Afatinib-induced toxic epidermal necrolysis: A case report with a literature review.

We present a 70-year-old female patient diagnosed with epidermal growth factor receptor-mutated metastatic non-small cell lung cancer (T4N2M1a), who developed afatinib-induced toxic epidermal necrolysis (TEN). We have also performed a PubMed/Medline literature review to detect other possible cases of TEN/Stevens-Johnson syndrome associated with afatinib treatment and found only 5 other cases reported. To our best knowledge, this is the first case of afatinib-induced TEN successfully treated with cyclosporine.

Effectiveness and Safety of Immune Checkpoint Inhibitors in Older Cancer Patients.

BACKGROUND: The development of immunotherapy checkpoint inhibitors (ICIs) has revolutionized cancer care. However, old patients are underrepresented in most clinical trials, although they represent a significant proportion of real-world patients. We aimed to evaluate the effectiveness and safety of ICIs in patients older than the age of 70. METHODS: We performed a retrospective chart review of 145 patients aged 70 or older treated with ICIs for metastatic or unresectable cancer. RESULTS: Median progression-free survival (PFS) was 10.4 months (95% CI 8.6-13.7), with no differences between octogenarians and septuagenarians (p = 0.41). Female gender (p = 0.04) and first-line treatment setting (p < 0.0001) were associated with a longer median PFS. Median overall survival (OS) was 20.7 months (95% CI 13.5-35.0 months), with no difference based on performance status, cancer site, gender, or between septuagenarians and octogenarians (all p > 0.005). Patients treated with ICIs in the first-line setting reported longer OS compared to treatment in the second-line setting (p < 0.001). Discontinuation of ICIs due to adverse effects was associated with both shorter PFS (p = 0.0005) and OS (p < 0.0001). CONCLUSION: The effectiveness of ICIs in older cancer patients primarily depends on the line of treatment and treatment discontinuation. Octogenarians experienced similar treatment responses, PFS, OS, and adverse effects compared to septuagenarians.

Reply to Chen, A.; Zhang, X. Comment on "Golcic et al. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers 2023, 15, 4081".

We appreciate the comment made by Chen et al. on our manuscript evaluating the systemic treatment options for gastrointestinal stromal tumours (GIST) [...].

Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy.

Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy.

Smoking Cessation after a Cancer Diagnosis: A Cross-Sectional Analysis in the Setting of a Developing Country.

Since smoking accounts for around 30% of all cancer deaths, public health campaigns often focus on smoking cessation as a means of primary prevention. However, smoking after cancer diagnosis is also associated with a higher symptom burden and lower survival rate. As data regarding smoking cessation vary dramatically between different populations, we aimed to analyze smoking prevalence in cancer patients, smoking cessation after cancer diagnosis, and the factors associated with smoking cessation in the setting of a developing country. We performed a cross-sectional survey on 695 patients in two clinical hospital centers. After cancer diagnosis, 15.6% of cancer patients stopped smoking. Male gender, younger age, and smoking-related cancer were the main factors associated with greater smoking cessation (p < 0.05). A total of 96% of breast cancer patients continued to smoke after cancer diagnosis and, compared to lung and colorectal cancer patients, exhibited a lower reduction in the number of cigarettes smoked (p = 0.023). An alarming rate of smoking prevalence was recorded in younger patients (45.6% at the time of cancer diagnosis) suggesting a future rise in smoking-related cancers and complications. These results should guide anti-smoking public health campaigns in transitional countries with a critical focus on younger and breast cancer patients.

Analysis of clinical factors associated with survival in patients with soft-tissue sarcoma receiving trabectedin.

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignancies. Treatment for advanced STS usually starts with anthracycline-based therapies, with no clear sequence for further treatment. A preferred option is trabectedin, especially for liposarcoma and leiomyosarcoma (L-sarcoma). However, due to severe side effects and few clinical trials, further research of the parameters affecting survival is necessary for the optimal selection of patients. We retrospectively analyzed 73 consecutive patients with STS treated with trabectedin at the University Hospital Centers at Zagreb and Osijek from 2014 to 2021. Our primary goals were evaluating factors affecting progression-free survival (PFS) and overall survival (OS). The median PFS and OS for trabectedin were 3.6 months and 13.7 months, respectively. Patients with L-sarcoma exhibited longer PFS and a trend towards longer OS compared to those with non-L-sarcoma. However, these effects were primarily a result of the myxoid liposarcoma subtype, which exhibited a median PFS of 21.1 months and a median OS of 33.3 months, both significantly longer compared to non-myxoid L-sarcoma. Additionally, patients with three or more sites of metastases exhibited shorter median PFS (3.1 months vs. 3.6 months) and OS (5.7 months vs. 23.8 months) compared to only one metastatic site. There was no correlation between the PFS values of trabectedin and pazopanib and no difference in survival, regardless of the treatment sequence. Trabectedin treatment yields the greatest survival benefit in patients with myxoid liposarcoma and low metastatic burden, whereas the additional use of pazopanib provides further clinical benefit, regardless of treatment sequence.

Relative Change in S100 as a Biomarker of Survival in Patients With Metastatic Melanoma Treated With Pembrolizumab.

BACKGROUND/AIM: There is a lack of quality biomarkers of survival for patients with metastatic melanoma treated with immunotherapy. Although the baseline level of S100 has prognostic value, its role during/after therapy in survival is unclear. PATIENTS AND METHODS: We evaluated patients with metastatic melanoma treated with pembrolizumab with the goal of analysing the relationship between a relative change in S100 level at 12 weeks of immunotherapy and survival. RESULTS: Patients with a relative change in S100 level >145% at 12 weeks of immunotherapy had significantly shorter progression-free (5.1 vs. 18.5 months, p≤0.0001) and overall survival (5.7 vs. 26.3 months, p<0.0001), further confirmed on multivariate analysis with hazard ratio of 32.25 (95% confidence interval=4.78-217.6, p=0.0004) for overall survival. CONCLUSION: A relative change in S100 level might be useful as a more precise biomarker of survival for patients with metastatic melanoma treated with pembrolizumab.

Should we treat pain in the elderly palliative care cancer patients differently?

Opioids are considered the cornerstone of pain management in palliative care. Available data suggest that older patients use different analgesics and lower opioid doses compared to younger patients. However, it has not been elucidated yet whether such dosing is associated with worse pain levels or shorter survival in the palliative care setting. We evaluated the relationship among pain scores, quality of life, opioid dose, and survival in palliative care cancer patients in a hospice setting. A total of 137 palliative care cancer patients were analyzed prospectively. We divided patients into two groups using the age of 65 as a cut-off value. Younger patients exhibited significantly higher pain ratings (5.14 vs. 3.59, p=0.01), although older patients used almost 20 mg less oral morphine equivalent (OME) on arrival (p=0.36) and 55 mg OME/day less during the last week (p=0.03). There were no differences in survival between the two groups (17.36 vs. 17.58 days). The elderly patients also used nonsteroidal analgesics less often and paracetamol more often. Hence, using lower opioid doses in older palliative care cancer patients does not result in worse pain rating, and could be a plausible approach for pain management in this patient group.

BURKITT LYMPHOMA IN GASTROINTESTINAL TRACT: A REPORT OF TWO CASES.

Burkitt lymphoma, a type of non-Hodgkin B-cell lymphoma, is the fastest growing human cancer, presenting pathologically with a 'starry sky' pattern. It is most often found in the abdomen and the jaw, however, localization in the abdomen other than the ileocecal area is very rare and described only in a handful of cases. Standard treatment consists of initial tumor cytoreduction followed by intense chemotherapy. Most of the relapses occur within one year of the diagnosis, while the 5-year survival is around 80%. We present two cases which are specific for unusual location of Burkitt lymphoma in the colon and stomach, in immunocompetent patients with negative Epstein-Barr virus tests. Also, one of the patients presented is one of the oldest ever reported with abdominal Burkitt lymphoma, while the other patient is an example of diagnostic difficulties in distinguishing Burkitt lymphoma from similar lymphomas. Due to the rapidly growing tumors and urgent need for cytoreductive surgery, it is crucial to consider the diagnosis of Burkitt lymphoma even in atypical localizations or absence of the common risk factors associated with Burkitt lymphoma.

Differences between Transdermal Fentanyl and Buprenorphine in the Elderly Hospice Patients.

INTRODUCTION: Opioids are the most important drugs in treating pain in palliative care patients. Transdermal formulations are especially useful due to their noninvasive nature and minimal interference in daily life. However, studies have shown a controversial relationship of opioids to survival and a rise in deaths associated with the use of transdermal opioids. Although applying precise doses is paramount, we have no clear recommendations for the exact equianalgesic ratio for buprenorphine patch and no recommendation for the type of transdermal opioid to use in hospice. METHODS: We analyzed the differences between the transdermal fentanyl and buprenorphine group by analyzing patient characteristics and evaluating the differences in survival in hospice patients over the age of 65, from 2013 to 2017. RESULTS: A total of 292 patients (75.8%) used fentanyl patch and 93 (24.1%) were on buprenorphine patch. Patients had virtually the same characteristics in both groups. However, when using a 1:100 buprenorphine equianalgesic ratio, there were significant differences in initial and final doses, and it seems that a 1:80 conversion rate is more accurate for elderly hospice patients. Finally, there was no difference in survival between the two groups using transdermal opioids, with or without adjuvant analgesics. DISCUSSION: There were no differences in survival between the group using transdermal fentanyl and the group using buprenorphine in the elderly hospice population. Although adjuvant NSAIDs could be useful in the treatment of pain in terminal cancer, they do not affect survival or reduce the opioid doses, while a 1:80 equianalgesic ratio of buprenorphine might be the most appropriate in this population.

Do Physicians Underestimate Pain in Terminal Cancer Patients? A Prospective Study in a Hospice Setting.

OBJECTIVES: Unrelieved pain is present in a majority of terminal cancer patients. However, the treatment of pain in palliative and hospice care is affected by the lack of validated pain assessment. The goal of this study was to evaluate differences in pain evaluation between terminal cancer patients and physicians and evaluate the pain levels as a survival biomarker. MATERIALS AND METHODS: Patients were evaluated every 7 days for a total of 4 assessments. Physicians evaluated patients' pain on an numeric rating scale (NRS) scale after clinical examination, after which the patients completed NRS, Quality of Life Questionnaire Core 15 Pal (QLQ-C15-PAL), and Edmonton Symptom Assessment System (ESAS) questionnaires. RESULTS: On average, physicians minimally underestimated the pain level in patients (3.47 vs. 3.94 on an NRS scale). Pain was overestimated in 28% and underestimated in 46% of the patients. However, half of all underestimation was clinically meaningful, compared with 28% of the overestimation. For patients with an NRS score of ≥7, pain underestimation was both clinically and statistically significant (5.56 vs. 8.17). Pain ratings exhibited a very small correlation to survival (up to r=-0.22), limiting their use as a survival biomarker. DISCUSSION: Although physicians can accurately assess mild pain in terminal cancer patients in the hospice setting, the underestimation of pain is still clinically significant in almost a quarter of patients, and especially pronounced in patients with higher levels of pain and in female patients. Hence, validated pain assessment is a necessity in hospice care, with the choice of pain evaluation tool dependent on patient and physician preference.

Physical Exercise: An Evaluation of a New Clinical Biomarker of Survival in Hospice Patients.

PURPOSE: Survival analysis is an important issue in palliative care. However, there is a lack of quality clinical biomarkers for assessing survival, especially in bedridden patients. Recent research supports the benefit of physiotherapy in palliative care, as majority of hospice patients are able to perform physical therapy. We propose the hypothesis that the difference in activity during physical exercise can be used as a biomarker of survival in hospice care. METHODS: We examined 536 consecutive patients who performed physical exercises in our hospice from March 2013 to July 2017. Univariate, multivariate, and Kaplan-Meier analysis were performed to explore the association between the level of physical exercise activity and survival. RESULTS: Physical exercises were performed by almost 70% of our hospice patients. The patients who initially performed active exercises lived longer, on average, compared to patients who only managed passive exercises (15 days vs 6 days, hazard ratio 0.60, 0.49-0.74). Surprisingly, the difference in survival based on the level of physical activity remained consistent regardless of the patient performance score, emphasizing its usefulness as an independent survival biomarker in a hospice setting. This tool also gave us an option to recognize a significant proportion of bedridden patients performing active exercises (30%), previously unrecognized using standard performance scales, exhibiting longer survival compared to others with the same performance score. CONCLUSION: Patients' level of activity during physical exercises has the potential to be a valuable new clinical biomarker in palliative care, whether used individually or combined with commonly used performance scales.

Quality of Life in a Hospice: A Validation of the Croatian Version of the EORTC QLQ-C15-PAL.

PURPOSE: Quality of life is the cornerstone of palliative care, and assessing it requires validated and standardized questionnaires. However, the majority of questionnaires are not tested in a hospice setting. The purpose of this study is to evaluate the quality of life in a hospice using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 for Palliative Care (PAL) (EORTC QLQ-C15-PAL) questionnaire and validating it in Croatian language. METHODS: The study was conducted prospectively on 151 consecutive patients who were evaluated at the admittance to the hospice and after 7 days. Along with the EORTC QLQ-C15-PAL, both evaluations included the Edmonton Symptom Assessment System (ESAS) and the Palliative Performance Score (PPS) version 2. Cronbach α coefficient was used to test the reliability of multi-item scales, while construct and concurrent validity was tested using the Pearson correlation coefficients. Known-group validity was evaluated using the Student t test. RESULTS: Physical functioning, pain, and emotional functioning scales all exhibited high reliability on both assessments and met the criteria of Cronbach α ≥.70, while fatigue scale met the predetermined criteria in the follow-up assessment (α = .90). Adequate validity was also displayed, with the highest correlation coefficients between the EORTC QLQ-C15-PAL and ESAS scales recorded for the corresponding items. The EORTC QLQ-C15-PAL was also able to distinguish patients with different PPS scores, exhibiting excellent clinical validity. CONCLUSIONS: The EORTC QLQ-C15-PAL can be used successfully in Croatian palliative care. However, inevitable issues such as low retest percentage due to short survival and low physical functioning scores need to be acknowledged in further formulations of quality of life questionnaires specific to hospice care.

The Impact of Combined Use of Opioids, Antipsychotics, and Anxiolytics on Survival in the Hospice Setting.

CONTEXT: Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics, and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients. OBJECTIVES: To analyze the relationship of a combination of opioids, anxiolytics, and antipsychotics on survival and the change of night-time death percentage. METHODS: A retrospective study of 765 consecutive patients admitted to hospice in Croatia over the period of four years (2013-2017). The main outcome was the total length of survival of hospice patients regarding different drug combination, along with night-time death percentage. RESULTS: Different combinations of opioids, anxiolytics, and antipsychotics were associated with longer survival in hospice compared with patients using no such drugs. When we included different parameters which affected overall survival into a multivariate analysis, only the patients who had the combination of both opioids, anxiolytics, and antipsychotics in their regular therapy were associated with longer survival in hospice (11 vs. five days, hazard ratio 0.54, P < 0.001). No combination of opioids, anxiolytics, and antipsychotics significantly changed the night-time death percentage. CONCLUSION: This research supports the safety of opioids, anxiolytics, and antipsychotics in the hospice setting when used both individually as well as in combination.

Endogenous erythropoietin and erythropoietin receptors in colorectal cancer; can we answer the questions?

Erythropoietin (Epo) is glycoprotein hormone which binds on erythropoietin receptors (EpoR) promoting proliferation and differentiation. Studies have shown that EpoR, apart from erythrocyte precursors, is expressed on no hematopoietic tissue and various tumor cells. Despite the progress in modern medicine, colorectal carcinoma (CRC) is still the leading cause of increased morbidity and mortality between oncology patients worldwide. Its precursors are benign villous adenomas, which in certain percentage progress to cancer. Anemia of chronic disease is common finding in CRC patients. Some of them are treated with Epo. Epo/EpoR seems to correlate with tumor progression and metastasizing. Therefore, the identification of at-risk group remains a clinical challenge. Vascular endothelial growth factor (VEGF) is a signal protein that stimulates angiogenesis and concentration of VEGF is positive correlated with tumor growth in numerous tumors. The importance of Epo in tumor pathogenesis has led to a growing interest in the potential prognostic value. By our point of view there are many open questions about role of Epo/EpoR in CRC.

Changes in metabolic profile, iron and ferritin levels during the treatment of metastatic renal cancer - A new potential biomarker?

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.