Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

BACKGROUND: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. MATERIALS AND METHODS: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. RESULTS: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. CONCLUSIONS: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.

The Current Treatment Trends and Survival Patterns in Melanoma Patients with Positive Sentinel Lymph Node Biopsy (SLNB): A Multicenter Nationwide Study.

BACKGROUND: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice. METHODS: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis. RESULTS: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors). CONCLUSIONS: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients.

Fluorescence Imaging Using Methylene Blue Sentinel Lymph Node Biopsy in Melanoma.

INTRODUCTION: Fluorescence imaging of sentinel node biopsy in melanoma is a novel method. Both indocyanine green (ICG) and methylene blue (MB) have fluorescent properties. The aim of this study was to present, for the first time in a clinical series of patients, the possible usage of MB as a fluorescent dye for sentinel node biopsy during surgery for melanoma. MATERIAL AND METHODS: Twenty patients with skin melanoma, who were candidates for sentinel node biopsy were enrolled in our study. All patients underwent simultaneous use of standard nanocolloid and blue dye. Transcutaneous visualization of the sentinel node, visualization of lymphatic channels as well as sentinel node fluorescent visualization were all measured. We also performed calculations of Signal to Background ratios (SBR). RESULTS: In 15% (3/20) of patients, the fluorescent sentinel node was visible through the skin. The median SBR for the sentinel node visualization by fluorescence was 3.15 (range, 2.7-3.5). Lymphatic channels were visible in lymphatic tissue via fluorescence before visualization by the naked eye in 4 patients (20%). The median SBR ratio was 3.69 (range, 2.7-4.2). Sentinel nodes were visible by fluorescence in 13 cases (65%). The median SBR ratio was 2.49 (range, 1.5-5.7). No factors were found to be associated with fluorescent MB visualization of a sentinel node during biopsy. CONCLUSION: This is the first clinical study presenting the usefulness of fluorescent sentinel node biopsy in melanoma patients using MB as a fluorophore. Further studies are necessary to provide methods for its' clinical implementation.

[Synchronous gastrointestinal stromal tumor of stomach and invasive ductal carcinoma of both breasts]. / Synchroniczne wystepowanie nowotworu podscieliska przewodu pokarmowego w zoladku oraz raka przewodowego inwazyjnego obu gruczolów piersiowych.

Gastrointestinal stromal tumor (GIST), despite the fact that it accounts for less than 5% of all sarcomas, is the most common mesenchymal tumor of the alimentary canal. Synchronous and metachronous stromal tumors are very rare findings. Only a few such cases can be found in the literature, and yet most of them is connected with Von Recklinghausen's disease or Carney's triad in which it is proved a much higher frequency of occurrence of this kind of tumors. CASE REPORT: We present a case of 64 years old women, who was diagnosed with invasive ductal carcinoma of both breast due to screening mammography. Patent was qualified to bilateral mastectomy. Perioperative computer tomography scan revealed an additional pathological abnormality situated beyond stomach light, which after resection and immunohistochemistry was found to be a gastrointestinal stromal tumor. This case emphasize the problem of synchronous stromal tumors, the detection of which is often difficult due to nonspecific symptoms. Despite the fact that the most common localization of coexisting tumors is the digestive tract, one should remember about the possibility of occurrence in less frequent locations such as the breast.

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.

BACKGROUND: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. METHODS: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. FINDINGS: From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). INTERPRETATION: From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

[Primary squamous cell carcinoma of the breast - a case report]. / Pierwotny rak plaskonablonkowy gruczolu piersiowego - opis przypadku.

UNLABELLED: Breast cancer is the most common malignant tumor among women in Poland. According to the Center of Oncology (The National Cancer Registry) in 2010 in our country 15,784 new cases have been noted. Since 1970s worldwide growth of new cases of breast cancer have been reported. Among the well-known histological types of breast tumors, small percentage - only 0.1% - include squamous cell component. CASE REPORT: A 69-year-old female met her doctor because of the right breast tumor. After two months of observation, in the last two weeks before the visit, the tumor started to grow very rapidly. As the diagnosis from fine needle aspiration biopsy (squamous cell carcinoma) was very rare for this location, and considering the other clinical symptoms the woman reported, it was suspected to be metastatic. Finally, as the other origins of the primary tumor have been declined and as the patient's condition begun to worsen very rapidly, the urgent treatment: mastectomy (toilet mastectomy) and adjuvant chemotherapy afterward, according to the pathological report were performed. CONCLUSIONS: Rare histological types of the breast cancer use to suggest a metastatic origin or behave as tumors with highly malignant histological grade.

Improved overall survival in melanoma with combined dabrafenib and trametinib.

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

[Pseudomyxoma peritonei spread into the right inguinal hernia sac--a case report]. / Sluzak rzekomy otrzewnej ze wszczepem do worka przepukliny pachwinoweJ prawel--opis przypadku.

Pseudomyxoma peritonei (PMP) is a rare, progressive disease of unknown origin. The incidence is estimated at about 1-2/100,000,000 per year. The primary tumor site is usually discovered in the appendix or- in case of women--in ovaries, appearing as tumors of low malignancy. Making an accurate diagnosis causes difficulties--symptoms tend to be misleading, suggesting more frequent pathologies of the abdominal cavity. It is also not rare that the patient is for a long time asymptomatic. We present a case of a 68-year-old patient of the Surgical Oncology Department treated for pseudomyxoma peritonei, diagnosed incidentally at the time of clinical examination for the reasons of chronic hypertension. The symptoms reported by the patient did not suggest any neoplastic process of the peritoneal cavity. Systemic chemotherapy of two paths (a total number of 10 cycles) did not result and at the time of post-treatment control, due to no response to standard chemotherapy, it was decided to administer chemotherapy intraperitoneally in hyperthermia (HIPEC). During the operation, peritoneal cytoreduction prior to the scheduled HIPEC was performed; the right-sided inguinal hernia was repaired. Within the hernia sac the implanted myxoid cells were found, their presence inside was probably the main reason of clinical manifestation of the disease.

Metachronous adenocarcinoma in a gastric tube after radical surgery for oesophageal cancer.

In recent years the prognosis for oesophageal squamous cell carcinoma patients has improved. Together with this improvement, the occurrence of second primary carcinoma, especially gastric carcinoma, in tubes constructed from the stomach after oesophagectomy must be taken into account. We report a case of a patient who had this clinical presentation, which was revealed not in the normal follow-up, but in a consecutive operation carried out because of an anastomotic problem.

Heart laceration during oesophagectomy for the treatment of oesophageal carcinoma.

Oesophagectomy remains an acceptable treatment option for oesophageal cancer. However, it is associated with relatively high morbidity with potentially devastating complications, especially for patients who have undergone previous thoracic surgery. The majority of these complications, however, can be minimised by prevention and early recognition. In this report we present a case of a patient whose right ventricle was injured during the oesophagectomy. We try to analyse the reasons for this complication and establish an algorithm of preoperative planning for such cases.

Possibilities of improving the parameters of hyperthermia in regional isolated limb perfusion using epidural bupivacaine and accurate temperature measurement of the three layers of limb tissue.

The present study presents the author's modification of the method, which aims to create proper parameters of the treatment. The selected group consisted of 15 women and eight men, with a mean age of 57.2 years (range from 26 to 72 years). The patients were divided into two groups, depending on whether they were given epidural bupivacaine (group I - 13 patients treated between the years 2001 and 2004) or not [group II (control) - 10 patients treated earlier, between the years 1997 and 2000]. We observed a significant change in the temperature of thigh muscles (P=0.009) and shank muscles (P=0.006). In the control group II, there was a statistically significant difference (P=0.048) in the temperatures between the muscles and subcutaneous tissue on the one hand and the shank skin on the other. That difference was mean 0.67 degrees Celsius (from 0.4 to 0.9) during the perfusion after applying the cytostatic. The temperature of the skin was lower than the temperature of the deeper tissues of the shank and did not exceed 39.9 degrees Celsius. Such a difference in the temperatures was not observed in case of the group I patients who were given bupivacaine into the extrameningeal space before applying the cytostatic. The difference in the temperatures was on average 0.26 degrees Celsius and was not statistically significant (P=0.99), whereas the shank skin temperature was 40.0-40.6 degrees Celsius. The attained results imply that despite the noticeable improvement in the heating of the limb muscles after application of bupivacaine, the improvement in the heating of the skin and subcutaneous tissue is still not satisfactory, although the growing tendency implies such a possibility.

Coexistence of hepatocellular carcinoma and gastrointestinal stromal tumor: a case report.

Malignant gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors originating from the wall of the gastrointestinal tract. Their coexistence with other tumors originating from other germ layers is unique. We have reported a case of a 63-year-old GIST patient presenting as an epigastric mass associated with hepatic tumor. Histologically, the mesenteric tumor was composed of spindle cells showing both neural and smooth muscle differentiation. Immunohistochemical examination showed positive staining for CD117, vimentin, S-100, and SMA, while CD34 antigen was negative. The hepatic tumor was diagnosed as hepatocellular carcinoma (HCC). To the best of our knowledge, this is the first case of GIST and HCC coexistence. The rarity of the case, however, should not lead to ignoring such a possibility in differential diagnosis.

Jan Mikulicz-Radecki (1850-1905): pioneer of endoscopy and surgery of the sinuses, throat, and digestive tract.

The authors described the medical achievements of Jan Antoni Mikulicz-Radecki--a famous surgeon and laryngologist of Polish origin, belonging to the Viennese surgical school of Prof. Theodor Billroth at the turn of the 20th century. His scientific and clinical activity in Vienna, Cracow, Konigsberg, and Wroclaw resulted in 232 publications and several new surgical methods. He changed the opinion on scleroma and described benign lymphoepithelial lesions. He was one of the authors of modern aseptics, antisepsis in surgery, and is regarded as a pioneer of endoscopic procedures. He was interested mainly in thoracic surgery, surgery of the abdomen, orthopedics, and laryngology. Mikulicz was the first to describe the method of surgical treatment of the maxillary sinus, osteoplastic surgery of the nose, esophagoscopy, and lateral pharyngotomy in tonsil carcinoma. Prof. Mikulicz was the first to perform thoracic surgery; he performed the first pyloroplasty, the first partial esophagectomy and gave rise to antiseptic procedures and general surgical management. He described many modifications of surgical operations and he constructed the esophagoscope, scoliozymeter, and many other useful surgical devices.