Predicting Trifluridine/Tipiracil Treatment Outcomes in Refractory Metastatic Colorectal Cancer Patients: A Multicenter Exploratory Analysis.

INTRODUCTION: There are no recommended biomarkers to identify patients with refractory metastatic colorectal cancer (mCRC) who would benefit the most from trifluridine/tipiracil (TTP). The exploratory analysis of the RECOURSE trial revealed that patients with low tumor burden and indolent disease derive greater benefit in terms of both progression-free survival (PFS) and overall survival (OS). Nevertheless, the final answer on the TTP real impact on the well-being of patients with late-stage mCRC will come from real-world data. METHODS: The aim of this retrospective exploratory study was to investigate the effectiveness of TTP in mCRC with regard to the duration of standard treatment and other influencing variables. The study included 260 patients from the three largest Croatian oncology centers who began treatment with TTP in the third or fourth line between 2018 and 2020. RESULTS: The median OS and PFS for the entire cohort were 6.53 and 2.50 months, respectively. Patients with more aggressive disease, defined as those whose time to progression on the first two lines of standard therapy was less than 18 months, had significantly shorter PFS (2.40 vs. 2.57 months, hazard ratio [HR] 1.34, 95% confidence interval [CI]: 1.03-1.84). There was also a tendency toward shorter OS (6.10 vs. 6.30 months, HR 1.32, 95% CI: 0.99-1.78) but without statistical significance. Patients with ECOG PS 0, without liver metastases, and with RAS mutation had both longer OS and PFS. No influence was detected from other variables including age, sex, primary tumor location, and tumor burden. CONCLUSION: With regard to the results of the previously conducted trials, the study concludes that indolent disease, good general condition, and absence of liver metastases are positive predictive factors for TTP treatment.

Long-term follow-up of complete remission in a patient with advanced hepatocellular carcinoma treated with sorafenib: a case report.

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer and can be caused by well-known risk factors, including infection with hepatitis B and C viruses, alcohol intake, and metabolic syndrome. The overall prognosis remains poor with a median survival of 1 year for symptomatic advanced-stage cases treated with systemic therapies. Case description: In July 2020, a 73-year-old male patient presented at our institution with mild abdominal pain and an attack of intense cold. After a radiological workup, the diagnosis of HCC located in the caudate lobe was established. The patient underwent atypical caudate lobe resection, and pathology confirmed the diagnosis of grade 3 HCC. Postoperative MRI showed a new metastasis in the 6th liver segment 1.3 cm in diameter, and a PVT progression which now affected the whole right lobe. The patient was started on sorafenib and demonstrated a complete response which still lasts for more than two years. Conclusion: We present a rare case of a patient who demonstrated a complete response to sorafenib treatment in advanced HCC with unfavorable prognostic factors.

The effectiveness of nab-paclitaxel plus gemcitabine and gemcitabine monotherapy in first-line metastatic pancreatic cancer treatment: A real-world evidence.

Pancreatic cancer is one of the most lethal malignancies with a rise in mortality rates. FOLFIRINOX and nab-paclitaxel plus gemcitabine demonstrated a survival benefit compared to gemcitabine alone. Both protocols are now considered the standard of first-line treatment with no significant difference between them, primarily based on observational studies. Although new therapeutic options have emerged recently, the prognosis remains poor. We conducted a retrospective single-center study on 139 patients treated for metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine monotherapy (Gem) or nab-paclitaxel + gemcitabine (Nab-P/Gem) in the first line. The aim of our study was to evaluate the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) as well as the influence of patient and disease characteristics on outcomes. Nab-P/Gem resulted in OS of 13.87 months compared to 8.5 months in patients receiving Gem. The same trend was achieved in PFS, 5.37 versus 2.80 months, respectively, but without reaching statistical significance. Furthermore, the 6-month survival in the Nab-P/Gem group was also higher, 78.1% versus 47.8%. In terms of survival, the group of elderly patients, patients of poorer performance, with higher metastatic burden and liver involvement, benefited the most from combination therapy. In our analysis ECOG performance status (p.s.), previous primary tumor surgery, and liver involvement were found to be independent prognostic factors. The addition of nab-paclitaxel to gemcitabine resulted in a significant improvement in the OS of patients with mPDAC. Subgroup analysis demonstrated that patients with some unfavorable prognostic factors benefited the most.

Frequency of Body Weight Loss is an Independent Prognostic Factor of First-Line Treatment Outcomes in Metastatic Colorectal Cancer.

One of the main features of wasting in cancer is an involuntary weight loss which is most pronounced in gastrointestinal tract tumors and leads to worse clinical outcomes. The aim of this study is to analyze the frequency of body weight loss (FBWL) as an additional prognostic factor in the treatment of patients with metastatic colorectal cancer (mCRC).In this observational, single-center study, data were retrieved for 236 patients treated for mCRC. FBWL was defined as a percent of change in weight divided by weeks of therapy. Patients were stratified into two groups according to the median of FBWL which equaled to the loss of 0.05%/week. Patients who lost >0.05%/week (N = 116) had shorter progression-free survival (PFS) in the first-line treatment, then the ones who lost <0.05%/week (N = 120); 28.3 vs 46.3 weeks, respectively. Cox regression model showed that FBWL and sidedness were significant predictors of PFS, while age, sex and ECOG were not. Significantly more patients with stable weight were also eligible for second-line treatment. In conclusion, stabilization of body weight is important and independent predictor of longer PFS in first-line therapy of patients with mCRC.

A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor.

BACKGROUND: Li-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia. CASE REPORT: We present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity. CONCLUSIONS: The knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.

Leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma.

Small-vessel vasculitis is an uncommon diagnosis associated with many causes, including certain medication. Characteristic findings are immune complex deposition, vessel wall damage, and erythrocyte extravasation. We present a case of a 77-year-old man with advanced hepatocellular carcinoma who was treated with sorafenib. Twenty days post introduction to sorafenib, the patient experienced high fever and painful purpura on the lower limbs. The results of the skin biopsy confirmed the diagnosis. More extensive diagnostics was undertaken, which excluded other possible causes of vasculitis and infectious disease. Following a full recovery, after the steroid treatment was completed, sorafenib has been continued until the progression of the carcinoma. This is the second described case of hepatocellular carcinoma associated with sorafenib treatment and leukocytoclastic vasculitis. Sorafenib is a potential cause of vasculitis, and clinicians should bear in mind to differentiate it from hand-foot skin reaction, which is a common side effect of multikinase inhibitors. The result of our assessment is important considering that vasculitis requires more specific diagnostic procedures, treatment, and often drug discontinuation.

In search of decoding the syntax of the bioelements in human hair - A critical overview.

The principles and practice of assessing the human body nutritional status or its environmental exposure through hair bioelement analysis are presented; herein the term "bioelements" is used as a common denominator for the major elements, trace elements and ultra-trace elements that are found in the human body. The accumulation of bioelements in the hair followed the statistical Power Law and the resulting sigmoid curve can be zoned into five regions in the ascending order of abundance (Low, Marginal, Adequate, High, and Excessive). The Adequate linear region of the bioassay sigmoid curve may be further subdivided into Low adequate, Recommended, and Ample adequate sub regions in a 60:30:10 ratio. Phosphorus was the most invariant bioelement since its hair concentration varies minimally regardless of the geographical place of living, the twenty years' time interval between the analyses, sex, race and instrumentation, i.e., atomic absorption spectrometry (AAS) atomic emission spectrometry (AES), and inductively plasma mass spectrometry (ICP MS). The osteotrophic (bone seeking) bioelements: Ca, Mg, and Sr, were 2.5 times more abundant in the hair of women than men. Two principal electrolytes of the body (Na, K) of the multi-bioelement hair profile were markedly increased in the depressed subjects diagnosed according to the American Psychiatric Association MSD-IV classification criteria. This increase in the hair Na and K of the depressed subjects was also associated with the decrease of vasopressin in the peripheral blood. The factor analysis revealed strong association of depression with sex (women > men in a 2.5:1 ratio), and with the metals from the Nieboer-Richardson series which form strong covalent bonds with proteins. We propose that the biological roots of depression are related to the non-specific impairment of the intracellular osmotic balance and ionic gradient due to the Na+K+ATPase failure from whatever cause acting either separately or in combination. We also put forward the idea of how children's autism may be related to a disproportional growth rate of various organs and tissues if children are fed up to their maximal genetic growth capacity. Finally, we have suggested the hypothesis on how the syntax or integration of the internal metabolic wiring of the bioelements in the body may occur. We have suggested the hypothetical existence of two complex distinct five-bioelement "rotors", the P-rotor and the N-rotor, where the P-rotor integrates the mileau interior (Na, K) ions with the perception/excitability (Mg, Ca) ions. Thus, the complex five element interdependence is cross related to P which provides the energy from the phosphorus of the DNA nucleotide backbone. The hair multi-bioelement profile analysis allows us to envisage the more complex structural metabolic features that bioelements are playing in our bodies.

Assessing the boron nutritional status by analyzing its cummulative frequency distribution in the hair and whole blood.

Boron is a non-essential ubiquitous trace element in the human body. The aim of this study was to assess boron nutritional status by analyzing boron frequency distribution in the long-term biological indicator tissue of hair and the short-term biological indicator of whole blood. Hair samples were analyzed in 727 apparently healthy subjects (263 ♂ and 464 ♀) and the whole blood boron was analyzed in the random subsample of them (80 ♂ and 152 ♀). Samples were analyzed by the ICP-MS at the Center for Biotic Medicine, Moscow, Russia. The adequate reference range for hair boron concentration was (µg∙g-1) 0.771- 6.510 for men and distinctly lower 0.472-3.89 for women; there was no detectable difference in the whole blood boron for the adequate reference range between men (0.020-.078) and women (0019-0.062). Boron may play an essential role in the metabolism of the connective tissue of the biological bone matrix.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY OF MEDICAL ONCOLOGY CLINICAL GUIDELINES Part III: neuroendocrine neoplasms, hepatocellular carcinoma, pancreatic cancer, cancer of the bile ducts]. / PRACENJE ONKOLOSKIH BOLESNIKA ­ KLINICKE PREPORUKE HRVATSKOG DRUSTVA ZA INTERNISTICKU ONKOLOGIJU HLZ-a III. dio: neuroendokrine neoplazme, hepatocelularni karcinom, rak gusterace, rak zucnih vodova.

The treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not based on prospective studies, but on the experts opinion of individual oncological centers or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures algorithm in the follow-up of oncological patients after primary treatment, in patients with neuroendocrine neoplasms, hepatocellular carcinoma, pancreatic cancer and cancer of the bile ducts.

Fluorouracil, leucovorin and irinotecan combined with intra-arterial hepatic infusion of drug-eluting beads preloaded with irinotecan in unresectable colorectal liver metastases: side effects and results of a concomitant treatment schedule. Clinical investigation.

AIM: Safety evaluation of concomitant systemic chemotherapy and liver chemoembolization in patients with colorectal cancer. PATIENTS AND METHODS: Seven patients with metastases confined to the liver were included and stratified into two groups, depending of dosage of systemic chemotherapy. The first group received systemic chemotherapy (FOLFIRI) with 20% dose reduction, and the second group received the full dose of the same chemotherapy. In both groups, chemoembolization of liver metastases with drug-eluting bead irinotecan (DEBIRI) was performed following the application of systemic chemotherapy. The toxicity profiles of the two groups were compared. RESULTS: Of the 7 patients included, 4 received the reduced systemic chemotherapy dose and 3 received the full chemotherapy dose. DEBIRI was performed in all 7 patients. The main toxicities observed in the reduced chemotherapy dose group were leukopenia (25%), anorexia (75%), diarrhea (25%), vomiting (25%), right upper abdominal quadrant pain (100%) and elevated serum amylase level (25%). Main toxicities observed in the full chemotherapy dose group were anorexia (66.6%), vomiting (33.3%), right upper abdominal quadrant pain (100%), and elevated serum amylase level (66.6%). There were no significant differences between the two groups ( P = 0.78541). CONCLUSIONS: Patients with isolated liver metastases from a colorectal primary can safely be treated with DEBIRI chemoembolization and a full dose of systemic chemotherapy (FOLFIRI).

Hair iodine for human iodine status assessment.

BACKGROUND: Today, human iodine deficiency is, after iron, the most common nutritional deficiency in developed European and underdeveloped third world countries. A current biological indicator of iodine status is urinary iodine, which reflects very recent iodine exposure; a long-term indicator of iodine status remains to be identified. METHODS: We analyzed hair iodine in a prospective, observational, cross-sectional, and exploratory study involving 870 apparently healthy Croatians (270 men and 600 women). Hair iodine was analyzed with inductively coupled plasma mass spectrometry. RESULTS: The hair iodine median was 0.499 µg/g, and was 0.482 and 0.508 µg/g for men and women respectively, suggesting no sex-related difference. We studied hair iodine uptake by analyzing the logistic sigmoid saturation curve of the median derivatives to assess iodine deficiency, adequacy, and excess. We estimated overt iodine deficiency to occur when hair iodine concentration was below 0.1-0.15 µg/g. Then there was a saturation range interval of about 0.1-2.0 µg/g where the deposition of iodine in the hair was linearly increasing (R(2)=0.994). Eventually, the sigmoid curve became saturated at about 2.0 µg/g and upward, suggesting excessive iodine exposure. CONCLUSION: Hair appears to be a valuable and robust biological indicator tissue for assessing long-term iodine status. We propose that an adequate iodine status corresponds with hair iodine uptake saturation of 0.565-0.739 µg/g (55-65%).

Paraneoplastic stiff person syndrome associated with colon cancer misdiagnosed as idiopathic Parkinson's disease worsened after capecitabine therapy.

OBJECTIVES: To refresh clinical diagnostic dilemmas in patients presenting with symptoms resembling to those of parkinsonism, to report rare association of colon cancer and paraneoplastic stiff person syndrome (SPS), and to draw attention on the possible correlation of capecitabine therapy with worsening of paraneoplastic SPS. METHODS: Case report of the patient with paraneoplastic SPS due to colon cancer that was misdiagnosed as idiopathic Parkinson's disease (iPD), whose symptoms worsened after beginning adjuvant capecitabine chemotherapy. RESULTS: We describe a 55-year-old woman with subacute onset of symmetrical stiffness and rigidity of the truncal and proximal lower limb muscles that caused lower body bradykinesia, gait difficulties, and postural instability. Diagnose of iPD was made and levodopa treatment was initiated but failed to provide beneficial effect. Six months later, colon cancer was discovered and the patient underwent surgical procedure and chemotherapy with capecitabine thereafter. Aggravation of stiffness, rigidity, and low back pain was observed after the first chemotherapy cycle and capecitabine was discontinued. Furthermore, levodopa was slowly discontinued and low dose of diazepam was administered which resulted in partial resolution of the patient's symptoms. CONCLUSION: Paraneoplastic SPS is rare disorder with clinical features resembling those of parkinsonian syndrome and making the correct diagnosis remains a challenge. The diagnosis of parkinsonian syndrome should be re-examined if subsequent examinations discover an associated malignant process. Although it remains unclear whether the patients with history of SPS are at the greater risk for symptoms deterioration after administration of capecitabine, clinicians should be aware of capecitabine side effects because recognition and appropriate management can prevent serious adverse outcomes.

Successful resection of hepatocellular cancer not amenable to Milan criteria and durable complete remission induced by systemic polichemotherapy after development of metastases - should we think about revising the current treatment guidelines in selected patients?

OBJECTIVES: To refresh clinical diagnostic and therapeutic dilemmas in patients presenting with hepatocellular cancer (HCC) and to report a rare success of systemic polichemotherapy in metastatic HCC. METHODS: Case report of a patient with successfully resected HCC although initially deemed inoperable according to current guidelines, and who was successfully treated by systemic polichemotherapy after development of metastatic disease, resulting in a sustained complete remission. RESULTS: We describe a 71-year-old female with HCC initially treated by atypical liver resection, although not amenable to initial surgery according to current treatment guidelines, which resulted in 6 months disease-free interval. After development of pulmonary metastases, the patient was treated by systemic polichemotherapy, due to local unavailability of novel biologic agents. After 3 months of chemotherapy biochemical remission was confirmed, and after 10 months of active treatment complete radiological remission was verified according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, now exceeding 9 months in duration. CONCLUSION: There is an increasing body of evidence that criteria for surgical interventions in HCC should be revised and expanded, and our case is an example of such an approach. Although novel biologic therapies are not widely available in all regions of the world due to their cost, currently there are no hard recommendations for use of chemotherapy in such areas. Since this is a large problem in clinical practice, we conclude that chemotherapy should be offered to selected patients of good performance status if novel agents are unavailable.

Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors.

AIM: To investigate primarily the prognostic value of Ki-67, as well as other parameters, in gastrointestinal stromal tumors (GISTs). METHODS: Ki-67, c-KIT, platelet-derived growth factor receptor-alpha (PDGFRα), smooth muscle actin (SMA), CD34, S100 were stained for immunohistochemistry which was performed on formalin-fixed, paraffin-embeded sections on representative block from each case. Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells. Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively (weak, intermediate, strong) and for c-KIT type of reactivity was analyzed (cytoplasmic, membrane and "dot-like" staining). Immunoreactivity for SMA, CD34 and S100 were was evaluated as positive or negative antigen expression. Pathologic parameters investigated in this study included tumor size, cell type (pure spindle, pured epitheloid mixed spindle and epitheloid), mitotic count, hemorrhage, necrosis, mucosal ulceration. Clinical data included age, gender, primary tumor location and spread of disease. χ² test and Student's t-test were used for comparisons of baseline characteristics. The Cox's proportional hazard model was used for univariable and multivariable analyses. Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test. RESULTS: According to the stage of disease, there were 36 patients with localized disease, 29 patients with initially localized disease but with its recurrence in the period of follow up, and finally, 35 patients had metastatic disease from the very beginning of disease. Tumor originated most commonly in the stomach (41%), small intestine was the second most common location (36%). The mean size of primary tumors was 6.5 cm. The mean duration of follow-up was 60 mo. Multiple parameters were analyzed for their effect on overall survival, but no one reached statistical significance (P = 0.06). Analysis of time to progression/relapse in initially localized disease (univariate analysis), tumor size, mitotic count, Ki-67 and type of d-KIT distribution (cytoplasmic vs membrane/"dot-like") showed statistically significant correlation. In multivariate analysis in the group of patients with localized disease, there were only 2 parameters that have impact on relapse, Ki-67 and SMA (P < 0.0001 and P < 0.034, respectively). Furthermore, Ki-67 was analyzed in localized disease vs localized with recurrence and metastatic disease. It was shown that there is a strict difference between these 2 groups of patients (median value was 2.5 for localized disease vs 10.0 for recurrent/metastatic disease, P < 0.0001). It was also shown that the cut-off value which is still statistically significant in terms of relapse on the level of 6%. The curves for survival on that cut-off level are significantly different (P < 0.04, Cox F). CONCLUSION: Ki-67 presents a significant prognostic factor for GIST recurrence which could be of great importance in evaluating malignant potential of disease.

The sister chromatide exchange rate is inversely related to the Se, Sr, Mn, Cu, and Be trace element nutritional status.

We studied the relationship of the 39 whole blood trace elements and the peripheral lymphocyte sister chromatide exchange (SCE) by factor analysis. Se, Sr, Mn, Cu, and Be were inversely related to SCE, and hence protective against the free radicals.