Total Synthesis of Psammaplysins A, M, O, and Q and Ceratinamide A.

The psammaplysins are a unique class of brominated marine alkaloids bearing a signature 5/7-spiroisoxazoline-oxepine core linked to a variable tyramine-derived unit. Here, we report the total synthesis of several members of this family via a dipolar cycloaddition between an in situ generated nitrile oxide and an unusual seven-membered enediol diether dipolarophile. Carefully orchestrated oxidative transformation toward the fully functionalized spirocycle and direct coupling with tyramine-derived amines provides access to five representative family members, psammaplysins A, M, O, and Q and ceratinamide A, the latter four for the first time. Additionally, kinetic resolution of a late-stage intermediate enables the first asymmetric synthesis of (-)-psammaplysin A, thereby confirming its absolute configuration.

Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.

BACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

The Use of Indocyanine Green and Near-Infrared Fluorescence Imaging Versus Blue Dye in Sentinel Lymph Node Biopsy in Cutaneous Melanoma: A Retrospective, Cohort Study.

BACKGROUND: The use of indocyanine green (ICG) and near-infrared fluorescence imaging is a promising option for sentinel lymph node (SLN) mapping in cutaneous melanoma. The study objective was to compare the performance of ICG and blue dye at detecting SLNs with radioisotope nanocolloid (technetium-99). METHODS: Between April 2018 and June 2022, 293 consecutive patients with cutaneous melanoma (Breslow thickness ≥ 0.8 mm) underwent wide local excision and SLN biopsy. Patients were divided into group A (ICG; n = 122) and group B (blue dye; n = 163). All patients underwent SPECT/CT imaging preoperatively. SLN detection parameters and complications were compared between the groups. RESULTS: A total of 285 patients had complete data and were included in the analysis. The median age was 62.0 (range 10-91) years, and 139 (48.8%) were female patients. The mean Breslow thickness was 2.6 mm, 89 (31.2%) patients had ulceration, and 179 (62.8%) patients had mitosis ≥ 1 mm2. The mean number of SLNs detected per patient in group A was 1.58 and group B was 1.48. In groups A and B, the SLN detection rate was 96.7% versus 89.6% (p = 0.022) and the pathological SLN detection rate was 92.3% versus 97.1% (p = 0.481), respectively. CONCLUSIONS: ICG had a higher SLN detection rate and equal pathological SLN detection rate to blue dye. ICG may not be inferior to blue dye and is a useful adjunct to radioisotope in SLN biopsy in cutaneous melanoma.

Prognosis of Patients with Cutaneous Angiosarcoma After Surgical Resection with Curative Intent: Is There a Difference Between the Subtypes?

BACKGROUND: The etiology of cutaneous angiosarcoma (cAS) may be idiopathic (I-cAS), or arise secondary to radiotherapy (RT-cAS), in chronic lymphedema (ST-cAS), or related to UV exposure (UV-cAS). The aim of this study was to evaluate oncological outcomes of different cAS subtypes. PATIENTS AND METHODS: Non-metastatic cAS patients, treated with surgery for primary disease with curative intent, were retrospectively analyzed for oncological outcome, including local recurrence (LR), distant metastases (DM), and overall survival (OS). RESULTS: A total of 234 patients were identified; 60 I-cAS, 122 RT-cAS, 9 ST-cAS, and 43 UV-cAS. The majority was female (78%), the median age was 66 years (IQR 57-76 years), the median tumor size was 4.4 cm (IQR 2.5-7.0 cm), and most common site of disease was the breast (59%). Recurrence was identified in 66% (44% LR and/or 41% DM), with a median follow up of 26.5 months (IQR 12-60 months). The 5-year OS was estimated at 50%, LRFS at 47%, and DMFS at 50%. There was no significant difference in LR, DM, or OS between the subtypes. Age < 65 years and administration of radiotherapy (RT) were significantly associated with lower LR rates (HR 0.560, 95% CI 0.3373-0.840, p = 0.005 and HR 0.421, 95% CI 0.225-0.790, p = 0.007, respectively), however no prognostic factors were identified for development of DM. Development of DM, but not LR (p = 0.052), was significantly associated with decreased OS (HR 6.486, 95% CI 2.939-14.318 p < 0.001). CONCLUSION: We found no significant difference in oncological outcome between the different cAS subtypes. OS remains relatively poor, and RT is associated with lower LR rates.

Oncological Outcome After Lymph Node Dissection for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Although cutaneous squamous cell carcinoma (cSCC) is common, lymph node metastases are relatively rare and are usually treated with lymph node dissection (LND). The aim of this study was to describe the clinical course and prognosis after LND for cSCC at all anatomical locations. METHODS: A retrospective search at three centres was performed to identify patients with lymph node metastases of cSCC who were treated with LND. Prognostic factors were identified by uni- and multivariable analysis. RESULTS: A total of 268 patients were identified with a median age of 74. All lymph node metastases were treated with LND, and 65% of the patients received adjuvant radiotherapy. After LND, 35% developed recurrent disease both locoregionally and distantly. Patients with more than one positive lymph node had an increased risk for recurrent disease. 165 (62%) patients died during follow-up of whom 77 (29%) due to cSCC. The 5-year OS- and DSS rate were 36% and 52%, respectively. Disease-specific survival was significantly worse in immunosuppressed patients, patients with primary tumors >2cm and patients with more than one positive lymph node. CONCLUSIONS: This study shows that LND for patients with lymph node metastases of cSCC leads to a 5-year DSS of 52%. After LND, approximately one-third of the patients develop recurrent disease (locoregional and/or distant), which underscores the need for better systemic treatment options for locally advanced cSCC. The size of the primary tumor, more than one positive lymph node, and immunosuppression are independent predictors for risk of recurrence and disease-specific survival after LND for cSCC.

Symmetry-Driven Total Synthesis of Myrioneurinol.

We report a total synthesis of the Myrioneuron alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol's complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent cis-1,3-bis(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.

Worldwide Techniques and Outcomes in Robot-assisted Minimally Invasive Esophagectomy (RAMIE): Results From the Multicenter International Registry.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Desmoid tumors: who, when and how to treat?

PURPOSE OF REVIEW: The objective of this article is to summarize new treatment strategies of desmoid tumors. RECENT FINDINGS: Desmoid tumor has an unpredictable evolution that may spontaneously regress or stabilize. A shift toward an initial frontline active surveillance has been acknowledged by experts. Surveillance monitoring should be performed frequently after the diagnosis to avoid missing a significant progression and then spaced in case of stabilization. Treatment is based on significant tumor growth or symptoms. Recent guidelines recommend commencing medical treatment. Kinase inhibitors and cytotoxic agents are the two classes of drugs where studies included progressive desmoid tumors and should be selected to guide medical practice. In a randomized trial, 2 years progression-free survival (PFS) was significantly better in the sorafenib group (81 versus 36% in the placebo group). In another randomized phase 2, 6 months PFS was 83.7% with pazopanib versus 45% with methotrexate and vinblastine. In a retrospective study, including progressive desmoid tumors, methotrexate + vinca alkaloids achieved 75 months median PFS. Cryotherapy is an alternative option in desmoid tumors with compatible locations and tumor sizes. Following medical treatment or cryotherapy failure, superficial sites represent the best indications for surgery in cases of continuous progression. In the event of a contra-indication or failure of medical treatment, in locations where surgery would be mutilating and incomplete, radiotherapy is an effective option. SUMMARY: Active surveillance with planned imaging has become the first-line management in desmoid tumor.

Frailty in Very Elderly Patients is Not Associated with Adverse Surgical or Oncological Outcomes in Extremity Surgery for Soft Tissue Sarcoma.

BACKGROUND: While surgery remains the mainstay of treatment for limb sarcoma, extreme old age is a relative contraindication to oncological surgery. METHODS: Patients >80 years referred with primary extremity soft-tissue sarcoma (ESTS) between 2007 and 2016 were retrospectively reviewed. Prognostic variables, including ASA status and Clinical Frailty Scores, were collected. Endpoints were perioperative morbidity, locoregional (LRR) and distant recurrence (DR), disease-specific survival (DSS) adjusted using competing risk modelling, and overall survival (OS). RESULTS: A total of 141 primary tumours were identified, with 116 undergoing resections. Main motives for nonoperative management were severe frailty or significant comorbidity (56.0%). The operative group had a median age of 84 (range 80-96) years and median follow-up of 16 months (range 0-95). 45.7% of patients received radiotherapy. Median hospital stay was 7 (range 0-40) days, with frailty (p = 0.25) and ASA (p = 0.28) not associated with prolonged admission. 12.9% developed significant complications, with one perioperative mortality. 24.1% had LRR, occurring at a median of 14.5 months. All patients with reported DR (28.4%), except one, died of their disease. Frailty did not confer a significant difference in adjusted LRFS (p = 0.95) and DMFS (p = 0.84). One- and 5-year adjusted DSS and OS was 87.0% versus 74.9% and 62.3% versus 27.4%, respectively. Frailty (CFS ≥4) was associated with worse OS (hazard ratio [HR] 2.49; 95% confidence interval [CI] 1.51-4.12; p < 0.001), however not with adjusted DSS (p = 0.16). Nonoperative management conferred a 1- and 5-year adjusted DSS was 58.3% and 44.4%, respectively. CONCLUSIONS: Extremity surgery for sarcoma is well tolerated in the frail very elderly population with low morbidity and comparable oncological outcomes.

Management of Locally Recurrent Retroperitoneal Sarcoma in the Adult: An Updated Consensus Approach from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Surgery is the mainstay of treatment for retroperitoneal sarcoma (RPS), but local recurrence is common. Biologic behavior and recurrence patterns differ significantly among histologic types of RPS, with implications for management. The Transatlantic Australasian RPS Working Group (TARPSWG) published a consensus approach to primary RPS, and to complement this, one for recurrent RPS in 2016. Since then, additional studies have been published, and collaborative discussion is ongoing to address the clinical challenges of local recurrence in RPS. METHODS: An extensive literature search was performed, and the previous consensus statements for recurrent RPS were updated after review by TARPSWG members. The search included the most common RPS histologic types: liposarcoma, leiomyosarcoma, solitary fibrous tumor, undifferentiated pleomorphic sarcoma, and malignant peripheral nerve sheath tumor. RESULTS: Recurrent RPS management was evaluated from diagnosis to follow-up evaluation. For appropriately selected patients, resection is safe. Nomograms currently are available to help predict outcome after resection. These and other new findings have been combined with expert recommendations to provide 36 statements, each of which is attributed a level of evidence and grade of recommendation. In this updated document, more emphasis is placed on histologic type and clarification of the intent for surgical treatment, either curative or palliative. Overall, the fundamental tenet of optimal care for patients with recurrent RPS remains individualized treatment after multidisciplinary discussion by an experienced team with expertise in RPS. CONCLUSIONS: Updated consensus recommendations are provided to help guide decision-making for treatment of locally recurrent RPS and better selection of patients who would potentially benefit from surgery.

Outcome after treatment for sebaceous carcinoma: A multicenter study.

BACKGROUND: Sebaceous carcinoma (SC) is a rare malignant tumour whereby, comprehensive long-term data are scarce. This study aimed to assess the outcome of patients treated with resection for SC. METHODS: Patients treated at four tertiary centres were included. Cumulative incidence curves were calculated for recurrences. RESULTS: A total of 100 patients (57 males, 57%) were included with 103 SCs. The median age was 72 (range, 15-95) years with a median follow-up of 52 (interquartile range [IQR], 24-93) months. Most SCs were located (peri)ocular (49.5%). Of all SCs, 17 locally recurred (16.5%) with a median time to recurrence of 19 (IQR, 8-29) months. The cumulative incidence probability for recurrence was statistically higher for (peri)ocular tumours (p = 0.005), and for positive resection margins (p = 0.001). Two patients presented with lymph node metastases and additional seven patients (8.7%) developed lymph node metastases during follow-up with a median time to metastases of 8 (IQR, 0.5-28) months. Three patients had concurrent in-transit metastases and one patient also developed liver and bone metastases during follow-up. CONCLUSION: SC is a rare, yet locally aggressive tumour. Positive resection margins and (peri)ocular SCs are more frequently associated with local recurrence. SC infrequently presents with locoregional or distant metastases.

Ripretinib in advanced gastrointestinal stromal tumors: an overview of current evidence and drug approval.

Over the past 20 years, the management of gastrointestinal stromal tumors has acted as an important model in the advancement of molecularly targeted therapies for solid tumors. The success of imatinib has established it as a lasting therapy in the management of early-stage and advanced disease in the first-line setting. Imatinib resistance inevitably develops, resulting in the need for further lines of therapy. Ripretinib is an orally administered switch-control tyrosine kinase inhibitor, specifically developed to target both primary and secondary KIT and PDGFRα resistance mutations. Herein, the authors discuss the molecular rationale, the preclinical evidence and the clinical use of ripretinib in the treatment of gastrointestinal stromal tumors in the advanced stages of disease.

KIT Exon 9-Mutated Gastrointestinal Stromal Tumours: Biology and Treatment.

BACKGROUND: The majority of gastroinstestinal stromal tumours (GISTs) harbour oncogenic mutations in the gene encoding for the tyrosine kinase (TK) KIT. The most common mutations are found in exon 11, followed by mutations in exon 9. The latter mutations are associated more frequently with GISTs in extra-gastric locations and with a more aggressive clinical behaviour. SUMMARY: Here, we review the unique and often poorly recognized molecular, biological, and clinical characteristics that differentiate KIT exon 9-mutant GISTs from other GIST subtypes. In particular, KIT exon 9 mutations are associated to KIT mutants with retained sensitivity to stimulation by stem cell factor and localization to the cell membrane. Moreover, KIT exon 9-mutant GISTs display significant activation of KIT-independent oncogenic pathways. These characteristics may explain the limited activity of the TK inhibitor imatinib in the adjuvant setting in KIT exon 9-mutant GISTs, as well as their lower sensitivity to standard dose imatinib in the advanced setting. In contrast, the multi-TK inhibitor sunitinib displays better activity in KIT exon 9-mutant GISTs compared to others. KEY MESSAGES: KIT exon 9-mutant GISTs represent a subtype of GIST distinct from other GISTs, including the more common KIT exon 11-mutant GISTs. A better understanding of the molecular biology and clinical behaviour of KIT exon 9-mutant GISTs may help identify more improved treatment options.

Oncological Outcome After Diagnostic Biopsies in Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.

OBJECTIVE: To analyze whether the route of preoperative biopsy influences oncological outcome in GIST patients. SUMMARY OF BACKGROUND DATA: Preoperative biopsies are widely used for diagnosing GIST. Little is known about the risk of tumor seeding after different routes of biopsy. METHODS: Patients who underwent resection of a primary GIST between 1996 and 2014 were identified from 2 databases from 2 tertiary referral centers. Survival data were obtained using the Kaplan-Meier method. Possible confounders were identified using Cox regression analysis. The primary endpoint was local recurrence free survival (RFS) and the secondary endpoint was DSS. RESULTS: A total of 228 patients were included, with a median age of 62 years (range 17-86) and a median follow-up time of 53 months (range 1-204). From these patients, 42 patients did not have a biopsy (18%), 70 underwent a transcutaneous biopsy (31%), and 116 a transluminal biopsy (51%). A total of 42 patients (19.0%) had a local and/or distant recurrence. From the 70 patients with a transcutaneous biopsy, only 1 patient developed a needle tract recurrence (1.4%). Local RFS and DSS were both significantly shorter in the transcutaneous biopsy group on univariate analysis compared to the other groups; however, in multivariate analysis the route of biopsy did not influence local RFS (P = 0.128) or DSS (P = 0.096). CONCLUSIONS: Transluminal or transcutaneous biopsies for diagnosing GIST do not significantly alter the risk of local recurrent disease or DSS in multivariate Cox regressions. The risk of needle tract seeding after transcutaneous biopsy was low.

Management of Primary Retroperitoneal Sarcoma (RPS) in the Adult: An Updated Consensus Approach from the Transatlantic Australasian RPS Working Group.

BACKGROUND: Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document. METHODS: The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation. RESULTS: Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies. CONCLUSIONS: Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.

Tumor necrosis is significantly associated with reduced recurrence-free survival after curative resection of gastrointestinal stromal tumors.

BACKGROUND OBJECTIVES: The impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs. METHODS: Patients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified. Patients who received neoadjuvant imatinib were excluded. Multivariable Cox regression models were produced, to assess whether tumor necrosis was an independent predictor of either overall or recurrence-free survival. RESULTS: Forty-one out of 195 (21.0%) patients had tumor necrosis. Tumor necrosis was associated with a significantly higher modified National Institute of Health risk score, with 29 out of 41 (70.7%) patients with necrosis classified as high risk, compared to 52 out of 153 (34.0%) without (p < .001). Tumor necrosis was found to be independently predictive of recurrence-free survival (hazard ratio: 5.26, 95% CI: 2.62-10.56, p < .001) on multivariable analysis. At 5 years, 44.3% of patients with necrosis had either died or developed recurrence, compared to 9.9% of those without. CONCLUSION: Tumor necrosis is an independent predictor of recurrence-free survival in patients with operable GISTs. It should be routinely reported by pathologists, and used by clinicians when counseling patients and deciding on adjuvant therapy.

Conservative Re-excision is a Safe and Simple Alternative to Radical Resection in Revision Surgery for Dermatofibrosarcoma Protuberans.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma often diagnosed by excision biopsy, and is often incompletely excised, with high recurrence rates. Traditional wide excision involves resection margins of 2-4 cm, often resulting in morbid procedures requiring surgical reconstruction. An alternative is conservative re-excision (CRE), which results in narrower margins and less-frequent reconstruction. The aim of this study is to assess the effectiveness of CRE in providing local control. PATIENTS AND METHODS: A retrospective review of patients treated for DFSP at a tertiary sarcoma centre over a 10-year period. RESULTS: Ninety-eight patients were analysed. Median follow-up was 53 months. Fifty-four patients had microscopically incompletely excised DFSP, and of these, 41 underwent CRE of DFSP scar. Seven (17.1%) patients required more than one CRE to achieve negative margins. The mean width of CRE was 15.4 mm. Fifty-four patients had resection of intact tumours, with 19 (35.2%) requiring surgical reconstruction. One patient (1%) developed local recurrence, and one patient (1%) distant recurrence-both of these patients had high-grade fibrosarcomatous DFSP. No patient with classical DFSP who had clear margins sustained recurrence, regardless of whether their surgery was CRE of scar or wide excision of tumour. CONCLUSIONS: CRE is a safe and acceptable alternative to traditional wide excision, with no patients developing local recurrence (LR). CRE results in low rates of surgical reconstruction, and hence lower morbidity; this is partially offset by the higher rates of inadequate excision requiring further surgery. However, the lesser rate of inadequate excision compared with rates of reconstruction makes CRE an attractive option.

Robotic surgery for gastric gastrointestinal stromal tumors: A single center case series.

BACKGROUND AND OBJECTIVES: The aim of surgical treatment of gastrointestinal stromal tumors (GIST) is a microscopically complete resection. Initial indications for laparoscopic surgery were limited to smaller tumors, in favorable locations. Over time, indications for minimal invasive surgery (MIS) have expanded, however concerns remain when considering resection of larger GISTs. Our aims were to assess the utility of robotic resection of gastric GISTs for challenging tumors. METHODS: GIST resections, in this study were performed using the Intuitive Da Vinci Surgical Xi System. GIST's were considered challenging if tumor size was >50 mm at the time of surgery and/or the location of the tumor was type II, III, or IV using Privette/Al-Thanai classification. RESULTS: Robotic resections were performed on 12 consecutive patients, 83% were considered challenging cases, 6 out of 12 for location and 5 out of 12 for size. Initial median tumor size on imaging was 53.7 mm, and post-imatinib was 45.8 mm. All tumors were removed with clear margins (R0) via wedge resections, with no complications. Median operative time was 192 minutes (95-250). Length of hospital stay was 2 days (2-6). CONCLUSIONS: Robotic resection of gastric GIST's appears oncologically safe, and may expand the benefits of MIS to a greater cohort of complex cases.

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

OPINION STATEMENT: The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.

Prostate-specific membrane antigen expression in melanoma metastases.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a prostatic epithelial protein that is used as a radiotracer (68Ga-PSMA-11) for prostate cancer staging. PSMA-PET/CT (positron emission tomography/computed tomography) performed for prostate cancer has been observed to detect melanoma metastases. The aim of this study was to investigate the performance of PSMA immunohistochemistry on resected melanoma metastases to explore its use as a diagnostic imaging biomarker for melanoma. METHODS: A total of 41 specimens with stage III/IV melanoma were stained with PSMA immunohistochemistry. All specimens required both disease and control regions. Two pathologists scored the specimens and a receiver operating characteristic (ROC) curve was plotted. Western blot and multiplex immunofluorescence were also performed. RESULTS: The area under the ROC curve was 0.82, suggesting that PSMA has excellent discriminatory power in melanoma metastases. Sensitivity is 82.9% and specificity 73.2%. Immunohistochemistry and Western blot reveal that PSMA staining in melanoma consistently and most intensely occurs in tumor neovasculature. Multiplex immunofluorescence shows that melanocytes may also weakly express PSMA. CONCLUSION: The performance of PSMA immunohistochemistry in melanoma metastases contrasts with that reported in prostate cancer studies. This study indicates that PSMA shows promise for use as a novel biomarker in melanoma and justifies further research in the clinical setting with potential as a PET/CT radiotracer and intraoperative fluorescence marker for melanoma.