Prognostic Importance of Axillary Lymph Node Response to Neoadjuvant Systemic Therapy on Axillary Surgery in Breast Cancer-A Single Center Experience.

Neoadjuvant systemic treatment (NST) is the standard treatment for HER2+, triple-negative (TN), and highly proliferative luminal HER2- early breast cancer. Pathologic complete response (pCR) after NST is associated with improved outcomes. We evaluated the predictive factors for axillary-pCR (AXpCR) and its impact on the extent of axillary node surgery. This retrospective study included 92 patients (median age of 50.4 years) with an initially node-positive disease. Patients were treated with molecular subtype-specific NST (4.3% were luminal A-like, 28.3% luminal HER2-, 26.1% luminal HER2+, 18.5% HER2+ non-luminal, and 22.8% TN). Axillary-, breast- and total-pCR were achieved in 52.2%, 48.9%, and 38% of patients, respectively. In a binary logistic regression model for the whole population, the only independent factor significantly associated with AXpCR was breast-pCR (OR 7.4; 95% CI 2.6-20.9; p < 0.001). In patients who achieved breast-pCR, aggressive subtypes (HER2+ and TN; OR 11.24) and clinical tumor stage (OR 0.10) had a significant impact on achieving AXpCR. Axillary lymph node dissection was avoided in 53.3% of patients. In conclusion, in node-positive patients with HER2+ and TN subtypes, who achieved breast-pCR after NST, de-escalation of axillary surgery could be considered in most cases.

Clinical and Analytical Validation of Two Methods for Ki-67 Scoring in Formalin Fixed and Paraffin Embedded Tissue Sections of Early Breast Cancer.

Proliferation determined by Ki-67 immunohistochemistry has been proposed as a useful prognostic and predictive marker in breast cancer. However, the clinical validity of Ki-67 is questionable. In this study, Ki-67 was retrospectively evaluated by three pathologists using two methods: a visual assessment of the entire slide and a quantitative assessment of the tumour margin in 411 early-stage breast cancer patients with a median follow-up of 26.8 years. We found excellent agreement between the three pathologists for both methods. The risk of recurrence for Ki-67 was time-dependent, as the high proliferation group (Ki-67 ≥ 30%) had a higher risk of recurrence initially, but after 4.5 years the risk was higher in the low proliferation group. In estrogen receptor (ER)-positive patients, the intermediate Ki-67 group initially followed the high Ki-67 group, but eventually followed the low Ki-67 group. ER-positive pN0-1 patients with intermediate Ki-67 treated with endocrine therapy alone had a similar outcome to patients treated with chemotherapy. A cut-off value of 20% appeared to be most appropriate for distinguishing between the high and low Ki-67 groups. To summarize, a simple visual whole slide Ki-67 assessment turned out to be a reliable method for clinical decision-making in early breast cancer patients. We confirmed Ki-67 as an important prognostic and predictive biomarker.

Emerging Prognostic and Predictive Significance of Stress Keratin 17 in HPV-Associated and Non HPV-Associated Human Cancers: A Scoping Review.

A growing body of literature suggests that the expression of cytokeratin 17 (K17) correlates with inferior clinical outcomes across various cancer types. In this scoping review, we aimed to review and map the available clinical evidence of the prognostic and predictive value of K17 in human cancers. PubMed, Web of Science, Embase (via Scopus), Cochrane Central Register of Controlled Trials, and Google Scholar were searched for studies of K17 expression in human cancers. Eligible studies were peer-reviewed, published in English, presented original data, and directly evaluated the association between K17 and clinical outcomes in human cancers. Of the 1705 studies identified in our search, 58 studies met criteria for inclusion. Studies assessed the prognostic significance (n = 54), predictive significance (n = 2), or both the prognostic and predictive significance (n = 2). Altogether, 11 studies (19.0%) investigated the clinical relevance of K17 in cancers with a known etiologic association to HPV; of those, 8 (13.8%) were focused on head and neck squamous cell carcinoma (HNSCC), and 3 (5.1%) were focused on cervical squamous cell carcinoma (SCC). To date, HNSCC, as well as triple-negative breast cancer (TNBC) and pancreatic cancer, were the most frequently studied cancer types. K17 had prognostic significance in 16/17 investigated cancer types and 43/56 studies. Our analysis suggests that K17 is a negative prognostic factor in the majority of studied cancer types, including HPV-associated types such as HNSCC and cervical cancer (13/17), and a positive prognostic factor in 2/17 studied cancer types (urothelial carcinoma of the upper urinary tract and breast cancer). In three out of four predictive studies, K17 was a negative predictive factor for chemotherapy and immune checkpoint blockade therapy response.

The Possible Role of Anti- and Protumor-Infiltrating Lymphocytes in Pathologic Complete Response in Early Breast Cancer Patients Treated with Neoadjuvant Systemic Therapy.

The tumor microenvironment, composed of pro- and antitumor immune cells, affects cancer cell behavior. We aimed to evaluate whether tumor-infiltrating lymphocyte (TIL) density and TIL subtypes in core biopsies at the diagnosis of breast cancer patients could predict a pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD-1+, FOXP3+) immune cells. A prospective, noninterventional study, including 171 participants undergoing NST, was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p = 0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p = 0.232), Ki-67 (p = 0.001), node-negative status (p = 0.024), and HER2+/triple negative vs. luminal B-like subtype (p < 0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant and we could not make any conclusions on the direction of associations in the model with all four biomarkers. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

Association of Circulating Tumor Cells, Megakaryocytes and a High Immune-Inflammatory Environment in Metastatic Breast Cancer.

Liquid biopsy is becoming an important source of new biomarkers during the treatment of metastatic cancer patients. Using size-based microfluid technology, we isolated circulating tumor cells (CTCs) from metastatic breast cancer patients to evaluate their presence and cluster formation, as well as the presence of megakaryocytes and immune-inflammatory blood cells, and to correlate their presence with clinicopathological data and overall survival (OS). In total, 59 patients (median age 60.4 years) were included in the study: 62.7% luminal A/B-like, 20.3% HER2-positive, and 17% triple-negative. Our results showed that at least one CTC was present in 79.7% and ≥5 CTCs in 35.2% of the patients. CTC clusters were present in patients with ≥5 CTCs only (in 19.2% of them), and megakaryocytes were present in 52% of all patients. The presence of CTC clusters and megakaryocytes was positively associated with the CTC count. Patients with low pan-inflammatory value (PIV), low systemic immune-inflammatory index (SII), and low relative change from baseline (ΔPIV%, ΔSII%) were associated with significantly higher OS than their counterparts. ΔPIV%, the presence of infection in the last month, and a long duration of metastatic disease were identified as independent prognostic factors for OS. The interplay of CTCs, CTC clusters, megakaryocytes, and PIV needs to be further explored.

Changes in the quality of life of early breast cancer patients and comparison with the normative Slovenian population.

BACKGROUND: We aimed to identify changes in quality of life after breast cancer treatment and compare them with the normative population data for the Slovenian population. PATIENTS AND METHODS: A prospective, single-group, cohort design was used. A total of 102 early breast cancer patients treated with chemotherapy at the Institute of Oncology Ljubljana were included. Of those, 71% returned the questionnaires after one-year post-chemotherapy. The Slovenian versions of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and BR23 questionnaires were used. Primary outcomes were a comparison of global health status/quality of life (GHS) and C30 Summary Score (C30-SumSc) at baseline and one-year post-chemotherapy with the normative Slovenian population. The exploratory analysis evaluated the differences in symptoms and functional scales of QLQ C-30 and QLQ BR-23 between baseline and one-year post-chemotherapy. RESULTS: At baseline and one-year post-chemotherapy, C30-SumSc of patients was lower than the predicted C30-SumSc from the normative Slovenian population by 2.6 points (p = 0.04) and 6.5 points (p < 0.001), resp. On the contrary, GHS was not statistically different from predicted either at baseline or after one year. Exploratory analysis revealed that one-year post-chemotherapy compared to the beginning of chemotherapy, patients had statistically significantly and clinically meaningful lower scores in body image and cognitive functioning, and increased symptom scores for pain, fatigue, and arm symptoms. CONCLUSIONS: The C30-SumSc is reduced one-year post-chemotherapy. Early interventions should be directed toward the prevention of the decline of cognitive functioning and body image, and to alleviate fatigue, pain, and arm symptoms.

Biomarkers for Outcome in Metastatic Melanoma in First Line Treatment with Immune Checkpoint Inhibitors.

INTRODUCTION: A high proportion of metastatic melanoma patients do not respond to immune checkpoint inhibitors (ICI), and until now, no validated biomarkers for response and survival have been known. METHODS: We performed a retrospective analysis of outcomes in patients with metastatic melanoma treated with first-line ICI at the Institute of Oncology Ljubljana from January 2018 to December 2020. The immune-related adverse events (irAEs) and serum immune-inflammation parameters (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (LR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV)) were analyzed as potential biomarkers for response and survival. Survival rates were calculated using the Kaplan-Meier method and then compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors for progression-free survival (PFS) and overall survival (OS). RESULTS: Median follow-up was 22.5 months. The estimated median progression-free survival (PFS) was 15 months (95% CI 3.3-26.2). The two-year survival rate (OS) was 66.6%. Among 129 treated patients, 24 (18.6%) achieved complete response, 28 (21.7%) achieved partial response, 26 (20.2%) had stable disease and 51 (39.5%) patients experienced a progressive disease. There was a higher response rate in patients with irAEs (p < 0.001) and high NLR before the second cycle of ICI (p = 0.052). Independent prognostic factors for PFS were irAE (HR 0.41 (95% CI 0.23-0.71)), SII before the first cycle of ICI (HR 1.94 (95% CI 1.09-3.45)) and PLR before the second cycle of ICI (HR 1.71 (95% CI 1.03-2.83)). The only independent prognostic factor for OS was SII before the first cycle of ICI (HR 2.60 (95% CI 0.91-7.50)). CONCLUSIONS: Patients with high pre-treatment levels of SII had a higher risk of progression and death; however, patients with irAEs in the high-SII group might respond well to ICI. Patients who develop irAEs and have high NLRs before the second ICI application have higher rates of CR and PR, which implicates their use as early biomarkers for responsiveness to ICI.

Application of a 21-Gene Recurrence Score in a Swiss Single-Center Breast Cancer Population: A Comparative Analysis of Treatment Administration before and after TAILORx.

In patients with hormone receptor positive, human epidermal receptor 2 negative (HR+/HER2-) negative breast cancer (BC), the TAILORx study showed the benefit of adding chemotherapy (CHT) to endocrine therapy (ET) in a subgroup of patients under 50 years with an intermediate Oncotype DX recurrence score (RS 11-25). The aim of the present study was to determine if the TAILORx findings, including the changes in the RS categories, impacted CHT use in the intermediate RS (11-25) group in daily practice, as well as to identify the main factors for CHT decisions. We conducted a retrospective study on 326 BC patients (59% node-negative), of which 165 had a BC diagnosis before TAILORx (Cohort A) and 161 after TAILORx publication (Cohort B). Changes in the RS categories led to shifts in patient population distribution, thereby leading to a 40% drop in the low RS (from 60% to 20%), which represented a doubling in the intermediate RS (from 30% to 60%) and an increase of 5% in the high RS (from 8-10% to 15%). The overall CHT recommendation and application did not differ significantly between cohort B when compared with A (19% vs. 22%, resp., p = 0.763). In the intermediate RS (11-25), CHT use decreased by 5%, while in the high-risk RS category (>25), there was an increase of 13%. The tumor board recommended CHT for 90% of the patients according to the new RS guidelines in cohort A and for 85% in cohort B. The decision for CHT recommendation was based on age (OR 0.93, 95% CI 0.08-0.97, p = 0.001), nodal stage (OR 4.77, 95% CI 2.03-11.22, p < 0.001), and RS categories (RS 11-25 vs. RS 0-10: OR 0.06 (95% CI 0.02-0.17), p < 0.001; RS > 26 vs. RS 11-25: OR 618.18 95% CI 91.64-4169.91, p < 0.001), but did not depend on the cohort. In conclusion, while the tumor board recommendation for CHT decreased in the intermediate RS category, there was an increase being reported in the high RS category, thus leading to overall minor changes in CHT application. As expected, among the younger women with intermediate RS and unfavorable histopathological factors, CHT use increased.

Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy: Time to Rethink Our Approach.

BACKGROUND: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. SUMMARY: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions. KEY MESSAGES: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

Neuroendocrine Carcinoma of the Larynx and Pharynx: A Clinical and Histopathological Study.

Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995-2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein-Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs ≥ 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.

Outcome of Patients with Locally Advanced Metastatic Medullary Thyroid Cancer and Induction Therapy with Tyrosine Kinase Inhibitors in Slovenia.

BACKGROUND: The aim of our retrospective study was to evaluate the outcome of patients with metastatic medullary thyroid cancer (MTC) treated with tyrosine kinase inhibitors (TKIs) and/or chemotherapy with the emphasis on analysis on the cohort treated by induction TKI because of locally advanced metastatic MTC. METHODS: We analyzed the outcome of 30 patients (21 males, 9 females; median age 63.8 years) with metastatic MTC treated between 2000-2020. Sunitinib was used in 20 patients. RESULTS: Median progression-free survival on TKI and on chemotherapy was 10.6 (95% CI 7.1-14) months and 3.5 (95% CI 1.4-5.5) months, respectively. Median overall survival from diagnosis and from metastasis presentation was 38.2 (95% CI 4.7-71.7) months and 20.9 (95% CI 13.8-27.9) months, respectively. Eight patients (five females, three males; 58-86 years of age, median age 70 years) were treated with induction TKI because of inoperable locally advanced and metastatic MTC. The response rate to induction TKI was 50%; two patients (25%) had stable disease, and two patients (25%) had progressive disease. CONCLUSION: Our data support a new paradigm that TKIs may be the first treatment option in selected patients with locally advanced metastatic MTC, followed by locoregional treatment with surgery and/or external beam radiotherapy. Further studies are required to consolidate the presented data.

A new paradigm of surgery after neoadjuvant/induction tyrosine kinase inhibitors is not accepted as a standard of care in patients with medullary thyroid cancer. The aim of our retrospective study was to evaluate the outcome of all patients with metastatic medullary cancer treated in a 20-year period in Slovenia and, among these, the cohort treated with induction tyrosine kinase inhibitors because of locally advanced metastatic medullary thyroid cancer. Our first hypothesis was that the outcome of metastatic medullary cancer treated with tyrosine kinase inhibitors is better than in those treated with chemotherapy. Our second hypothesis was that induction therapy with tyrosine kinase inhibitors was effective in the treatment of initially inoperable primary tumors. In the treatment of metastatic medullary cancer a systemic therapy was used in 83.4% (25/30) patients. Patients on targeted treatment with tyrosine kinase inhibitors had more often a partial remission than on chemotherapy (65% vs. 17%, respectively). Eight patients were treated with induction tyrosine kinase inhibitors because of locally advanced metastatic disease. The computer tomography evaluation of the primary tumor during tyrosine kinase inhibitor therapy revealed partial response in four cases and stable disease in four cases, but surgery was performed in two cases only. Our data support a new paradigm that tyrosine kinase inhibitors may be the first treatment option in patients with locally advanced metastatic medullary thyroid carcinoma followed by locoregional treatment with surgery and/or external beam radiotherapy. However, further studies are required to consolidate the presented data.

Graves disease and metastatic hormonal-active Hürthle cell thyroid cancer: A case report.

RATIONALE: A hormone-active metastatic Hürthle cell thyroid carcinoma (HCTC) and Graves disease (GD) present a therapeutic challenge and is rarely reported. PATIENT CONCERNS: We present a 64-year-old male patient, who had dyspnea and left hip pain lasting 4 months. He had clinical signs of hyperthyroidism and a tumor measuring 9 cm in diameter of the left thyroid lobe, metastatic neck lymph node and metastases in the lungs, mediastinum, and bones. DIAGNOSIS: Laboratory findings confirmed hyperthyroidism and GD. Fine-needle aspiration biopsy and cytological investigation revealed metastases of HCTC in the skull and in the 8th right rib. A CT examination showed a thyroid tumor, metastatic neck lymph node, metastases in the lungs, mediastinum and in the 8th right rib measuring 20 × 5.6 × 4.5 cm, in the left acetabulum measuring 9 × 9 × 3 cm and parietooccipitally in the skull measuring 5 × 4 × 2 cm. Histology after total thyroidectomy and resection of the 8th right rib confirmed metastatic HCTC. INTERVENTIONS: The region of the left hip had been irradiated with concomitant doxorubicin 20 mg once weekly. When hyperthyroidism was controlled with thiamazole, a total thyroidectomy was performed. Persistent T3 hyperthyroidism, most likely caused by TSH-R-stimulated T3 production in large metastasis in the 8th right rib, was eliminated by rib resection. Thereafter, the patient was treated with 3 radioactive iodine-131 (RAI) therapies (cumulative dose of 515 mCi). Unfortunately, the tumor rapidly progressed after treatment with RAI and progressed 10 months after therapy with sorafenib. OUTCOMES: Despite treatment, the disease rapidly progressed and patient died due to distant metastases. He survived for 28 months from diagnosis. LESSONS: Simultaneous hormone-active HCTC and GD is extremely rare and prognosis is dismal. Concomitant external beam radiotherapy and doxorubicin chemotherapy, followed by RAI therapy, prevented the growth of a large metastasis in the left hip in our patient. However, a large metastasis in the 8th right rib presented an unresolved problem. Treatment with rib resection and RAI did not prevent tumor recurrence. External beam radiotherapy and sorafenib treatment failed to prevent tumor growth.

Preclinical and Clinical Evaluation of Magnetic-Activated Cell Separation Technology for CTC Isolation in Breast Cancer.

Circulating tumor cell (CTC) count is an independent prognostic factor in early breast cancer. CTCs can be found in the blood of 20% of patients prior to neoadjuvant therapy. We aimed to assess the suitability of magnetic-activated cell separation (MACS) technology for isolation and cytological characterization of CTCs. In the preclinical part of the study, cell lines were spiked into buffy coat samples derived from healthy donors, and isolated using MACS. Breast cancer cells with preserved cell morphology were successfully isolated. In the clinical part, blood for CTC isolation was drawn from 44 patients with early and locally advanced breast cancer prior to neoadjuvant chemotherapy. Standard Giemsa, Papanicolaou and pancytokeratin staining was applied. 2.3% of samples contained cells that meet both the morphological and immunocytochemical criteria for CTC. In 32.6% of samples, partially degenerated pancytokeratin negative cells with morphological features of tumor cells were observed. In 65.1% of samples, CTCs were not found. In conclusion, our results demonstrate that morphologically intact tumor cells can be isolated using MACS technology. However, morphologically intact tumor cells were not detected in the clinical part of the study. At present, MACS technology does not appear suitable for use in a clinical cytopathology laboratory.

Mobile App for Symptom Management and Associated Quality of Life During Systemic Treatment in Early Stage Breast Cancer: Nonrandomized Controlled Prospective Cohort Study.

BACKGROUND: Providing patients with cancer who are undergoing systemic therapy with useful information about symptom management is essential to prevent unnecessary deterioration of quality of life. OBJECTIVE: The aim was to evaluate whether use of an app for symptom management was associated with any change in patient quality of life or use of health resources. METHODS: Outpatients with early stage breast cancer receiving systemic therapy were recruited at the Institute of Oncology in Ljubljana, Slovenia. Patients who received systemic therapy between December 2017 and March 2018 (control group) and between April 2018 and September 2018 (intervention group) were eligible. All patients received standard care, but only those in the intervention group were asked to use mPRO Mamma, an Android-based smartphone app, in addition. The app supported daily tracking of 50 symptoms, allowed users to grade their symptom severity (as mild, moderate, or severe), and also provided in-depth descriptions and recommendations based on reported symptom level. Patient-reported outcomes in both groups were assessed through the European Organisation for Research and Treatment of Cancer (EORTC) core (C-30) and breast cancer (BR-23) questionnaires, as well as a questionnaire about health resources use. The primary outcomes were the difference in the global quality of life between groups and the difference in summary score of the EORTC C-30 questionnaire between groups after 3 time periods (the first week of treatment, the first treatment cycle, and the entire treatment). The secondary outcome was the use of health resources (doctor visits and hospitalizations) in each time period. Other scales were used for exploratory analysis. RESULTS: The mean difference between the intervention group (n=46) and the control group (n=45) in global quality of life (adjusted for baseline and type of surgery) after the first week was 10.1 (95% CI 1.8 to 18.5, P=.02). The intervention group summary scores were significantly higher than those of the control group after the first week (adjusted mean difference: 8.9, 95% CI 3.1 to 14.7, P=.003) and at the end of treatment (adjusted mean difference: 10.6, 95% CI 3.9 to 17.3, P=.002). Use of health resources was not statistically significant between the groups in either the first week (P=.12) or the first treatment cycle (P=.13). Exploratory analysis findings demonstrated clinically important improvements (indicated by EORTC C-30 or BR-23 scale scores)-social, physical, role, and cognitive function were improved while pain, appetite loss, and systemic therapy side effects were reduced. CONCLUSIONS: Use of the app enabled patients undergoing systemic therapy for early stage breast cancer to better cope with symptoms which was demonstrated by a better global quality of life and summary score after the first week and by a better summary score at the end of treatment in the intervention group compared to those of the control group, but no change in the use of health resources was demonstrated.

Importance of magnesium sulfate supplementation in the prevention of hypomagnesemia and hypocalcemia during chemoradiation in head and neck cancer.

In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.

Skin Reaction to Cetuximab as a Criterion for Treatment Selection in Head and Neck Cancer.

BACKGROUND/AIM: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.

TPF induction chemotherapy and concomitant irradiation with cisplatin and cetuximab in unresectable squamous cell carcinoma of the head and neck.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of docetaxel, cisplatin/5-fluorouracil (TPF) induction chemotherapy and concomitant immunochemoradiotherapy with cetuximab and cisplatin in unresectable head and neck carcinoma. METHODS: Treatment consisted of TPF induction chemotherapy (docetaxel 75 mg/m(2) day 2; cisplatin, 75 mg/m(2) day 2; and 5-fluorouracil 750 mg/m(2) days 1-4; 4 cycles), followed by radiotherapy (RT) and concomitant weekly cetuximab, (250 mg/m(2), after a loading dose of 400 mg/m(2)) and cisplatin (30 mg/m(2)). RESULTS: Twenty-five of 30 patients completed 4 cycles of induction chemotherapy. Six or more concomitant infusions of cisplatin and cetuximab were administered in 13 of 25 and 18 of 25 patients, respectively. The 2-year locoregional control, disease-free survival (DFS), and overall survival (OS) were 47%, 47%, and 50%, respectively. Patients with grade ≥ 2 skin reaction to cetuximab had a superior outcome. CONCLUSION: The tested regimen was effective; however, cetuximab and low-dose cisplatin after induction TPF increased the treatment toxicity. A grade ≥ 2 skin rash correlated with improved efficacy.

Mibefradil is more effective than verapamil for restoring post-ischemic function of isolated hearts of guinea pigs with acute renal failure.

The deleterious intracellular Ca(2+) overload in the ischemic-reperfusion injury of the heart can be even more expressed in subjects with acute renal failure in whom maintenance of intracellular Ca(2+) has already been disturbed in normoxia. To study the influence of acute renal failure in ischemic-reperfusion injury on the heart, we used isolated Langendorff's hearts of guinea pigs with gentamicin-induced acute renal failure. We examined arrhythmias, heart contractility and myocardial cell damage during reperfusion. Two specific Ca(2+) channel antagonists, mibefradil (0.1 and 1 microM) and verapamil (0.1 microM), were used to test the possible involvement of T-type and L-type Ca(2+) channels in these processes. We exposed hearts to 50 min of zero-flow global ischemia and 60 min of reperfusion. During reperfusion, unrecoverable ventricular fibrillation appeared more often in hearts of animals with acute renal failure than in control hearts (80% vs. 0%, respectively). Mibefradil, but not verapamil, applied either pre- or post-ischemically, terminated ventricular fibrillation in all hearts of animals with acute renal failure. Mibefradil (0.1 microM only) improved contractility in hearts of animals with acute renal failure during reperfusion by 30%. During reperfusion, lactate dehydrogenase (LDH) release rate increased less in hearts of guinea pigs with acute renal failure than in control hearts and only verapamil decreased it additionally. Thus, our results suggest a more important role of T- than of L-type Ca(2+) channels in ischemic-reperfusion injury in isolated guinea pig hearts with acute renal failure.