Monday, July 27, 2020

Sew Chaotically! ~ Sewing Quarantine-while = Summer Scrap Busting!


Waste not, want not.  Figured I might as well turn these bits and bobs into some breezy summer tops.

Roo really liked the Merchant and Mills fabric I used for their Dress Shirt, so I turned my last smidge into a Polly Top, a FREE pattern from By Hand London, for her! 
Had to cut two pieces for the back, rather than cutting one on the fold and had to piece one of those at that.  The solid front section is pieced as well!!  Still, it should keep my girl cool and cute while she is working in her yard!
Here's a double save.  I shortened a little rtw tank I never wore into a cool crop top for Rosie and used what I think must have been a silk table runner, part of some pieces Kay gave me when clearing out some of her fabric stash, to make up a Wrap skirt, another FREE pattern!  This one is courtesy Peppermint and The Fabric store.
The tie is pieced...and a little bit too stiff for the skirt...but hey - that's what I had on hand!
This project was useful for turning scraps into a cool summer top, but also served as a wearable muslin! I used the last bit of a lovely shirting I used in making Freddo's Christmas shirt ~


~ to stitch up The Basic Blouse (a shortened version of The T-shirt Dress) from the Nani Iro Sewing Studio book.  Consistent with the theme here, I had to piece the back!
But, I have a wearable top and discovered that the s/m of this pattern is aces.  I did drop the front neckline just a tad and lengthened the sleeves.  I think my plans for the dress will work out well, as the intended fabric is even more fluid.
A strange mish mash of makes which seems appropriate for the crazy mish mash that is our world just now.  At any rate, working on them kept me occupied and the finished products should provide some useful wear.  Stay cool.  Stay safe.  Keep your distance.  WEAR A MASK!!!  And as always ~ live and sew chaotically! - les

Friday, July 24, 2020

Colitis in melanoma patients treated with immunotherapy - biopsies to check bowel that looks normal may be important!


Colitis is unfortunately a fairly common, and sometimes persistent, side effect folks treated with immunotherapy deal with.  This may be helpful to those with symptoms who keep getting told their bowel "looks fine"!!!


Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma.  Favara, Au, Clark, et al.  ESMO Open.  July 2020.
Background: Immune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined.

Methods: All advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables. 

Results: 117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and greater than/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%). 

Conclusion: Rates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.
For what it's worth. - c

Late addition.  Not really news, but ~
Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors.  Singh, Marshall, He.  Oncologist. 2020 Mar;25.

As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side-effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune-mediated toxicities need special attention. One of the most common is immune-mediated colitis. Workup and management of immune-mediated colitis can be challenging and is the purpose of this review. KEY POINTS: Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune-mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.

- c

Thursday, July 23, 2020

Sew Chaotically! ~ A lovely first excursion! Cades Cove Loop and the Petula Top, by Republique du Chiffon


In this crazy time, we have stayed put.  B picks up groceries curbside from Wally World after ordering on-line.  I've been out only for a couple of required doctor visits - my 3 month recheck which included an abdominal ultrasound due to ascites on my last CT.  B hypothesized at the time that it was fluid accumulation secondary to the 9 zillion biopsies that were done during a follow-up  colonoscopy just prior to the CT.  And so it must have been as it was resolved on ultrasound.  The subsequent MD visit was uneventful and all labs, including protein markers for my ex-goblet cell adenocarcinoma, were all normal.  So....enough of that biz for three months anyway.

We have visited all the kiddos in a weird quarantine-while sort of way.  Going up to Knoxville to visit Fred and Irina a couple of times - socially distancing, while sharing a meal outside on separate tables outdoors.  The same when going over to Roo and the Jamester, or having them here.  We sit outside one place and they sit in another.

In an early spring visit to Freddo, we did take a driving tour of Cades Cove Loop.  It was lovely as ever and I got wear a new light as air blouse.  The Petula by Republique du Chiffon in pink dotted Swiss.

I probably could have gone down a size, but made a 40 with no mods in that regard.  However, I did make the sleeve cuffs and front placket as one piece that I folded, rather than two pieces sewn together as the pattern recommends.  And one more time ~ why no seam allowance Republique du Chiffon?  WHY?????  The pants were made in 2017 from a pattern I wore in high school - M2077.  Still going strong!



It makes a pretty little top, doesn't it?




Yes.  We saw a bear!  I mean, you'll have to take my word for it!  HA!  It was in a different field from the one I was in!  Keeping our distance from dangerous creatures - those that are visible and those that are not!
Stay safe.  Much love and virtual hugs! - les

Tuesday, July 21, 2020

Encorafenib/Binimetinib ~ BRAF/MEK inhibitor combo in patients with V600E/K mutant tumors


I've provided reports on this BRAF/MEK inhibitor combo before.  Here's a link to some of the posts:  Encorafenib/Binimetinib  Here's a link to reports on the COLUMBUS study in particular:  COLUMBUS

For this study, inclusion criteria on the Clinicaltrial.gov website notes:  "Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation"


A phase 1b/2 study of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAF V600E/K-mutant solid tumors.  Sullivan, Weber, Patel, et al.  Clin Cancer Res. 2020 Jul 15.
This open-label, dose-finding phase 1b/2 study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors. (NCT01543698). 
In phase 1, the recommended phase 2 doses (RP2D) were established (primary objective). In phase 2, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma. Results 126 patients with BRAF mutant solid tumors were enrolled (phase 1: 47 patients; phase 2: 79 patients). The RP2D was encorafenib 450 mg QD plus binimetinib 45 mg BID and pharmacokinetic (PK) data suggest that drug-exposures of each agent were similar in combination compared with single-agent studies. In the phase 2 cohorts, confirmed responses were seen in 2 of 11 (18%) evaluable mCRC patients, 11 of 26 (42%) evaluable BRAFi-pretreated melanoma patients, and 28 of 42 (67%) BRAFi-naïve melanoma patients. The most common grade 3/4 adverse event in phase 2 was increased alanine aminotransferase. 
The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.  
For what it's worth.  - c

Sunday, July 19, 2020

Sew Chaotically! ~ Merchant and Mills fabric and The Dress Shirt!


This pattern and fabric combo is a Merchant and Mills double win!  The pattern is their Dress Shirt made up in 'red red wine', a light cotton block print with a stitched line running through it from their shop in Rye. Both are soooooo good!  I made up a straight size 12, with an inverted front pleat, in the longest length.  I cut the bib in one piece across the grain so as to make the most of the stripe.  I did assemble things in a slightly different order than the pattern recs so as to have clean finishes inside.


Oddly enough, I've been in Rye!!!  Years ago we had a fabulous trip to London with the kiddos and made a circular excursion via the train with stops in Bath and Rye!  We had a lovely visit in the old town and even shopped along the main streets, including at stop at "My Sweet Old Etc." (Yes, it was named after the E.E. Cummings poem!!!!  I asked!) But, I didn't even notice this amazing fabric shop!!!!  Who knew years later I would love it so - albeit from afar????!!!!










And because such good material can't go to waste - I made a matching headband...

...along with quite a few others!  They are a bit addictive!  They are made using a FREE pattern from Isabella of What Bella Made She makes many beautiful things, so be sure to check her out!!!
Just a few more for a dear friend!!!

In the midst of all the crazy, there is still beauty in the simple things!!!    Sew chaotically! ~ les

Friday, July 10, 2020

Skin rashes, vitiligo and prognosis when on immunotherapy for melanoma


I have shared many research articles and posts on vitiligo:  A zillion reports on vitiligo

Now, there are these ~

Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study.  Nakano, Takahashi, Namikawa, et al.  J Dermatol.  2020 Mar 11.


Treatment for patients with unresectable melanoma has been dramatically changed by the use of immunocheckpoint inhibitors (ICI). In this study, we reviewed patients with unresectable stage III/IV melanoma, who were treated with nivolumab between July 2014 and March 2017 at the Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, and retrospectively recorded cutaneous adverse events (cAE), development of vitiligo, clinical characteristics and clinical responses. We identified 128 patients, 61 (47.7%) of whom showed cAE, including 30 (23.4%) with development or exacerbation of vitiligo. The prognosis of patients with melanoma treated with ICI correlated with cAE, including development of vitiligo. Patients with cAE showed better objective responses (41.0% vs 6.0%), progression-free survival (PFS) (377 vs 61 days) and overall survival (OS) (763 vs 209 days) than did patients without cAE. Patients who developed vitiligo showed better objective responses (53.3% vs 29.0% vs 6.0%), PFS (median, not reached vs 317 vs 65 days) and OS (not reached vs 689 vs 209 days) than did patients with other cAE and patients without cAE. Landmark analysis showed development of vitiligo starting 20 weeks after starting nivolumab correlated with better OS. In multivariate analysis, OS correlated with performance status, number of metastasized organs, cAE other than vitiligo and development of vitiligo. Despite the fact that the correlation between other cAE and OS was less than that of vitiligo, cAE may be a simple marker of favorable prognosis.

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study.  Matsuya, Nakamura, Matsushita, et al.  Dermatol. 2020 Apr 10. 


Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response. Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering greater than/= to 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response but were associated with prolonged progression-free survival. Grade 2 vitiligo also showed a trend for prolonged overall survival. Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.


Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences.  Cohen, Manga, Lin and Elbuluk.  Am J Clin Dermatol.  2020 May 28.  
Background: There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes.  
Objective: The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies.  
Methods: PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13).  
Results: The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo.  
Conclusions: Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.
Here's to a whiter shade of pale! - c

Sunday, July 5, 2020

Intratumoral (intralesional) therapy and a new guy in town: IL-12 Plasmid Transfection (tavo) with pembro


I've been a fan of incorporating intratumoral/intralesional therapy into melanoma care for some time.  Here's proof:  A zillion articles on intralesional therapy

Now this ~

Intratumoral Immunotherapy-Update 2019.  Hamid, Ismail, Puaznov.  Oncologist.  2020 Mar;25.

Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications.  This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

And this ~

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.  Algazi, Twitty, Tsai, et al.  Clin Cancer Res.  2020 May 6.

Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).

Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.

The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.


The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.

And finally, this ~



Insights Into the Molecular Mechanisms Behind Intralesional Immunotherapies for Advanced Melanoma.  Vidovic and Giacomantonio.  Cancers (Basel) 2020 May 22. 
 The incidence of cutaneous melanoma, a highly malignant skin cancer, is increasing yearly. While surgical removal of the tumor is the mainstay of treatment for patients with locally confined disease, those with metastases face uncertainty when it comes to their treatment. As melanoma is a relatively immunogenic cancer, current guidelines suggest using immunotherapies that can rewire the host immune response to target melanoma tumor cells. Intralesional therapy, where immunomodulatory agents are injected directly into the tumor, are an emerging aspect of treatment for in-transit melanoma because of their ability to mitigate severe off-target immune-related adverse events. However, their immunomodulatory mechanisms are poorly understood. In this review, we will summarize and discuss the different intralesional therapies for metastatic melanoma with respect to their clinical outcomes and immune molecular mechanisms.
For what it's worth.  Hang tough, ratties!!! - c

Thursday, July 2, 2020

Sew Chaotically! ~ Olya!


Spring stayed cooler than usual for a while this year.  This over sized shirt, The Olya by Paper Theory, made up in the softest double gauze from Fabricdotcom, became my perfect comfy staple.  I made up the size 10 with no mods other than omitting the pockets.  





Stay home.  Stay safe.  Wear a mask and keep your distance!!!!   - les