Lidija Beketic-Oreskovic - Academia.edu (original) (raw)

Papers by Lidija Beketic-Oreskovic

Libri oncologici, Jan 29, 2019

Pregnancy-associated breast cancer is a diffi cult psychosocial and health problem for the patien... more Pregnancy-associated breast cancer is a diffi cult psychosocial and health problem for the patient, demanding an individual multidisciplinary treatment approach. Due to the need for aggressive oncological treatment with minimal adverse eff ects on the growing fetus, numerous studies are carried out to fi nd an optimal protocol, concerning the interest of both the mother and the child. Due to the physiological changes in the breasts in pregnancy, the diagnosis of breast cancer can be delayed and therefore patients have often higher clinical stage of the disease at initial presentation comparing to non-pregnant patients. Pregnancy termination due to breast cancer diagnosis had no eff ect on the prognosis of the patient, and longterm studies did not fi nd a higher incidence of malignant disease in children who were exposed to chemotherapy in utero compared to the general population. Although prognosis data of those patients is controversial, recent studies have not found a worse outcome compared to breast cancer unrelated to pregnancy.

Libri oncologici, Jan 29, 2019

Uveal melanoma represents 5% of all melanomas and the eye is the second most common site for prim... more Uveal melanoma represents 5% of all melanomas and the eye is the second most common site for primary melanoma after the skin. Delays or failure to make an accurate and early diagnosis may have fatal consequences. Advances in the diagnosis and local and systemic treatment of uveal melanoma in recent times have caused a shift from enucleation to eye-conserving treatment modalities. Currently, radiotherapy is the most commonly used therapeutic option, which can include: brachytherapy-radioactive plaque, as the most frequently used form, than stereotactic external beam radiotherapyradiosurgery as well as proton therapy, as a form of charged-particle radiotherapy. However, surgery as an inevitable therapeutic option has to be performed in some cases. In the treatment of primary tumor, local treatment methods are eff ective in preventing local recurrence in over 95% of cases. However, metastatic disease develops in up to 50% of patients, with liver metastases, as the most common. At this stage of the disease there is a poor survival rate of the patients (4-15 months) and this has remained relatively unchanged over the past decades. Although potential therapeutic targets have been identifi ed, there is no currently eff ective treatment of metastatic disease. Pending clinical trials involving chemotherapeutic, immunotherapeutic and molecularly targeted agents off er hope for successful tumor control and vision preservation as well as metastases prevention and improvement of overall patient survival.

Libri oncologici, Jan 29, 2019

Management of young women with breast cancer is complex and has several particularities, one of w... more Management of young women with breast cancer is complex and has several particularities, one of which is fertility preservation, a very important quality of life issue for young breast cancer survivors. Chemotherapy can be gonadotoxic and signifi cantly reduce woman`s reproductive potential and cause premature ovarian insuffi ciency while endocrine therapy requires a delay of pregnancy and indirectly aff ects fertility. Therefore every woman of reproductive age diagnosed with breast cancer should be informed about potential gonadotoxic eff ect of cancer treatment, the risk of premature ovarian insuffi ciency and associated symptoms, available fertility preservation methods, delay of cancer treatment and chances of subsequent pregnancy. If interested in fertility preservation breast cancer patients should be referred as early as possible to a reproductive specialist to further discuss the risk of infertility and available fertility preservation options. Currently established methods for fertility preservation are embryo and oocyte cryopreservation, while ovarian tissue cryopreservation, cryopreservation of immature oocytes and ovarian suppression with gonadotropin-releasing hormone agonists are still considered experimental. The aim of this review is to highlight the importance of fertility preservation as an important quality of life issue for young breast cancer survivors.

PubMed, 1993

Our previous report revealed the production of monoclonal antibody (MoAb) CDI 315B by immunizatio... more Our previous report revealed the production of monoclonal antibody (MoAb) CDI 315B by immunization of mice with tumor extract proteins of human invasive ductal breast carcinoma. In the present study we report on the immunocytochemical reactivity of this MoAb with formalin or methacarn fixed, paraffin embedded tissue sections and also with cell cultures. Among breast tissues, positive staining was detected in 88% (64 of 73) of primary breast carcinomas, 77% (7 of 9) of metastatic lymph nodes, 24% (8 of 33) of benign breast disease and 15% (2 of 13) of normal breast tissue. No immunostaining was detected with several other tumors, with the exception of melanoma, where 63% (5 of 8) of positive staining was found. On in vitro cell lines, positive reaction was detected only with breast carcinoma and melanoma cells, but not with other examined cell lines. On benign breast disease tissue sections, positive reaction was detected in areas with cell hyperplasia. On normal breast tissue sections MoAb 315B stained the epithelial cells of terminal ductuli. Since the MoAb 315B recognized some antigen present in the cytoplasm of most breast carcinoma cells, this MoAb may have potential application in diagnosis and management of breast cancer.

PubMed, Sep 1, 2014

An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pron... more An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. Because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. In the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. Ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required.

PubMed, 1994

In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to ci... more In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to cis-diamminedichloroplatinum(II) (CDDP) due to acute (CA3 cells), or continuous (CK2 cells) treatments with increased CDDP concentrations. CA3 line was 2.3-fold resistant, and CK2 line 3.7-fold resistant to CDDP as compared to the parental cells. In this study the sensitivity of CDDP resistant and parental cells to several antitumor drugs was examined using clonogenic survival assay. CK2 cells were 1.7-fold more resistant to vincristine than parental cells, while CA3 cells exhibited resistance to vincristine only at higher concentrations of this drug. Verapamil, an inhibitor of P-glycoprotein, was not able to reverse the resistance of CK2 cells to vincristine, indicating that this cross-resistance did not involve P-glycoprotein. As compared to the parental cells, CK2 cells were 2.1-fold resistant, and CA3 cells 1.7-fold resistant to mitomycin C. CK2 cells were 2-fold more resistant to 5-fluorouracil than the parental cells, while CA3 cells did not exhibit any change in the sensitivity to this drug. CA3 cells were 0.4-fold sensitive to epoxide and 0.53-fold sensitive to doxorubicin, while CK2 cells had the same sensitivity to these drugs as the parental cells. Our results showed that treatment schedule determines the response of CDDP resistant human larynx carcinoma cells to additional drugs, suggesting the complexity of the judicious choice of the drugs in the combined modality treatments of cancer.

PubMed, 1994

The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant c... more The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant cell lines established from human larynx carcinoma HEp2 cells through repeated treatments with increased CDDP concentrations. CK2 cells obtained by continuous treatments were more resistant to CDDP than CA3 cells obtained by acute treatments. The examination of growth characteristics showed that both CDDP resistant cells had doubling times identical to that of the parental cells, but had lower plating efficiency. The possible involvement of glutathione (GSH), glutathione transferases (GST), metallothioneins, P-glycoprotein and drug accumulation in CDDP resistance was examined. Glutathione contents were elevated in both CDDP resistant lines. However, neither GSH nor GST were involved in CDDP resistance. This was demonstrated by simultaneous incubation of parental and CDDP resistant cells with CDDP and specific inhibitors of GSH and GST alpha and pi (buthionine sulfoximine and ethacrinic acid). Similarly, verapamil, an inhibitor of P-glycoprotein, did not influence the sensitivity of parental and resistant cells to CDDP. As compared to the parental cells, CK2 cells became resistant and CA3 cells became sensitive to cadmium, indicating increased level of metallothioneins in CK2 cells, and reduced level in CA3 cells. Measurements of platinum contents in parental and CDDP resistant cells after 1, 3 and 6 hours exposure to 70 mumol CDDP showed reduction in platinum accumulation after each exposure time in CK2 cells, and after 6 hours exposure in CA3 cells. This study identified decreased platinum accumulation as an important mechanism of CDDP resistance in human larynx carcinoma cells.

Critical Reviews in Oncology Hematology, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Gynecological Endocrinology, Jul 11, 2014

The aim of this review is to analyse the pathophysiology and complications of thrombosis in conju... more The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67-75%) involving upper limbs and neck, then arterial (25-33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation.

PubMed, Mar 1, 1996

A fluctuation analysis experiment was performed by exposing 15 expanded populations of MES-SA sar... more A fluctuation analysis experiment was performed by exposing 15 expanded populations of MES-SA sarcoma cells to paclitaxel (Taxol) at a concentration of 10 nM for 7 days. The mutation rate was approximately 8 multiplied by 10(-7)/cell generation. ANOVA supports a stochastic cell survival mechanism of spontaneous mutation rather than induction of an adaptive response under these selection conditions. Surviving colonies were found in 12 populations, 9 of which had clones that remained resistant to paclitaxel after a 2-month period of propagation. Analysis of mdr1 gene expression by reverse transcription PCR demonstrated positive clones in 4 of the 9 populations with stable resistance. Accumulation of [(3)H]paclitaxel was decreased in these clones but not in the mdr1-negative clones compared with parental cells. A high degree of resistance to paclitaxel (36- to 93-fold) was selected by this single drug exposure in all 9 stably resistant mutants. Those with mdr1 activation demonstrated a broad cross-resistance to vinblastine, doxorubicin, and etoposide, whereas the other 6 mutants were cross-resistant only to the Vinca alkaloids. Because tubulins are the target molecules for paclitaxel cytotoxicity, we evaluated total tubulin content by immunoblotting and performed semiquantitative reverse transcription PCR analysis for expression of the alpha-tubulin isotypes B alpha 1, K alpha 1 and H alpha 44, the beta-tubulin isotypes M40, beta9, 5beta, beta2 and beta4, and gamma-tubulin. Total tubulin content was decreased significantly in one of the single-step mutants. All surviving clones, both resistant and sensitive to paclitaxel, displayed reduced expression of the 5beta and beta 4 beta-tubulin isotype transcripts in comparison with the parental cell line. These data suggest that stringent exposure to paclitaxel selected clones with reduced transcript levels of 5beta and beta4 beta-tubulin isotypes, but that these reduced levels were not directly involved in the resistance of the clones to paclitaxel. The results suggest an important role for non-multidrug-resistant mechanisms of resistance to paclitaxel. These mechanisms do not involve reduced drug accumulation and provide cross-resistance among both paclitaxel and tubulin depolymerizing agents.

International Journal of Hyperthermia, 1997

The aim of the present study was to examine the effect of hyperthermia on cisplatin resistance in... more The aim of the present study was to examine the effect of hyperthermia on cisplatin resistance in two sublines of human larynx carcinoma HEp2 cells. Hyperthermia was tumouricidal for both parental and cisplatin resistant cells, but cisplatin resistant cells were more sensitive to the heat at 43 and 44 degrees C. In combined cisplatin-hyperthermia treatment, heat chemosensitization was observed for parental, as well as for cisplatin resistant cells. At 42 degrees C, and at 43 degrees C, the thermal enhancement ratio (TER) for cisplatin toxicity was higher in resistant than in parental cells. The heating at 42 degrees C decreased the resistance factors in CA3 and CK2 cells from 2.2 and 3.5 to 1.8 and 2.2 respectively. At 43 degrees C, the resistance factors were decreased to 1.7 for CA3 cells and 2.0 for CK2 cells. The heating at 43 degrees C increased intracellular platinum accumulation in all cell lines examined. This effect was more pronounced in resistant, than in parental cells, causing complete reversal of the reduced platinum accumulation found at 37 degrees C in resistant cells. In conclusion, the resistance to cisplatin was partially reversed by hyperthermia in CA3 and CK2 cells. Increased drug accumulation was one of the mechanisms involved in hyperthermic potentiation of cisplatin toxicity and partial reversal of cisplatin resistance in human larynx carcinoma HEp2 cells.

Acta Clinica Croatica, Nov 3, 2014

An increase in the incidence of breast cancer in women aged <40 years in conjunction with a prono... more An increase in the incidence of breast cancer in women aged <40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. in the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required.

Rad Hrvatske akademije znanosti i umjetnosti. Medicinske znanosti, 2017

Colorectal cancer (CRC) is one of the most frequent type of cancers, and also one of the most fre... more Colorectal cancer (CRC) is one of the most frequent type of cancers, and also one of the most frequent causes of death among cancer patients worldwide. Approximately 25% of newly diagnosed patients with CRC have already developed metastases, and 50% of all CRC patients will develop metastases over time as the disease progresses. Active oncological treatment of patients having metastatic CRC nowadays includes fluoropyrimidines in combination with irinotecan and/or oxaliplatin ± monoclonal antibodies (mAbs). Development and introduction of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (EGFR; cetuximab, panitumumab) in treatment algorithms for patients with wild-type K/N-RAS have significantly improved median overall survival (OS) of patients with metastatic colorectal cancer. Clinical experience supported by various patohistological and molecular biology data indicates that CRC is a heterogeneous disease. The novel approach to treatment decisions should be patient personalized, i.e. such decisions should be tailored according to patient clinical (age, performance status, comorbidities) and molecular (pharmacogenetic) characteristics, tumor disease stage, tumor location and tumor molecular characteristics and patient preferences. Treatment decision for patients with metastatic CRC must be evidence based. The role of the multidisciplinary team in recommendation preparation is unavoidable.

Libri oncologici, Dec 22, 2022

The aim of this review article is to present current options for fertility preservation in young ... more The aim of this review article is to present current options for fertility preservation in young women with gynecological tumors (ovarian, endometrial or cervical cancer). An early pretreatment referral to multidisciplinary team which consists of general gynecologists, gynecologic oncologists, embryologists, radiologists, pathologists, and reproductive endocrinologists should be suggested to young women with gynecologic cancer, concerning the risks and benefits of fertility preservation options. Only a small percentage of patients with ovarian cancer and borderline ovarian tumors, are appropriate candidates for fertility preservation (FIGO stage IA and IC epithelial ovarian cancer). Following oophorectomy, ovarian tissue or oocytes are removed from the ovary for the use of cryopreservation; after completion of oncological treatment patient undergoes orthotopic retransplantation of ovarian tissue whereas oocytes may be used for in vitro fertilization. Live birth rates up to 53.8% have been reported after fertility preservation treatment in selected patients. In patients with endometrial cancer fertility preservation treatment means conserving of the uterus. Appropriate candidates for fertility preservation are younger women with well differentiated endometrial cancer, which does not invade the myometrium. Fertility preservation treatment in endometrial cancer is hormonal, based on progestins. After completion of fertility preservation treatment, frequent follow-ups are necessary, with tissue sampling (via curettage or endometrial biopsy) remaining standard approach in follow-up. Live birth rates after progestin therapy are around 60%, or even higher with the help of assisted reproductive procedures. In cervical cancer, fertility preservation treatment can be considered in women with early-stage disease (FIGO IA1, IA2, or IB1). Cone biopsy or conization followed by laparoscopic lymphadenectomy has been described as an appropriate procedure, with conception rates up to 47%.

Pharmaceuticals

After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/... more After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/kg, 0.1 mL into rat inferior caval vein, assessment at 15, 30, 60 min, prime lung lesions, thromboemboli occluding lung vessels), as a severe occlusion/occlusion-like syndrome, might be resolved as a whole by stable gastric pentadecapeptide BPC 157 therapy. At 5 min after laurate injection, stable gastric pentadecapeptide BPC 157 was implemented as therapy (10 µg/kg, 10 ng/kg intraperitoneally or intragastrically). As before, confronted with the occlusion of major vessel(s) or similar noxious procedures, such as rapidly acting Virchow triad circumstances, the particular effect of the therapy (i.e., collateral pathways activation, “bypassing vascular key”, i.e., direct blood flow delivery via activation of azygos vein) assisted in the recovery of the vessel/s and counteracted multiorgan failure due to occlusion/occlusion-like syndrome as a whole in the laurate-injected rats. Along with pr...

Libri oncologici, Jan 29, 2019

Pregnancy-associated breast cancer is a diffi cult psychosocial and health problem for the patien... more Pregnancy-associated breast cancer is a diffi cult psychosocial and health problem for the patient, demanding an individual multidisciplinary treatment approach. Due to the need for aggressive oncological treatment with minimal adverse eff ects on the growing fetus, numerous studies are carried out to fi nd an optimal protocol, concerning the interest of both the mother and the child. Due to the physiological changes in the breasts in pregnancy, the diagnosis of breast cancer can be delayed and therefore patients have often higher clinical stage of the disease at initial presentation comparing to non-pregnant patients. Pregnancy termination due to breast cancer diagnosis had no eff ect on the prognosis of the patient, and longterm studies did not fi nd a higher incidence of malignant disease in children who were exposed to chemotherapy in utero compared to the general population. Although prognosis data of those patients is controversial, recent studies have not found a worse outcome compared to breast cancer unrelated to pregnancy.

Libri oncologici, Jan 29, 2019

Uveal melanoma represents 5% of all melanomas and the eye is the second most common site for prim... more Uveal melanoma represents 5% of all melanomas and the eye is the second most common site for primary melanoma after the skin. Delays or failure to make an accurate and early diagnosis may have fatal consequences. Advances in the diagnosis and local and systemic treatment of uveal melanoma in recent times have caused a shift from enucleation to eye-conserving treatment modalities. Currently, radiotherapy is the most commonly used therapeutic option, which can include: brachytherapy-radioactive plaque, as the most frequently used form, than stereotactic external beam radiotherapyradiosurgery as well as proton therapy, as a form of charged-particle radiotherapy. However, surgery as an inevitable therapeutic option has to be performed in some cases. In the treatment of primary tumor, local treatment methods are eff ective in preventing local recurrence in over 95% of cases. However, metastatic disease develops in up to 50% of patients, with liver metastases, as the most common. At this stage of the disease there is a poor survival rate of the patients (4-15 months) and this has remained relatively unchanged over the past decades. Although potential therapeutic targets have been identifi ed, there is no currently eff ective treatment of metastatic disease. Pending clinical trials involving chemotherapeutic, immunotherapeutic and molecularly targeted agents off er hope for successful tumor control and vision preservation as well as metastases prevention and improvement of overall patient survival.

Libri oncologici, Jan 29, 2019

Management of young women with breast cancer is complex and has several particularities, one of w... more Management of young women with breast cancer is complex and has several particularities, one of which is fertility preservation, a very important quality of life issue for young breast cancer survivors. Chemotherapy can be gonadotoxic and signifi cantly reduce woman`s reproductive potential and cause premature ovarian insuffi ciency while endocrine therapy requires a delay of pregnancy and indirectly aff ects fertility. Therefore every woman of reproductive age diagnosed with breast cancer should be informed about potential gonadotoxic eff ect of cancer treatment, the risk of premature ovarian insuffi ciency and associated symptoms, available fertility preservation methods, delay of cancer treatment and chances of subsequent pregnancy. If interested in fertility preservation breast cancer patients should be referred as early as possible to a reproductive specialist to further discuss the risk of infertility and available fertility preservation options. Currently established methods for fertility preservation are embryo and oocyte cryopreservation, while ovarian tissue cryopreservation, cryopreservation of immature oocytes and ovarian suppression with gonadotropin-releasing hormone agonists are still considered experimental. The aim of this review is to highlight the importance of fertility preservation as an important quality of life issue for young breast cancer survivors.

PubMed, 1993

Our previous report revealed the production of monoclonal antibody (MoAb) CDI 315B by immunizatio... more Our previous report revealed the production of monoclonal antibody (MoAb) CDI 315B by immunization of mice with tumor extract proteins of human invasive ductal breast carcinoma. In the present study we report on the immunocytochemical reactivity of this MoAb with formalin or methacarn fixed, paraffin embedded tissue sections and also with cell cultures. Among breast tissues, positive staining was detected in 88% (64 of 73) of primary breast carcinomas, 77% (7 of 9) of metastatic lymph nodes, 24% (8 of 33) of benign breast disease and 15% (2 of 13) of normal breast tissue. No immunostaining was detected with several other tumors, with the exception of melanoma, where 63% (5 of 8) of positive staining was found. On in vitro cell lines, positive reaction was detected only with breast carcinoma and melanoma cells, but not with other examined cell lines. On benign breast disease tissue sections, positive reaction was detected in areas with cell hyperplasia. On normal breast tissue sections MoAb 315B stained the epithelial cells of terminal ductuli. Since the MoAb 315B recognized some antigen present in the cytoplasm of most breast carcinoma cells, this MoAb may have potential application in diagnosis and management of breast cancer.

PubMed, Sep 1, 2014

An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pron... more An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. Because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. In the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. Ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required.

PubMed, 1994

In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to ci... more In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to cis-diamminedichloroplatinum(II) (CDDP) due to acute (CA3 cells), or continuous (CK2 cells) treatments with increased CDDP concentrations. CA3 line was 2.3-fold resistant, and CK2 line 3.7-fold resistant to CDDP as compared to the parental cells. In this study the sensitivity of CDDP resistant and parental cells to several antitumor drugs was examined using clonogenic survival assay. CK2 cells were 1.7-fold more resistant to vincristine than parental cells, while CA3 cells exhibited resistance to vincristine only at higher concentrations of this drug. Verapamil, an inhibitor of P-glycoprotein, was not able to reverse the resistance of CK2 cells to vincristine, indicating that this cross-resistance did not involve P-glycoprotein. As compared to the parental cells, CK2 cells were 2.1-fold resistant, and CA3 cells 1.7-fold resistant to mitomycin C. CK2 cells were 2-fold more resistant to 5-fluorouracil than the parental cells, while CA3 cells did not exhibit any change in the sensitivity to this drug. CA3 cells were 0.4-fold sensitive to epoxide and 0.53-fold sensitive to doxorubicin, while CK2 cells had the same sensitivity to these drugs as the parental cells. Our results showed that treatment schedule determines the response of CDDP resistant human larynx carcinoma cells to additional drugs, suggesting the complexity of the judicious choice of the drugs in the combined modality treatments of cancer.

PubMed, 1994

The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant c... more The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant cell lines established from human larynx carcinoma HEp2 cells through repeated treatments with increased CDDP concentrations. CK2 cells obtained by continuous treatments were more resistant to CDDP than CA3 cells obtained by acute treatments. The examination of growth characteristics showed that both CDDP resistant cells had doubling times identical to that of the parental cells, but had lower plating efficiency. The possible involvement of glutathione (GSH), glutathione transferases (GST), metallothioneins, P-glycoprotein and drug accumulation in CDDP resistance was examined. Glutathione contents were elevated in both CDDP resistant lines. However, neither GSH nor GST were involved in CDDP resistance. This was demonstrated by simultaneous incubation of parental and CDDP resistant cells with CDDP and specific inhibitors of GSH and GST alpha and pi (buthionine sulfoximine and ethacrinic acid). Similarly, verapamil, an inhibitor of P-glycoprotein, did not influence the sensitivity of parental and resistant cells to CDDP. As compared to the parental cells, CK2 cells became resistant and CA3 cells became sensitive to cadmium, indicating increased level of metallothioneins in CK2 cells, and reduced level in CA3 cells. Measurements of platinum contents in parental and CDDP resistant cells after 1, 3 and 6 hours exposure to 70 mumol CDDP showed reduction in platinum accumulation after each exposure time in CK2 cells, and after 6 hours exposure in CA3 cells. This study identified decreased platinum accumulation as an important mechanism of CDDP resistance in human larynx carcinoma cells.

Critical Reviews in Oncology Hematology, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Gynecological Endocrinology, Jul 11, 2014

The aim of this review is to analyse the pathophysiology and complications of thrombosis in conju... more The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67-75%) involving upper limbs and neck, then arterial (25-33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation.

PubMed, Mar 1, 1996

A fluctuation analysis experiment was performed by exposing 15 expanded populations of MES-SA sar... more A fluctuation analysis experiment was performed by exposing 15 expanded populations of MES-SA sarcoma cells to paclitaxel (Taxol) at a concentration of 10 nM for 7 days. The mutation rate was approximately 8 multiplied by 10(-7)/cell generation. ANOVA supports a stochastic cell survival mechanism of spontaneous mutation rather than induction of an adaptive response under these selection conditions. Surviving colonies were found in 12 populations, 9 of which had clones that remained resistant to paclitaxel after a 2-month period of propagation. Analysis of mdr1 gene expression by reverse transcription PCR demonstrated positive clones in 4 of the 9 populations with stable resistance. Accumulation of [(3)H]paclitaxel was decreased in these clones but not in the mdr1-negative clones compared with parental cells. A high degree of resistance to paclitaxel (36- to 93-fold) was selected by this single drug exposure in all 9 stably resistant mutants. Those with mdr1 activation demonstrated a broad cross-resistance to vinblastine, doxorubicin, and etoposide, whereas the other 6 mutants were cross-resistant only to the Vinca alkaloids. Because tubulins are the target molecules for paclitaxel cytotoxicity, we evaluated total tubulin content by immunoblotting and performed semiquantitative reverse transcription PCR analysis for expression of the alpha-tubulin isotypes B alpha 1, K alpha 1 and H alpha 44, the beta-tubulin isotypes M40, beta9, 5beta, beta2 and beta4, and gamma-tubulin. Total tubulin content was decreased significantly in one of the single-step mutants. All surviving clones, both resistant and sensitive to paclitaxel, displayed reduced expression of the 5beta and beta 4 beta-tubulin isotype transcripts in comparison with the parental cell line. These data suggest that stringent exposure to paclitaxel selected clones with reduced transcript levels of 5beta and beta4 beta-tubulin isotypes, but that these reduced levels were not directly involved in the resistance of the clones to paclitaxel. The results suggest an important role for non-multidrug-resistant mechanisms of resistance to paclitaxel. These mechanisms do not involve reduced drug accumulation and provide cross-resistance among both paclitaxel and tubulin depolymerizing agents.

International Journal of Hyperthermia, 1997

The aim of the present study was to examine the effect of hyperthermia on cisplatin resistance in... more The aim of the present study was to examine the effect of hyperthermia on cisplatin resistance in two sublines of human larynx carcinoma HEp2 cells. Hyperthermia was tumouricidal for both parental and cisplatin resistant cells, but cisplatin resistant cells were more sensitive to the heat at 43 and 44 degrees C. In combined cisplatin-hyperthermia treatment, heat chemosensitization was observed for parental, as well as for cisplatin resistant cells. At 42 degrees C, and at 43 degrees C, the thermal enhancement ratio (TER) for cisplatin toxicity was higher in resistant than in parental cells. The heating at 42 degrees C decreased the resistance factors in CA3 and CK2 cells from 2.2 and 3.5 to 1.8 and 2.2 respectively. At 43 degrees C, the resistance factors were decreased to 1.7 for CA3 cells and 2.0 for CK2 cells. The heating at 43 degrees C increased intracellular platinum accumulation in all cell lines examined. This effect was more pronounced in resistant, than in parental cells, causing complete reversal of the reduced platinum accumulation found at 37 degrees C in resistant cells. In conclusion, the resistance to cisplatin was partially reversed by hyperthermia in CA3 and CK2 cells. Increased drug accumulation was one of the mechanisms involved in hyperthermic potentiation of cisplatin toxicity and partial reversal of cisplatin resistance in human larynx carcinoma HEp2 cells.

Acta Clinica Croatica, Nov 3, 2014

An increase in the incidence of breast cancer in women aged <40 years in conjunction with a prono... more An increase in the incidence of breast cancer in women aged <40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. in the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required.

Rad Hrvatske akademije znanosti i umjetnosti. Medicinske znanosti, 2017

Colorectal cancer (CRC) is one of the most frequent type of cancers, and also one of the most fre... more Colorectal cancer (CRC) is one of the most frequent type of cancers, and also one of the most frequent causes of death among cancer patients worldwide. Approximately 25% of newly diagnosed patients with CRC have already developed metastases, and 50% of all CRC patients will develop metastases over time as the disease progresses. Active oncological treatment of patients having metastatic CRC nowadays includes fluoropyrimidines in combination with irinotecan and/or oxaliplatin ± monoclonal antibodies (mAbs). Development and introduction of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (EGFR; cetuximab, panitumumab) in treatment algorithms for patients with wild-type K/N-RAS have significantly improved median overall survival (OS) of patients with metastatic colorectal cancer. Clinical experience supported by various patohistological and molecular biology data indicates that CRC is a heterogeneous disease. The novel approach to treatment decisions should be patient personalized, i.e. such decisions should be tailored according to patient clinical (age, performance status, comorbidities) and molecular (pharmacogenetic) characteristics, tumor disease stage, tumor location and tumor molecular characteristics and patient preferences. Treatment decision for patients with metastatic CRC must be evidence based. The role of the multidisciplinary team in recommendation preparation is unavoidable.

Libri oncologici, Dec 22, 2022

The aim of this review article is to present current options for fertility preservation in young ... more The aim of this review article is to present current options for fertility preservation in young women with gynecological tumors (ovarian, endometrial or cervical cancer). An early pretreatment referral to multidisciplinary team which consists of general gynecologists, gynecologic oncologists, embryologists, radiologists, pathologists, and reproductive endocrinologists should be suggested to young women with gynecologic cancer, concerning the risks and benefits of fertility preservation options. Only a small percentage of patients with ovarian cancer and borderline ovarian tumors, are appropriate candidates for fertility preservation (FIGO stage IA and IC epithelial ovarian cancer). Following oophorectomy, ovarian tissue or oocytes are removed from the ovary for the use of cryopreservation; after completion of oncological treatment patient undergoes orthotopic retransplantation of ovarian tissue whereas oocytes may be used for in vitro fertilization. Live birth rates up to 53.8% have been reported after fertility preservation treatment in selected patients. In patients with endometrial cancer fertility preservation treatment means conserving of the uterus. Appropriate candidates for fertility preservation are younger women with well differentiated endometrial cancer, which does not invade the myometrium. Fertility preservation treatment in endometrial cancer is hormonal, based on progestins. After completion of fertility preservation treatment, frequent follow-ups are necessary, with tissue sampling (via curettage or endometrial biopsy) remaining standard approach in follow-up. Live birth rates after progestin therapy are around 60%, or even higher with the help of assisted reproductive procedures. In cervical cancer, fertility preservation treatment can be considered in women with early-stage disease (FIGO IA1, IA2, or IB1). Cone biopsy or conization followed by laparoscopic lymphadenectomy has been described as an appropriate procedure, with conception rates up to 47%.

Pharmaceuticals

After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/... more After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/kg, 0.1 mL into rat inferior caval vein, assessment at 15, 30, 60 min, prime lung lesions, thromboemboli occluding lung vessels), as a severe occlusion/occlusion-like syndrome, might be resolved as a whole by stable gastric pentadecapeptide BPC 157 therapy. At 5 min after laurate injection, stable gastric pentadecapeptide BPC 157 was implemented as therapy (10 µg/kg, 10 ng/kg intraperitoneally or intragastrically). As before, confronted with the occlusion of major vessel(s) or similar noxious procedures, such as rapidly acting Virchow triad circumstances, the particular effect of the therapy (i.e., collateral pathways activation, “bypassing vascular key”, i.e., direct blood flow delivery via activation of azygos vein) assisted in the recovery of the vessel/s and counteracted multiorgan failure due to occlusion/occlusion-like syndrome as a whole in the laurate-injected rats. Along with pr...