overall survival of the entire group, this result was observed when the analysis was restricted to both the follicular histotype and the group of senior patients (>65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population.

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience.

Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

Patients with differentiated thyroid cancer who underwent radioiodine thyroid remnant ablation with low-activity ¹³¹I after either recombinant human TSH or thyroid hormone therapy withdrawal showed the same outcome after a 10-year follow-up.

BACKGROUND: No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (¹³¹I). AIM: The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq ¹³¹I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. PATIENTS: A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of ¹³¹I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. RESULTS: During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end of the 10-year follow-up, 140 of 159 (88.1%) patients were disease-free, whereas 19 of 159 (11.9%) remained affected. No correlation was found with the type of TSH stimulation, and no other clinical and pathological features showed any correlation with the final status. However, low levels of stimulated serum thyroglobulin (<5.4 ng/mL) at first control after remnant ablation identified a subgroup of not ablated patients who became spontaneously cured. CONCLUSIONS: Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) ¹³¹I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role.