Survival analysis, more than meets the eye

The log-rank test is a cornerstone of phase III oncology clinical trials. However, there are at least three different mathematical procedures that can be named the log-rank test and two of them are widely used by commercial statistical programs. Consequently, different P values can be obtained. In the case of a borderline statistical significance, this can mean the difference between the evidence (significant P value) and merely an observation. Since all three methods can be reported under the same name, space for possible data manipulation occurs. This should be of a particular concern in a drug regulatory context. Randomized clinical trials with borderline significant results should perhaps be required to report P values calculated by all three methods, in order to properly evaluate drug efficacy. An interactive MS Excel spreadsheet that uses all three logrank test variants is prepared as a supplementary file accompanying this article. Association of high grade of bone marrow fibrosis with poor outcome in patients with myelofibrosis is used as an example

Optimization of mode of administration of levothyroxine

Uvod: Levotiroksin (LT4) je lijek prve terapijske linije u liječenju hipotireoze, s uskim terapijskim indeksom koji se primjenjuje u vrlo malim količinama (μg), što ga čini osjetljivim na čimbenike koji utječu na njegovu apsorpciju, posebice prehrambene namirnice i lijekove. Stoga su takve interferencije uglavnom i klinički značajne. Kronična primjena LT4 i preporučeni režim uzimanja pola sata prije doručka (prema SmPC), koji je za mnoge bolesnike nepogodan, povećava rizik od smanjene adherencije. Svrha rada: Cilj je ovog istraživanja bio ispitati učinke različitih vremena uzimanja LT4 (A - pola sata prije doručka; B - jedan sat prije glavnog jela; C - prije spavanja (najmanje 2 sata nakon večere)) na parametre funkcije štitnjače i lipidnog statusa bolesnika. Medode i ispitanici: U istraživanje je bilo uključeno 84 bolesnika s dijagnozom primarne hipotireoze, koji su primali stabilnu dozu LT4. Bolesnici su na početku bili randomizirano svrstani u jednu od skupina (A, B ili C) te su unakrsno prošli sva tri vremenska načina uzimanja LT4, svaki u trajanju od osam tjedana. Serumske koncentracije parametara funkcije štitnjače (tiroidni stimulirajući hormon (TSH), slobodni tiroksin (fT4) i slobodni trijodtironin (fT3) i parametara lipidnog statusa (trigliceridi, HDL- (eng. high density lipoprotein) kolesterol, LDL- (eng. low density lipoprotein) kolesterol i ukupni kolesterol) određene su na početku svakog vremenskog režima i na kraju studije. Rezultati: Analizom dobivenih rezultata nisu utvrđene statistički značajne razlike u vrijednostima parametara funkcije štitnjače (TSH, fT4 i fT3), kao ni u parametrima lipidnog statusa (trigliceridi, HDL-, LDL- i ukupni kolesterol) između tri vremenska načina uzimanja LT4. Analizom stabilnosti nadomjesne terapije s LT4 nisu utvrđene statistički značajne razlike između koeficijenata varijacije parametara funkcije štitnjače te lipidnog statusa kao ni postotka bolesnika čije su vrijednosti ispitivanih parametara bile unutar pripadajućih referentnih intervala, nakon različitih vremenskih načina uzimanja LT4. Zaključak: Kako je primjena LT4 u sva tri vremena (A, B i C) bila jednako učinkovita u reguliranju parametara funkcije štitnjače i lipidnog statusa bolesnika, rezultati ovog istraživanja otvaraju dodatne mogućnosti personalizacije farmakoterapijskog pristupa i postizanja veće učinkovitosti liječenja, posebice za bolesnike koji standardnim načinom uzimanja nisu ostvarili terapijske ciljeve.Backgorund: Levothyroxine, a first-line therapy for hypothyroidism, is a drug with a narrow therapeutic index, used in a very small amount (μg). These features make LT4 particularly sensitive to various factors interfering with its absorption, e.g. food and drugs. These interferences are usually clinically relevant. Chronic use of LT4 therapy and the recommended timing of LT4 administration, half an hour before breakfast (according to the SmPC), which is not suitable for many patients, increase the risk of reduced adherence. Aim of study: The aim of this study was to investigate effects of different timing of LT4 administration (A – half an hour before breakfast; B – an hour before the main meal of the day; C – at bedtime (minimally 2 hours after dinner)) on the parameters of thyroid function status and lipid profile of the patients. Methods and patients: Study included 84 patients with the diagnosis of primary hypothyroidism and using a stable dose of LT4. Patients were randomized into three different groups (A, B or C) and passed all different timings of LT4 administration (each lasted for at least 8 weeks), in a crossover fashion. Serum concentrations of parameters of thyroid function (thyroid-stimulation hormone (TSH), free thyroxin (fT4) free triiodothyronine (fT3) and lipid profile (triglycerides, high density lipoprotein- (HDL), low density lipoprotein- (LDL), and total cholesterol) were measured at the beginning of every timing regime and at the end of the study. Results: The analysed results did not showed any statistically significant differences in parameters of thyroid function (TSH, fT4, or fT3) or the lipid profile (triglycerides, HDL-, LDL-, and total cholesterol) when compared between three different timing regimens of LT4 administration. Considering stability of LT4 supplemental therapy, there was no difference among the calculated coefficients of variation of the thyroid function and lipid profile parameters nor the difference in percentage of patients whose values of the examined parameters were within the corresponding reference intervals after different timing regimes of LT4 administration. Conclusion: Since there was no difference in effectiveness in regulating patients’ thyroid function and lipid profile between different timings of LT4 administration, this study provides additional options regarding the personalization of pharmacotherapy and achievement of increased efficacy of the treatment, especially for the patients who did not reached therapeutic goals with standard way of administration

Optimization of mode of administration of levothyroxine

Uvod: Levotiroksin (LT4) je lijek prve terapijske linije u liječenju hipotireoze, s uskim terapijskim indeksom koji se primjenjuje u vrlo malim količinama (μg), što ga čini osjetljivim na čimbenike koji utječu na njegovu apsorpciju, posebice prehrambene namirnice i lijekove. Stoga su takve interferencije uglavnom i klinički značajne. Kronična primjena LT4 i preporučeni režim uzimanja pola sata prije doručka (prema SmPC), koji je za mnoge bolesnike nepogodan, povećava rizik od smanjene adherencije. Svrha rada: Cilj je ovog istraživanja bio ispitati učinke različitih vremena uzimanja LT4 (A - pola sata prije doručka; B - jedan sat prije glavnog jela; C - prije spavanja (najmanje 2 sata nakon večere)) na parametre funkcije štitnjače i lipidnog statusa bolesnika. Medode i ispitanici: U istraživanje je bilo uključeno 84 bolesnika s dijagnozom primarne hipotireoze, koji su primali stabilnu dozu LT4. Bolesnici su na početku bili randomizirano svrstani u jednu od skupina (A, B ili C) te su unakrsno prošli sva tri vremenska načina uzimanja LT4, svaki u trajanju od osam tjedana. Serumske koncentracije parametara funkcije štitnjače (tiroidni stimulirajući hormon (TSH), slobodni tiroksin (fT4) i slobodni trijodtironin (fT3) i parametara lipidnog statusa (trigliceridi, HDL- (eng. high density lipoprotein) kolesterol, LDL- (eng. low density lipoprotein) kolesterol i ukupni kolesterol) određene su na početku svakog vremenskog režima i na kraju studije. Rezultati: Analizom dobivenih rezultata nisu utvrđene statistički značajne razlike u vrijednostima parametara funkcije štitnjače (TSH, fT4 i fT3), kao ni u parametrima lipidnog statusa (trigliceridi, HDL-, LDL- i ukupni kolesterol) između tri vremenska načina uzimanja LT4. Analizom stabilnosti nadomjesne terapije s LT4 nisu utvrđene statistički značajne razlike između koeficijenata varijacije parametara funkcije štitnjače te lipidnog statusa kao ni postotka bolesnika čije su vrijednosti ispitivanih parametara bile unutar pripadajućih referentnih intervala, nakon različitih vremenskih načina uzimanja LT4. Zaključak: Kako je primjena LT4 u sva tri vremena (A, B i C) bila jednako učinkovita u reguliranju parametara funkcije štitnjače i lipidnog statusa bolesnika, rezultati ovog istraživanja otvaraju dodatne mogućnosti personalizacije farmakoterapijskog pristupa i postizanja veće učinkovitosti liječenja, posebice za bolesnike koji standardnim načinom uzimanja nisu ostvarili terapijske ciljeve.Backgorund: Levothyroxine, a first-line therapy for hypothyroidism, is a drug with a narrow therapeutic index, used in a very small amount (μg). These features make LT4 particularly sensitive to various factors interfering with its absorption, e.g. food and drugs. These interferences are usually clinically relevant. Chronic use of LT4 therapy and the recommended timing of LT4 administration, half an hour before breakfast (according to the SmPC), which is not suitable for many patients, increase the risk of reduced adherence. Aim of study: The aim of this study was to investigate effects of different timing of LT4 administration (A – half an hour before breakfast; B – an hour before the main meal of the day; C – at bedtime (minimally 2 hours after dinner)) on the parameters of thyroid function status and lipid profile of the patients. Methods and patients: Study included 84 patients with the diagnosis of primary hypothyroidism and using a stable dose of LT4. Patients were randomized into three different groups (A, B or C) and passed all different timings of LT4 administration (each lasted for at least 8 weeks), in a crossover fashion. Serum concentrations of parameters of thyroid function (thyroid-stimulation hormone (TSH), free thyroxin (fT4) free triiodothyronine (fT3) and lipid profile (triglycerides, high density lipoprotein- (HDL), low density lipoprotein- (LDL), and total cholesterol) were measured at the beginning of every timing regime and at the end of the study. Results: The analysed results did not showed any statistically significant differences in parameters of thyroid function (TSH, fT4, or fT3) or the lipid profile (triglycerides, HDL-, LDL-, and total cholesterol) when compared between three different timing regimens of LT4 administration. Considering stability of LT4 supplemental therapy, there was no difference among the calculated coefficients of variation of the thyroid function and lipid profile parameters nor the difference in percentage of patients whose values of the examined parameters were within the corresponding reference intervals after different timing regimes of LT4 administration. Conclusion: Since there was no difference in effectiveness in regulating patients’ thyroid function and lipid profile between different timings of LT4 administration, this study provides additional options regarding the personalization of pharmacotherapy and achievement of increased efficacy of the treatment, especially for the patients who did not reached therapeutic goals with standard way of administration

Scurvy

Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to perios-teal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socio-economic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Here-in, we present an illustrative case of scurvy in order to raise the awareness of this disorder

Ekspresija hormonskih receptora i aktivnost ribocikliba u karcinomomu dojke s pozitivnim hormonskim receptorima i negativnim receptorom za humani epidermalni faktor rasta 2

In the randomized, placebo-controlled, phase 3 MONALESSA-2 trial, in patients with hormone receptor positive (HR+) [the estrogen receptor (ER) and/or progesterone receptor (PR)] and human epidermal growth factor 2 receptor negative (HER2-) advanced breast cancer (BC), progression-free survival (PFS) was signifi cantly longer among those receiving ribociclib [cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor] plus letrozole compared to patients receiving placebo plus letrozole. Additionally, ER+/PR+ cohort demonstrated higher hazard ratio for PFS than ER+/PR- cohort (0.62 vs. 0.36). Evidence from cell-line models suggests that PR signaling is tightly linked to cell-cycle regulation in terms of inhibition of CDK 4/6 activity when exposed to progestin. A possible explanation of this fi nding may be that high PR expression could interfere with ribociclib activity on the cyclin-kinase level. Furthermore, it is questionable whether PR level determines the efficacy of ribociclib administration with higher levels of this receptor being predictive of ribociclib ineffi cacy. Considering the safety profile of ribociclib, it’s necessary to perform analysis of PFS among ER+/PR+ patients receiving ribociclib, to potentially assess the cut-off value of PR expression (or ER/PR ratio) as a predictive marker of CDK4/6 efficacy.MONALESSA-2 je placebo kontrolirana randomizirana klinička studija faze 3 koja je uključila bolesnike s uznapredovalim karcinomom dojke s pozitivnim hormonskim receptorima (HR+) [estrogenski receptori (ER) i/ili progesteronski receptori (PR)] te negativnim receptorom za humani epidermalni faktor rasta 2 (eng. HER2-). Studija je pokazala kako je preživljenje bez progresije bolesti (eng. PFS) bilo značajno dulje u onih bolesnika koji su primali ribociklib [inhibitor ciklinovisne kinaze 4 i 6 (CDK4/6)] uz letrozol u usporedbi s pacijentima koji su primali placebo i letrozol. Međutim, ER+/PR+ grupa imala je viši omjer rizika (eng. hazard ratio) za preživljenje bez progresije bolesti (PFS) od ER+/PR- grupe (0.62 vs. 0.36). Dokazi iz modela staničnih linija sugeriraju kako je signalni put PR usko vezan za regulaciju staničnog ciklusa kod inhibicije aktivnosti CDK 4/6 nakon izlaganja progestinu. Moguće objašnjenje ovih saznanja može biti povezano s visokom ekspresijom PR koja interferira s aktivnošću ribocikliba na razine ciklin-kinaze. Stoga, upitno je da li razina ekspresije PR receptora utječe na učinkovitost primjene ribocikliba, tj. da li njegova veća ekspresija može uzrokovati smanjenje učinkovitosti ribocikliba. S obzirom na sigurnosni profil ribocikliba, potrebno je izvršiti analize PFS vrijednosti bolesnika koji primaju ribociklib ovisno o razinama ekspresije hormonskih receptora kako bi se potencijalno odredile vrijednosti ekspresije PR (ili ER/PR omjera) kao markera učinkovitosti inhibitora CDK4/6

Scurvy

Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to perios-teal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socio-economic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Here-in, we present an illustrative case of scurvy in order to raise the awareness of this disorder

Dabigatran Use Associated with Hemopericardium and Hemothorax

Concurrent spontaneous hemopericardium and hemothorax due to anticoagulant use are extremely rare in clinical practice. Dabigatran is an oral direct thrombin inhibitor approved to prevent stroke or thromboembolic episodes in patients with nonvalvular atrial fibrillation. We report the case of a 73-year-old man who received dabigatran therapy (150 mg twice a day) for 3 months and developed massive spontaneous hemothorax and hemopericardium associated with fever. Emergency chest computed tomography scan established higher-density pericardial effusion (22HU) and left pleural effusion of heterogeneous density (5–15 HU) which could be hemorrhagic content while the heart ultrasound finding confirmed pericardial effusion 7–9 mm thick, without affecting hemodynamics. Almost 1100 mL of blood was drained by ultrasoundguided thoracentesis. After excluding other possible causes, diagnostic withdrawal was performed for dabigatran and no further pleural or pericardium effusion developed after dabigatran was discontinued. Therefore, practitioners could be aware of hemothorax as well as hemopericardium as a potential complication of dabigatran therapy

Assessing serum albumin concentration, lymphocyte count and prognostic nutritional index might improve prognostication in patients with myelofibrosis

BACKGROUND: Primary and secondary myelofibrosis (PMF and SMF) are malignant diseases of hematopoietic stem cell characterized by the neoplastic myeloproliferation and a strong inflammatory milieu. The prognostic nutritional index (PNI) integrates information on albumin and absolute lymphocyte count (ALC) and reflects the inflammatory, nutritional and immune status of a patient. The clinical and prognostic significance of albumin, ALC and PNI in patients with myelofibrosis has not been previously investigated. ----- METHODS: We retrospectively analyzed a cohort of 83 myelofibrosis patients treated in our institution from 2006 to 2017. Albumin, ALC and PNI were assessed in addition to other disease specific markers. ----- RESULTS: The PMF and SMF patients had significantly lower ALC and PNI but similar albumin compared to controls. Lower albumin was significantly associated with older age and parameters reflecting more aggressive disease biology (e.g. anemia, lower platelet levels, higher lactate dehydrogenase (LDH), circulatory blasts, transfusion dependency, blast phase disease), inflammation (higher C reactive protein (CRP), constitutional symptoms) and higher degree of bone marrow fibrosis. Lower ALC was significantly associated with lower white blood cells (WBC) and lower circulatory blasts. Low PNI was associated with lower albumin, lower ALC, anemia, lower WBCs, lower serum iron and lower transferrin saturation. There was no difference in albumin, ALC and PNI regarding the driver mutations. In multivariate analysis adjusted for age and gender, low albumin (hazard ratio [HR] = 4.61, P = 0.001), low ALC (HR = 3.54, P = 0.004) and Dynamic International Prognostic Scoring System (DIPSS) (HR = 2.45, P = 0.001) were able to predict inferior survival independently of each other. Accordingly, low PNI (HR = 4.32, P < 0.001) predicted poor survival independently of DIPSS (HR = 3.31, P < 0.001). ----- CONCLUSION: Assessing albumin, ALC and PNI might improve prognostication in patients with myelofibrosis and could assist in recognition of patients under increased risk of death

Myelodysplastic syndromes – new discoveries and an “old” morphology

Mijelodisplastični sindrom heterogena je grupa bolesti koje dijele neka klinička i morfološka obilježja. Uzrok im je nepoznat. Budući da brz razvoj molekularne genetike omogućuje uvid u uzročne genske aberacije, danas se mogu odrediti neki patogenetski mehanizmi u nastanku mijelodisplastičnog sindroma. U ovom radu pokušat ćemo objasniti neka otkrića u tom području i njihovu vezu s citomorfološkim obilježjima, fenotipom mijelodisplastičnog sindroma.Myelodysplastic syndromes (MDS) are a heterogenous group of diseases sharing some clinical and morphological features. Their cause is unknown. Since the rapid development of molecular genetics allows an insight into underlying genetic aberrations, today it is possible to determine some pathogenetic mechanisms in MDS. In this presentation we would like to explain some of the discoveries in this area and their connection to the myelodysplastic phenotype as seen in everyday cytomorphology work

CLINICAL GUIDELINES FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH NON-INVASIVE BREAST CANCER

Rak dojke najčešća je maligna bolest u žena. Ranom dijagnostikom i sve uspješnijim liječenjem invazivnog raka dojke postignut je značajan pad mortaliteta, produljenje preživljenja i poboljšanje kvalitete života bolesnica. Postupak s neinvazivnim rakom dojke međutim povezan je s nekim dvojbama i sviješću o problemu predijagnosticiranja i pretjeranog liječenja nekih bolesnica. U tekstu koji slijedi multidisciplinarni tim stručnjaka donosi prve hrvatske smjernice čija je svrha standardizacija i optimalizacija kriterija i postupaka dijagnostike, liječenja i praćenja bolesnica s neinvazivnim rakom dojke u Republici Hrvatskoj.Breast cancer is the most common malignancy in women. Early diagnosis and more effective treatment of invasive breast cancer resulted in significant mortality reduction, improvement of survival and the quality of life of the patients. The management od non-invasive breast cancer, on the contrary, is still controversial and the problem of overdiagnosis and overtreatment of patients come to evidence. In the following text a multidisciplinary team of experts brings the first consensus guidelines aimed to standardize and optimize the criteria and management in diagnosis, treatment and monitoring of non-invasive breast cancer patients in the Republic of Croatia