Geography and melanoma options in the EU

We have more than our share of problems with access and coverage in the US, so this is in no way a statement regarding how 'we got this...but y'all still strugglin!!!'   However, here's the deal... (or at least part of it)!!!

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments. Kandolf Skulovic, Peris, Hauschild, et al. Eur J Cancer. 2017 Mar 2.

Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF).

Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes.

The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), health expenditure per capita and the Mackenbach score of health policy performance with the percentage of patients treated with innovative medicines and a number of reimbursed medicines.   

Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Hang tough, guys!  All for one and all for one!!! - c

Sew Chaotically! - Summer of Basics Make-Along - Garment #2 - Lisette B6464 Liberty of London Top!

On her Oliver + S Blog Liesl talks about this top...its cuteness (YASSSS!!!!) and its easy stitch-up (well.....)!!!

I loved the look of this top enough to cut into this precious Liberty of London fabric purchased in Paris!  However, until laid out for cutting, I thought it was just printed with a random pattern.  But, noooooooo!!!  There were stripes!  With much concentration, I finally wrapped my head around how to lay it out, having to keep a center back and front seam in mind!

I am very well pleased with the stripe/repeating print placement!  (See that yellow line beside the more aqua section???  It shows up a bit more in person!)  Anyhow, I made a straight 12 as directed by measurements and I think that was fine.  I did add 1 inch to the length.  I considered adding more and probably will on a second make so that I can tuck in or leave out...but wanted to keep the cropped look to go with the high waisted trousers I already made as the first garment of this project and because I don't have many "cropped" tops in my current closet.

I flat felled all the inside seams. The only difficulty was in the "collar"!  Much of that problem was due to the fact that on this fabric....there is NO COLOR you can mark this fabric with and SEE it!!!  I could have made little nips...but this fabric was so delicate I feared to do so!  Plus, while I used a very light weight interfacing on the facing side of the collar, it may have still been a bit too thick.  At any rate, I persevered.....

And there you go!  Garment #2 + Garment #1 of my summer of Basics Make-Along!!!

I think the little button closure for the top is super cute!

I am tickled with this make!  I think I chose the perfect top to work with my new cropped pants, that I can enjoy through more seasons with a sweater or jacket, or dress down for a 
barefoot-with-jeans on-the-back-porch kind of day!

Okay!  Garment #1 and #2 done for my Summer of Basics Make-Along!!! Sew Chaotically!!! - les

Ipi plus temozolomide in metastatic melanoma

Temozolomide, temodar, DTIC, dacarbazine...whatever you'd like to call it....it is one in the same. Here, it is combined with ipi:

A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma. Patel, Kim, Bassett, et al.  Cancer Immunol Immunother. 2017 Jun 13. 

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH less than or = to 2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m² orally days 1-4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

To my math 10 partial responses plus 10 complete responses of 64 patients = a response rate of about 31.25%.  Now if we just want to be kind and throw in a few extra points for patients with stable disease (though none are noted in this report) that might bring the ORR (overall response rate) to MAYBE 35%?????  Totally guessing there.  But my point is, this combo....though it does...at least in these particular patients....double the response rate to ipi...it still does not attain the response rate of 40% that either anti-PD-1 product (nivo/Opdivo or pembro/Keytruda) can attain alone. Plus, you get the lovely benefit of ipi's potential side effects along with those of old school chemo!  Now, if paired with anti-PD-1, drugs with much fewer side effects than ipi, temozolomide could double THAT response rate, we might have something to talk about!!!  Hmmmm.....

For what it's worth. ~ c

Sew Chaotically! - A t-shirt "quilt" with Roo!!

It has been a busy week, working 2 extra shifts, along with various other chaotic business!  Still, I was able to fit in this little project with Roo!  Her life continues to include lots of running and other exercise, but as a grown up working woman, she had little use for all the t-shirts she wore as a teen, many of which she won in races or wore on various track teams. But, they still meant something and she believes in the power of recycling ~ so.....

We made this!  It's a little wonky.  We cut squares of the back and front of the t's that were consistent in size and covered most of the fun front message, using the fronts for the front and backs for the back!  And since Friday, her goofy black cat, likes to attack any free ribbons or threads, we used little appliques of various shapes and snippets of printed messages from the sleeves and such to tack the back and front together, having already sewn the edges, with right sides together, then pulling right side out through a space we left and slip stitched.

We did have to piece some of the back squares to have equivalent coverage.  Roo has already dyed the neck bands and other left over strips purple and is in the process of braiding them together to use in a throw rug.

We had fun!  Thanks for playing, Rosie Roo!!!

Sew chaotically!!! - les

Everything Cures Melanoma....# 7

Yep, the list of melanoma cures (in a petri dish - for the most part) is long and varied!!!  The short list includes ~ coffee (multiple reports), tea, doxycycline, curcumin and curry (many reports), cimetadine, NSAID's, shiitake mushrooms, exercise, red wine, strawberry juice, snake venom, sephora root, glycoalkaloids (found in eggplants, potatoes, and tomatoes), dill and parsley extracts, wild olive leaves, emu oil, oyster extract, Brazilian lima beans, lichen, sandalwood, beta blockers, and vitamin D (there may actually be something to this one!!) ~ to name a few!!!  Here are links to the data:  Everything Cures Melanoma: Installment #6

But, there is still more!

Melanoma and brown seaweed: an integrative hypothesis.  Teas, Irhimeh.  J Apppl Phycol. 2017.  

Although relatively rare, melanoma accounts for 2 % of cancer diagnoses globally and accounts for about 1 % of all cancer deaths. Worldwide, the annual incidence of melanoma is 272,000 cases which vary hugely, ranging from Japan where it is incredibly infrequent, to Queensland, Australia, where it is nearly 100 times higher. Based on epidemiology and laboratory studies, there is compelling evidence suggesting that seaweed might be protective against different types of cancers such as breast cancer in seaweed consuming populations. By comparing countries where melanoma is more common with countries where it is infrequent, it is possible to construct a hypothesis for how consuming brown seaweeds which may hold clues to the differences in melanoma susceptibility between Japanese and Western nations. Unlike in these other countries, where melanoma incidence has increased dramatically over the last two decades, in Japan, rates have remained remarkably low and stable. There is limited evidence from clinical studies and animal models that have used whole seaweed or isolated fractions from seaweed and measured changes in biomarkers. They have demonstrated the effectiveness of seaweed at inhibiting melanoma development and progression. In this review, the various results will be described. Although there are several effective fractions, it is proposed that consuming whole seaweeds may hold additional benefits that could be lost by consuming only a single extract.

Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid. Su, Lin, Yu, et al. J Agric Food Chem. 2017 Jun 19.  

Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 ± 2.42 μM and 12.30 ± 1.67 μM after 24 h and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at S phase, along with the collapse of mitochondrial membrane potential (ΔΨm) and the accumulation of reactive oxygen species (ROS) level in cells but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor). Western blotting showed that the expressions of p53, cytochrome C, caspase-3 and PARP were up-regulated, the expression level of Bax/Bcl-2 ratio increased significantly. The 2527 significant differentially expressed genes were obtained by RNA-seq, which were assigned to 270 KEGG pathways. These results indicated that CM induced M14 cells apoptosis via the ROS triggered mitochondrial-associated pathways, which supports the potential application of CM for the therapy of melanoma cancer.

Young leaves of reed (Phragmites communis) suppress melanogenesis and oxidative stress in B16F10 melanoma cells. Sim, Ham, Lee. Biomed Pharmacother. 2017 Jun 16. 

This study investigated the effects young leaves of reed (Phragmites communis) water extract (YLR) on melanogenesis and oxidative stress using B16F10 cells. YLR decreased the intracellular melanin content, protein expression and enzyme activity of tyrosinase in a dose-dependent manner. YLR significantly decreased the gene and protein expression of melanogeneis-related proteins, such as microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein-1 and -2. In addition, YLR up-regulated the melanogenesis inhibitory proteins, extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), while it dose-dependently down-regulated p38 and cAMP response element-binding protein (CREB). Moreover, YLR significantly reduced H₂O₂-induced reactive oxygen species levels in B16F10 cells and showed antioxidant activity based on DPPH and ABTS free radical scavenging activity and SOD-like activity. These results suggest that YLR have anti-melanogensis properties that function through regulation of the CREB/MITF/tyrosinase pathway in B16F10 cells and antioxidant activity. Overall, these findings indicate that YLR has the potential for use in treatment of skin disorders and skin-whitening.

A polymethoxyflavone mixture extracted from orange peels, mainly containing nobiletin, 3,3',4',5,6,7,8-heptamethoxyflavone and tangeretin, suppresses melanogenesis through the acidification of cell organelles, including melanosomes. Yoshizaki, Hashizume, Masaki.  J Dermatol Sci. 2017 Jun 10.

Skin color is determined by melanin contents and its distribution. Melanin is synthesized in melanosomes of melanocytes, catalyzed by tyrosinase, melanogenic enzymes. Regarding the process of melanin synthesis, melanosomal pH is considered to play an important role, because it has been reported to differ between Caucasian and Black melanocytes.
Although polymethoxyflavone (PMF) has many beneficial effects, it has not been reported which PMF suppresses melanogenesis. In this study, we identified the mechanism underlying the effect of PMF on melanogenesis METHODS: We determined the effects of a PMF mixture extracted from orange peels on melanogenesis, on tyrosinase expression, on the localization of tyrosinase and on the acidification of organelles, including melanosomes, in HM3KO human melanoma cells. RESULTS TREATMENT: with the PMF mixture elicited the suppression of melanogenesis, the degradation of tyrosinase in lysosomes and the mislocalization of tyrosinase associated with the acidification of intracellular organelles, including melanosomes. The neutralization of cell organelle pH by ammonium chloride restored melanogenesis and the correct localization of tyrosinase to melanosomes, which had been suppressed by the PMF mixture.  These results suggest that the PMF mixture suppresses the localization of tyrosinase to melanosomes and consequently inhibits melanogenesis due to the acidification of cell organelles, including melanosomes.

Bioactivities of ethanol extract from the Antarctic freshwater microalga, Chloromonas sp. Suh, Yang, Lee, et al. Int J Med Sci. 2017 Apr 28.  

Cancer is the principal cause of human death and occurs through highly complex processes that involve the multiple coordinated mechanisms of tumorigenesis. A number of studies have indicated that the microalgae extracts showed anticancer activity in a variety of human cancer cells and can provide a new insight in the development of novel anti-cancer therapy. Here, in order to investigate molecular mechanisms of anticancer activity in the Antarctic freshwater microalga, Chloromonas sp., we prepared ethanol extract of Chloromonas sp. (ETCH) and performed several in vitro assays using human normal keratinocyte (HaCaT) and different types of cancer cells including cervical, melanoma, and breast cancer cells (HeLa, A375 and Hs578T, respectively). We revealed that ETCH had the antioxidant capacity, and caused significant cell growth inhibition and apoptosis of cancer cells in a dose-dependent manner, whereas it showed no anti-proliferation to normal cells. In addition, ETCH had a significant inhibitory effect on cell invasion without the cytotoxic effect. Furthermore, ETCH-induced apoptosis was mediated by increase in pro-apoptotic proteins including cleaved caspase-3 and p53, and by decrease in anti-apoptotic protein, Bcl-2 in ETCH-treated cancer cells. Taken together, this work firstly explored the antioxidant and anticancer activities of an Antarctic freshwater microalga, and ETCH could be a potential therapeutic candidate in the treatment of human cancer.

Anti-Metastatic Effect of Semi-Purified Nuphar Lutea Leaf Extracts. Ozer, Fishman, Eilam, et al.  J Cancer. 2017 May 12.  

Nuphar lutea L. SM., leaf and rhizome extracts (NUP), contain nupharidines as active components. Nupharidines belong to the sesquiterpene lactones class of a naturally occurring plant terpenoids. This family of compounds has gained considerable interest for treating infection, inflammation and cancer. NF-κB is a central, downstream regulator of inflammation, cell proliferation and apoptosis. In our previous work we demonstrated strong inhibition of NF-κB activity and induction of apoptosis by NUP. In addition, NUP exhibited anti-inflammatory properties and partial protection from LPS-induced septic shock by modulating ERK pathway and cytokine secretion in macrophages. In the present study, we examined the effect of NUP in a B16 melanoma experimental murine lung metastasis model and its ability to affect the ERK and NF-κB pathways in variety of cell lines. We showed that NUP and cisplatin combined treatment was synergistic and reduced the lung metastatic load. In addition NUP treatment inhibited TNFα-induced IκBα degradation and NF- κB nuclear translocation. We also observed that NUP induced ERK activation. Furthermore, ERK inhibition prevented NF-κB inactivation by NUP. Overall, our work implies that co-administration of NF-κB inhibitors such as NUP, with standard anti-cancer drugs, may act as "sensitizers" for more effective chemotherapy.

Antiproliferative and proapoptotic activities of anthocyanin and anthocyanidin extracts from blueberry fruits on B16-F10 melanoma cells. Wang, Liu, XU, Liu.Food Nutr Res. 2017 Jun 19.  

Background: Anthocyanins have been proven to affect multiple cancer-associated processes in different cancer cell lines. However, relatively few studies have investigated the effects of blueberry anthocyanins on metastatic melanoma. Thus, this study focuses on evaluating the chemopreventive potential of blueberry anthocyanins and their aglycones (anthocyanidins) in B16-F10 melanoma cells. Methods: Blueberry anthocyanin and anthocyanidin extracts were prepared mainly by combined chromatography techniques. Their antiproliferative and proapoptotic effects on B16-F10 cells were evaluated by MTT assay, calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) staining, and flow cytometry of the cell cycle and apoptosis. Results: The MTT and calcein-AM/PI staining results showed that both anthocyanin (purity of 62.5%) and anthocyanidin (75.1%) extracts could significantly inhibit the viability and proliferation of B16-F10 cells in a dose-dependent manner, while anthocyanidin extracts exhibited significantly higher (p < 0.05) cytotoxicity than anthocyanin extracts. Furthermore, anthocyanin and anthocyanidin extracts blocked cell cycle procession at the G0/G1 phase below 400 and 200 μg/mL, and induced early apoptosis below 400 and 300 μg/mL, respectively. Conclusions: These data suggest that both anthocyanin and anthocyanidin extracts inhibit the proliferation and trigger the apoptosis of B16-F10 cells, and anthocyanidin extracts may be a more promising candidate in preventing metastatic melanoma than anthocyanin extracts.

Hmmm, brown seaweed, cashew nut SHELL liquid, leaves of young (NOT old!!!) reeds, orange peels, microalga (Is there macro-algae????) from fresh water in the Antartic, lutea leaves, and blueberries!!!  Sounds like yuppie compost!  Hey, whatever works!

For what it's worth! - c

Sew Chaotically! - Summer of Basics Make-Along - Garment #1 - The BEST pants!!! Butterick 6178

Sewing pants has had a 50/50 chance of success for me of late.  You may recall these attempts: Mixed results,  Sad results,  Better!!,  Best!!!  However, having decided on these three garments  for my Summer of Basics Make-Along, it was time to get started on Butterick's 6178 wide legged, cropped pants as they are the base garment!  Here's the low down....

I love View C, but decided to go with D's more streamlined silhouette.

Keeping innards clean and 'beauty full' using some of the binding I made.

Just the hand stitched hem to go....

Ta-dahhhh!!!!!!!!!!!!!

Gotta say, I'm pretty pleased with the fit of these pants!!!

I made a straight 12 with no adjustments.

They went together perfectly!!

I think they will dress up or down easily for work or play and span several seasons!

These are definitely a "basic" my wardrobe can use that I will make again!!!

Okay! Summer of Basics Make-Along garment #1 done!!!  Lisette's B6464 little sleeveless top up next!!  Sew chaotically! - les

Sew Chaotically! - Crochet!

I have made MANY afghans!!!  Here are just a few!

Sadly, I don't have a pic of the red one for Tammy.  Danita's golden one. Kate's pink and brown one. The pink, black and white one (Girlie Zebra, don't 'cha know?) for Bella.  The pink and grey one for Emery.  The red and blues ones made as reflecting images of the other I made for the kids when they were little.  Fred's blue one.  Rosie's pink one.  B's other blue one. The two I made for Charlie and Shane.  A green one for my sister.  The pink and purple one for Roo.  The grey one for Fred-o. Two made for my parents.  Hmmm.....  They are not fancy. The effort is a mindless, enjoyable task for me. My challenge is to make them fit the user's style and wishes.

And now there is this one....

For Baby Boy Brewer!!!

I know, it hardly seems necessary in July.  But...eventually!

Thanks, Granny.  You gave me so many gifts.  "Suzzy" kittens. The value of books, reading, a hand written letter.  The ability to stand tall even when my 5'9" self was taller than everyone around me.  To respect others.  To believe in myself and wear heels.  To crochet.  To enjoy life today...rather than save our "special" things for a someday that will never come.  You meant more to me than you will ever know.   Love, Cess

Prognostic factors and survival in melanoma patients with brain mets

We have long known that melanoma patients with brain mets respond better to SRS than WBRT.
For review here are a zillion posts about brain mets in melanoma.
There is this from the European Cancer Conference....

Metastatic melanoma: Prognostic factors and survival in patients with brain metastases

Poster Discussion: R. Board (United Kingdom) European Cancer Conference.  Jan 2017.

Brain metastases from malignant melanoma carry a poor prognosis. Novel systemic agents have improved overall survival (OS), but the value of whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) remains uncertain. The melanoma-specific graded prognostic assessment (msGPA) provides useful prognostic information, but the relevance to the modern-day population has not been validated. The aim of this retrospective analysis was to identify prognostic factors for survival in patients with brain metastases from melanoma.

Since 2011, 53 patients received treatment for brain metastases from malignant melanoma at the Rosemere Cancer Centre medical oncology clinic. Data were collated [and statistically analyzed] on demographic factors and survival. 

OS from the date of diagnosis of brain metastases was 4.83 months (range = 0.27-30.4 months). On univariate analysis, BRAF, performance status and msGPA were significant prognostic indicators for OS. msGPA remained significant on multivariate analysis. OS for BRAF-positive patients receiving targeted treatment (n=22) was significantly better than for BRAF-negative patients (n=26), with median survival times of 8.2 months and 3.7 months respectively. SRS combined with systemic agents (n=16) produced an OS of 13.5 months. Patients receiving WBRT alone (n=21) had a poor prognosis (2.2 months).

The msGPA remains a valid prognostic indicator in the era of novel systemic treatments for melanoma. BRAF-positive patients receiving targeted agents during their treatment had favorable survival outcomes. WBRT alone has no role in the active management of melanoma brain metastases.

I am not clear on exactly what the authors mean by the msGPA (probably an assessment tool they have created), but what remains clear is that SRS and systemic therapy serve patients much better than those who were treated with whole brain radiation alone.  And if you recall, in this recent post:  SRS with any systemic therapy helps response in melanoma...but anti-PD-1 WITH SRS = best OS in brain mets  
Researchers reported:  Ipi with SRS = 7.5 month OS.  BRAF/MEK with SRS = 17.8 months OS.  Anti-PD-1 with SRS = 20.4 month OS.

We need to LIVE and learn....no more interferon....no more WBRT!!! Ratties have provided the proof.  Let's make sure no other melanoma peeps have to suffer needlessly!!! - c

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Pros and cons of whether or not to do a complete lymph node dissection (CLND) are varied.  Here is a post addressing both (with many links within):  Sentinel lymph node disection ~ "important diagnostic procedure and might be of therapeutic benefit re: DFS and OS!"

If you prefer the links following that one in a list - here they are:
Feb 2016:  "Patients with microscopically negative/PCR+ SLN have increased risk for nodal recurrence that was mitigated by CLND"!
Also Feb 2016:  Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!
Still Feb 2016, a little tangential...but addresses effect of positive SLN:  Women and melanoma risk
Post covering several reports from 2014:  With melanoma: You can never be too rich or too thin! But, you can be too young!!!
And this huge study from Faries et al in 2014:  Lymph node removal after superficial melanoma lesions...to do or not to do????

So....it is absolutely clear (at least to me) that removal of the sentinel node after a melanoma lesion is crucial to staging and treatment if nothing else.  Complete lymph node dissection in the area of that sentinel node is more complicated.

Now there's this:

Timing of completion lymphadenectomy after positive sentinel node biopsy in patients with melanoma. Oude, van Akkooi, Rutowski, et al. Br J Surg. 2017 Feb 20.

Nodal staging with sentinel node biopsy (SNB) and completion lymph node dissection (CLND) provides prognostic information to patients with melanoma and their physicians. It is not known whether the timing of CLND is associated with survival outcome and/or CLND tumour load. This study investigated whether CLND timing is associated with CLND tumour load, disease-free survival (DFS) and/or melanoma-specific survival (MSS).

A retrospective cohort of patients with SNB-positive melanoma from nine European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group centres undergoing surgery between 1993 and 2009 were examined. Patients were selected based on availability of CLND and follow-up data. The CLND interval was defined as the number of days between diagnosis and CLND. Patient and tumour characteristics were collected. Five-year DFS and MSS rates were calculated. Cox and logistic regression analysis were performed, adjusting for known prognostic/predictive indicators.

A total of 784 patients were included in the study. Their median age was 51 years, and 418 patients (53·3%) were men. Median Breslow thickness was 3·0 mm, and 148 patients (18·9%) had a residual tumour load. Median CLND interval was 84 days. Five-year DFS and MSS rates were not significantly different for patients operated on with a median CLND interval of less than 84 days and those with an interval of at least 84 days. In a multivariable Cox model, CLND interval was not a significant prognostic indicator. CLND interval was negatively correlated with identification of positive non-sentinel nodes, but following adjustment for known risk factors this effect was no longer found.

The time interval between diagnosis of melanoma and CLND did not influence CLND tumour load, DFS or MSS.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. Faries, Thompson, Cochran, Andtbacka, et al.  N Engl J Med. 2017 Jun 10.

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. 
In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence. Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. 
Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases.

So...if you note the 2014 study linked above, Faries has been looking at this stuff for a long time.  In this latest report, again, it is clear that sentinel lymph node biopsy is "associated with melanoma specific survival."  In this study, they placed patients with a positive sentinel node, randomly in either an immediate completion lymph-node dissection group or a nodal observation group that were followed with ultrasound. The group with the immediate CLND was "NOT associated with increased melanoma-specific survival".  The 3 year rate of survival was similar in the dissection and observation groups.  "The rate of disease free survival was slightly higher in the dissection group (68%) vs the observation group (63%) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92% vs 77%); these results must be interpreted with caution."  (Not sure why the caution unless they don't feel it was really a statistically significant finding.)

An interesting notation is that lymphedema was found in 24% of the folks with the CLND.  We already knew (mostly from breast cancer patients) that lymphedema is more common in older, heavier patients and more common in inguinal dissections than in those to the upper extremities. 

As Faries has done, we all need to move where the data and truth takes us.  I do not regret my two CLND's done to bilateral axilla in 2003 and 2007.  It is probably easier to take that stance since, despite some weird nerve stuff to my right (have had three surgeries there over the years!!!) I luckily, have not developed lymphedema. Additionally, back then we did not have the study results we have now...nor effective melanoma therapies.  Great strides have been made in understanding and treating melanoma in just the past 5-7 years.  For too many, however, it is not nearly enough. Keep pushing, researchers!!!  Keep pushing!

Hang in there, ratties!!! - c

Sew Chaotically! - Summer of Basics Make-Along

I LOVE all the Grainline Studio patterns that I have made!!  From their Morris Blazer to their Linden sweatshirt  to my adored Alder shirt dresses!!!  I even have plans for two Archers!!!

To finish my gushing, their blog (now on a super cool and easily navigable platform) is a great place to find inspiration and fab tutorials.  In my regular blog review I found out about this:  The Summer of Basics Make-Along  Here's a link to the originator:  Fringe Association's Summer of Basics Make-Along contest info

There are some cool prizes.  But, I am entering for fun and because recently I have been thinking about my sewing in a similar way.  I've sewed fairly steadily for the past 2 years.  I sewed a bit when my kiddos were small...little dresses for Roo and elastic waist play shorts for Fred-o and a few skirts and dresses for myself to play in along with them.  It was fun and served the purpose.  But, honestly those were not terribly well crafted garments!  Neither were some of my first efforts over the past couple of years!!!  Initially, I simply needed to improve my skills! Gradually, I think I have done that. However, for a good while I continued to limit myself to patterns that seemed "simple" rather than things I really wanted to wear.  Additionally, I limited myself to fabrics that were available locally (ie from Jo-Ann's or Hancocks') and even there I purchased "cheap" fabric because I didn't want to ruin "good" cuts with my limited abilities.  Those choices taught me a lot through practice and the unfortunate lesson that occurs when you use the wrong fabric for a particular pattern.  It's all good.  I have learned a great deal, though I certainly have many more lessons to go!  But, I do feel confident enough to now select fabrics and patterns from further afield and have been working hard to find things that really suit my life and wardrobe.  I love the florals that Ruthie makes and wears so well.  I love the drama and artistry that sewists like Marcy Harriell of Oonaballoona embrace.  But, are they really me?  So, with Brent's help and encouragement I've branched out in fabric and pattern choices. I've learned much from other sewists, through the tutorials they share so generously as well as access to materials and designers when examples of their work are posted.  As such, I hope to continue to improve my skills and build a wardrobe built on styles, designs, and fabrics that are me!!

With that long preamble, I've decided to enter the portion of the contest in which you make 3 sewn garments that play well in my life and together.  After much chaotic debate in my mind and aloud that poor Rosie and B were forced to listen to, here are my plans:

B6178 in View D.  Cropped wide legged pants in a substantial non-stretch khaki. 

This cute little sleeveless top by Lisettte, B6464, from some of my precious Liberty of London fabric I bought in Paris.  Oddly enough it is cheaper there than in New York!!!

And finally, this three quarter sleeve blouse, B6378, hopefully with no tie (We'll have to see how that goes!!!) also in a Liberty print.

I am quite excited about my various plans!!  (I have a baby blanket as well as a special surprise in process as well!!!) But, I better get to work on those pants!  Sew chaotically! - les

Sew Chaotically! - York by Colette via Seamwork

Colette makes some super cute patterns!  Though I don't think their "block" is exactly my body type (having shoulders a bit too broad and boobage a bit too small)...and ran into some fitting issues with their Aster, I continue to adore ALL, and I mean ALL my Sorbettos!! Then, when I signed up for Seamwork online, I was offered a free PDF pattern of their York blouse - a pattern I had already been eyeing!!!  My sleuthing had revealed that it was either much adored or much maligned by on-line sewists.  But I kept thinking, "What's not to like????"

Having just a bit of my lovely linen left over from my Demi Pants and a free pattern....I thought it would be a winning combo!!  After checking out the pattern pieces...I decided to make a straight 6, with no adjustments, as the shoulders appeared to be plenty broad and the bust dart okay.

I couldn't resist accenting the blue thread in the linen with some top stitching!  Again!!

I love this cuff!

Though the pattern includes an extension of the bias tape facing to the neck as a tie closure, I couldn't resist using this lone blue button, that has resided for years in my button collection, with an embroidered loop. 

I made my own bias tape for the neckline, with plenty left over for other projects, and just turned up the hem about an inch shorter than indicated.  For sewists who have pondered/criticized the pattern's line drawing for looking more like a boat neck while pics of York look more like a scoop....the reality is just a bit between.  It is not such a boat neck that bra straps are exposed, but left as drafted it falls about even across the collar bone.  Given the characteristics of my fabric, I did scoop out an inch at the center front rounded out over the front neckline.  The pattern went together very nicely with the arms and cuff working out particularly well.  I considered taking in the sides for a bit trimmer fit, but left them as they were since the linen held a pretty shape. 

A fun, easy sewing project!!  I really like my pretty, York!  Thanks Colette!!  Sew chaotically! - les

Side effects of immunotherapy - Part 9

And it continues....  Here is a link to Part 8 as well as prior posts:  The Saga of Side effects to Immunotherapy

Now these:

Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis. Lomax, McGuire, McNeil, et al. Int J Rheum Dis. 2017 May 8.  

Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis.  Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy.  Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1...cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy.  Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.

Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.  Diamantopoulos, Tsatsou, Benopoulou, et al. J Immunother. 2017 May 11.  

Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis.Larkin, Chmieloski, Lao, Hodi, Weber, et al. Oncologist. 2017 May 11.  

Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management.  We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.  In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal.  Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. The Oncologist 2017;22:1-10Implications for Practice: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Gauci, Laly, Vidal-Trecan, et al. Cancer Immunol Immunother. 2017 Jun 20. 

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. Makarious, Horwood, Coward.  Eur J Cancer. 2017 Jun 27.

The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon.

Pretty crazy stuff can develop as a side effect from immunotherapy.  Over 7 years ago, Weber told me, "This stuff is weird!"  No kidding.  So, as best you can...report any worrying signs or symptoms to your doc as soon as you can.  It may not result in completely eradicating the problem, but it could go a long way in curtailing additional damage or save your life!  Furthermore, there is good data that rapid treatment with prednisone, sometimes with a break in treatment and sometimes not, can:
1.  Bring the problem under control.
2.  Often allows a return to therapy.
3.  Does NOT adversely impact response to the melanoma treatment!!!!

Here are previously posted reports on how to deal with side effects to immunotherapy:
A discussion by Weber and Agarwala from 2015:  Side effects and how to manage them in targeted and immunotherapy for melanoma
From 2016:  How to deal with GI, endocrine, hepatic and pulmonary side effects subsequent to anti-PD-1
From 201:  Neurologic side effects to immunotherapy with treatment algorithm

Hang in there peeps!!!  - c